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Background The international, multicenter registry LOGGIC Core BioClinical Data Bank aims to enhance the understanding of tumor biology in pediatric low-grade glioma (pLGG) and provide clinical and molecular data to support treatment decisions and interventional trial participation. Hence, the question arises whether implementation of RNA sequencing (RNA-Seq) using fresh frozen (FrFr) tumor tissue in addition to gene panel and DNA methylation analysis improves diagnostic accuracy and provides additional clinical benefit. Methods Analysis of patients aged 0 to 21 years, enrolled in Germany between April 2019 and February 2021, and for whom FrFr tissue was available. Central reference histopathology, immunohistochemistry, 850k DNA methylation analysis, gene panel sequencing, and RNA-Seq were performed. Results FrFr tissue was available in 178/379 enrolled cases. RNA-Seq was performed on 125 of these samples. We confirmed KIAA1549::BRAF-fusion (n = 71), BRAF V600E-mutation (n = 12), and alterations in FGFR1 (n = 14) as the most frequent alterations, among other common molecular drivers (n = 12). N = 16 cases (13%) presented rare gene fusions (eg, TPM3::NTRK1, EWSR1::VGLL1, SH3PXD2A::HTRA1, PDGFB::LRP1, GOPC::ROS1). In n = 27 cases (22%), RNA-Seq detected a driver alteration not otherwise identified (22/27 actionable). The rate of driver alteration detection was hereby increased from 75% to 97%. Furthermore, FGFR1 internal tandem duplications (n = 6) were only detected by RNA-Seq using current bioinformatics pipelines, leading to a change in analysis protocols. Conclusions The addition of RNA-Seq to current diagnostic methods improves diagnostic accuracy, making precision oncology treatments (MEKi/RAFi/ERKi/NTRKi/FGFRi/ROSi) more accessible. We propose to include RNA-Seq as part of routine diagnostics for all pLGG patients, especially when no common pLGG alteration was identified.

Background Central nervous system (CNS) tumors cause the highest death rates among childhood cancers, and survivors frequently have severe late effects. Magnetic resonance imaging (MRI) is the imaging modality of choice, but its specificity can be challenged by treatment-induced signal changes. In adults, O-(2-[18F]fluoroethyl)-l-tyrosine ([18F]FET) PET can assist in interpreting MRI findings. We assessed the clinical impact and diagnostic accuracy of adding [18F]FET PET to MRI in children with CNS tumors. Methods A total of 169 [18F]FET PET scans were performed in 97 prospectively and consecutively included patients with known or suspected childhood CNS tumors. Scans were performed at primary diagnosis, before or after treatment, or at relapse. Results Adding [18F]FET PET to MRI impacted clinical management in 8% [95% confidence interval (CI): 4%-13%] of all scans (n = 151) and in 33% [CI: 17%-53%] of scans deemed clinically indicated due to difficult decision making on MRI alone (n = 30). Using pathology or follow-up as reference standard, the addition of [18F]FET PET increased specificity (1.00 [0.82-1.00] vs 0.48 [0.30-0.70], P = .0001) and accuracy (0.91 [CI: 0.87-0.96] vs 0.81 [CI: 0.75-0.89], P = .04) in 83 treated lesions and accuracy in 58 untreated lesions (0.96 [CI: 0.91-1.00] vs 0.90 [CI: 0.82-0.92], P < .001). Further, in a subset of patients (n = 15) [18F]FET uptake correlated positively with genomic proliferation index. Conclusions The addition of [18F]FET PET to MRI helped discriminate tumor from non-tumor lesions in the largest consecutive cohort of pediatric CNS tumor patients presented to date.

BACKGROUND Genomic alterations and dysregulation of RAF are the main oncogenic driver in almost all pediatric low-grade gliomas (pLGGs). About 50%‒60% of pLGGs harbor KIAA1549-BRAF fusion and 5%‒15% BRAF V600E mutation. No targeted therapy has received regulatory approval for either relapsed or newly diagnosed pLGG to date. Tovorafenib is an investigational, oral, selective, CNS-penetrant, small molecule, type II panRAF inhibitor. The registrational, phase 2 FIREFLY-1 (NCT04775485) study with tovorafenib in pediatric patients with recurrent/progressive LGG is currently ongoing. METHODS LOGGIC/FIREFLY-2 (EudraCT 2022-001363-27) is a registrational, randomized, multicenter, global (~100 sites across Australia, Canada, Egypt, Europe, New Zealand, Singapore, South Korea, Taiwan, and USA), phase 3 trial evaluating the efficacy, safety, and tolerability of tovorafenib vs. standard of care (SoC) chemotherapy in patients < 25 years old with LGG harboring a RAF-alteration and requiring first-line systemic therapy. Approximately 400 patients will be randomized 1:1 to receive oral tovorafenib, 420 mg/m2 ( ≤ 600 mg) weekly (tablet or liquid suspension for 26, 28-day cycles), or an investigator’s choice of SoC chemotherapy: COG-V/C regimen (60 weeks), SIOPe-LGG-V/C (81 weeks) regimen, or single-agent vinblastine (70 weeks). After completing 26 cycles tovorafenib, patients may continue tovorafenib or opt to enter a drug holiday at any point. Patients who progress in the SoC arm may receive tovorafenib. Patients who progress after stopping tovorafenib may be re-challenged. Primary endpoint is ORR based on RANO criteria, as determined by an independent radiology committee. Key secondary endpoints are progression-free survival and duration of response per RANO criteria, and ORR per RAPNO criteria. Other secondary endpoints include changes in neurological and visual function, and safety and tolerability. Exploratory objectives include quality of life and health utilization measures, molecular biomarker evaluation for treatment response and resistance, efficacy of tovorafenib after progression on chemotherapy and retreatment upon progression during drug holiday.

Background The aim of the project was to identify risk factors associated with visual progression and treatment indications in pediatric patients with neurofibromatosis type 1 associated optic pathway glioma (NF1-OPG). Methods A multidisciplinary expert group consisting of ophthalmologists, pediatric neuro-oncologists, neurofibromatosis specialists, and neuro-radiologists involved in therapy trials assembled a cohort of children with NF1-OPG from 6 European countries with complete clinical, imaging, and visual outcome datasets. Using methods developed during a consensus workshop, visual and imaging data were reviewed by the expert team and analyzed to identify associations between factors at diagnosis with visual and imaging outcomes. Results Eighty-three patients (37 males, 46 females, mean age 5.1 ± 2.6 y; 1–13.1 y) registered in the European treatment trial SIOP LGG-2004 (recruited 2004–2012) were included. They were either observed or treated (at diagnosis/after follow-up). In multivariable analysis, factors present at diagnosis associated with adverse visual outcomes included: multiple visual signs and symptoms (adjusted odds ratio [adjOR]: 8.33; 95% CI: 1.9–36.45), abnormal visual behavior (adjOR: 4.15; 95% CI: 1.20–14.34), new onset of visual symptoms (adjOR: 4.04; 95% CI: 1.26–12.95), and optic atrophy (adjOR: 3.73; 95% CI: 1.13–12.53). Squint, posterior visual pathway tumor involvement, and bilateral pathway tumor involvement showed borderline significance. Treatment appeared to reduce tumor size but improved vision in only 10/45 treated patients. Children with visual deterioration after primary observation are more likely to improve with treatment than children treated at diagnosis. Conclusions The analysis identified the importance of symptomatology, optic atrophy, and history of vision loss as predictive factors for poor visual outcomes in children with NF1-OPG.

Background Malignant brain tumors (BT) are among the cancers most frequently associated with constitutional mismatch repair deficiency (CMMRD), a rare childhood cancer predisposition syndrome resulting from biallelic germline mutations in mismatch repair genes. This study analyzed data from the European “Care for CMMRD” (C4CMMRD) database to describe their clinical characteristics, treatments, and outcome with the aim of improving its diagnosis/treatment. Methods Retrospective analysis of data on patients with CMMRD and malignant BT from the C4CMMRD database up to July 2017. Results Among the 87 registered patients, 49 developed 56 malignant BTs: 50 high-grade gliomas (HGG) (with giant multinucleated cells in 16/21 histologically reviewed tumors) and 6 embryonal tumors. The median age at first BT was 9.2 years [1.1–40.6], with nine patients older than 18. Twenty-seven patients developed multiple malignancies (including16 before the BT). Most patients received standard treatment, and eight patients immunotherapy for relapsed HGG. The 3- and 5-year overall survival (OS) rates were 30% (95% CI: 19–45) and 22% (95% CI: 12–37) after the first BT, with worse prognosis for HGG (3-year OS = 20.5%). Six patients were alive (median follow-up 2.5 years) and 43 dead (38 deaths, 88%, were BT-related). Other CMMRD-specific features were café-au-lait macules (40/41), multiple BTs (5/15), developmental brain anomalies (11/15), and consanguinity (20/38 families). Conclusions Several characteristics could help suspecting CMMRD in pediatric malignant BTs: giant cells on histology, previous malignancies, parental consanguinity, café-au-lait macules, multiple BTs, and developmental brain anomalies. The prognosis of CMMRD-associated BT treated with standard therapies is poor requiring new therapeutic up-front approaches.

INTRODUCTION Patients with recurrent medulloblastoma have a poor prognosis with only around 8% of patients surviving at 5 years irrespective of salvage therapy used. We report on 29 patients from four institutions treated with a “MEMMAT” based antiangiogenic combination therapy. PATIENTS AND METHODS From 11/2006 to 06/2016, 29 patients were diagnosed with a recurrent medulloblastoma (19 first, 10 multiple recurrences). Median age at start of antiangiogenic therapy was 10 years (range 1–27). Subgroup of medulloblastoma was available in 18 patients and was group 3 or 4 in all except two (one WNT, one SHH-infant). For their current relapse patients received an antiangiogenic combination therapy consisting of bevacizumab, thalidomide, celecoxib, fenofibrate, and etoposide, alternating with cyclophosphamide and augmented with intraventricular therapy (etoposide and liposomal cytarabine). RESULTS As of 01/2020, 8/29 patients are alive at a median of 44 months after recurrence. 6/8 surviving patients are currently in CCR between 66 and 134 months after recurrence that prompted MEMMAT therapy. Two patients are again in remission after intercurrent relapses 105 and 102 months after first starting MEMMAT therapy. Five patients died of another cause (accident, leukemia, septicemia). OS (median 44 months) was 44±10% at 5 years and 39±10% at 10 years, PFS was 33±10% at 5 years and 28 ±9% at 10 years. Therapy was well tolerated and toxicities were manageable. CONCLUSION Our results suggest that antiangiogenic metronomic chemotherapy has clinical activity in recurrent medulloblastoma. Further investigation with an international phase II study is ongoing (MEMMAT; ClinicalTrials.gov Identifier: NCT01356290).

BACKGROUND: (18)F-fluoro-ethyltyrosine ((18)F-FET) positron emission tomography (PET) in addition to MRI improves accuracy in adult patients with gliomas. We aimed to 1) collect a material of various pediatric brain tumors 2) determine sensitivity and specificity for tumor using (18)F-FET PET versus MRI alone 3) test the clinical impact of the scans. METHODS: Ninety-seven patients with primary pediatric CNS-tumors were included consecutively and prospectively, and a total of 151 hybrid (18)F-FET PET/MRI or PET/CT scans were performed. RESULTS: A high (18)F-FET uptake was seen in pilocytic astrocytoma, gangliogliomas and in high grade gliomas, while moderate uptake was seen in ependymomas and germinomas. Atypical teratoid/rhabdoid tumors (AT/RT) showed varying uptake. The addition of (18)F-FET PET to MRI added extra relevant information in 28% of all scans and influenced the clinical management in 8%. Of the 30 (18)F-FET PET scans that beforehand were rated desirable for a clinical decision (e.g. due to equivocal MRI), 40% added new information and 33% influenced clinical management. A subset consisting of 27 early postoperative (18)F-FET PET scans showed one case of influenced clinical management and a lesion-based sensitivity/specificity for diagnosing residual tumor of 0.80/0.75 for MRI alone and 0.73/1.00 for PET/MRI. CONCLUSIONS: The addition of (18)F-FET PET to MRI for imaging of pediatric CNS-tumors influenced clinical management in 8% of all scans and in 33% of the clinically indicated scans. Early postoperative (18)F-FET PET is not recommended routinely but supplementary (18)F-FET PET could be relevant when re-operation for residual tumor is considered based on early postoperative MRI.

INTRODUCTION: Neurofibromatosis type 1 (NF1) is commonly associated with optic pathway gliomas (OPG) in childhood. Data on natural history are lacking and clinical trials of chemotherapy, so far, have not reported visual outcomes. In the 2014 SIOPE NF1-OPG Nottingham Workshop a convenience cohort was assembled and studied to inform a consensus on imaging and visual function classification and a schematic for recording visual acuity results. METHODS: An expert group of ophthalmologists, paediatric neurooncologists, neurofibromatosis specialists and neuro-radiologists identified 83 NF1-OPG patients (46 females, mean age 5·1 ± 2·6 years; 1-13·1 years) from six European countries. All patients (recruited between 2004 and 2012) were registered in the SIOP LGG-2004 trial. They were either observed or received treatment at diagnosis or after follow-up. Visual data were analysed to explore changes over time. RESULTS: 154 eyes in 77 patients were analysed. When starting treatment, visual acuity (VA) was worse in patients being treated at diagnosis (p=0·046). VA remained unchanged in the observation group. Compared to patients treated at diagnosis, children treated after observation less frequently developed further vision loss or dropped to near-blindness/blindness, indicating a better overall visual status at end of treatment. Of 16 patients worsening during observation, Vincristine/Carboplatin could improve vision in 7. CONCLUSIONS: Initial management strategy determined different visual outcomes, justifying criteria for observation versus immediate or delayed treatment in future trials with primary visual outcome measures. The adverse outcome for those treated immediately may suggest unnoticed, irreversible nerve damage advocating initiation of trials seeking to recognise and reverse incipient nerve damage.

INTRODUCTION: A consensus survey involving 98 multi-disciplinary specialists for the first survey (10 cases) and 46 for the second survey (15 cases) in SIOP-E brain tumour group, European NF1 society and the Optic Pathway Glioma Working Group in North America were asked to identify case-based criteria for primary observation, treatment or randomisation in 25 representative, newly diagnosed, NF1-VPG childhood cases which had been the subject of a consensus workshop as part of the SIOP-LGG 2004 trial. Respondents provided justifying statements for their selection of preferred strategy which are the focus for this report. METHODS: Qualitative analysis following grounded theory, using the comparative method categorized 808 comments to: 173 for primary observation, 426 for primary treatment and 209 for primary randomization. These were grouped into 8 themes by two reviewers and compared with the kappa statistic. The themes were: 1) risk of progression, 2) visual function, 3) age and sex, 4) site/dimension of tumour, 5) other symptoms, 6) inconclusive comments, 7) equipoise and 8) parental consent. The themes were analysed by strategy selected for each case. RESULT: Good agreement was achieved for theme allocation between reviewers (k: 0.762). Comments selected for observation were supported by responses categorised as: unknown risk of progression (32%), good vision function (25%); for treatment as poor vision and intention to preserve-improve vision (38%); for randomization as unknown risk of progression (15%), tumour site/dimension (13%) and stable vision (12%). CONCLUSION: This survey and its qualitative analysis identified sufficient uncertainty to propose a randomised trial design for observation versus treatment in a subgroup of newly diagnosed NF1-VPG. A pilot cohort with vision assessment date, site of tumour and age is needed to conduct a power calculation to design a future international randomised trial to study risk of progression and response to new treatments. Collaborations would be welcome. This abstract submitted on behalf of the SIOP-e OPG Nottingham Workshop 2014 (Participating centres: Berlin, Copenhagen, GOS, Hamburg, Leeds, Nottingham, Padua, Paris, Vienna).

INTRODUCTION: The natural history of children with NF1-OPG is unpredictable, indications for therapy to save vision, using patient, imaging and visual factors have not been studied in Europe. The aim of this multi-disciplinary workshop was to promote a revised and standardised approach for the next SIOP LGG trial. METHOD: Eight SIOP-LGG2004 centres contributed 83 NF1-OPG cases with complete imaging, visual and clinical datasets (age at diagnosis: median 4.8 yrs range 1.1-13.1; m:F 37:46, median follow-up 19.2 months range 1.8-121 months). Severe visual impairment/blindness (LogMAR >= 1.0) at diagnosis and last follow up, respectively: unilateral 16,21; bilateral 3,7. Anatomical distribution at diagnosis: Dodge Stage A (nerves) 35; Stage B (chiasm) 16; Stage C (nearby structures) 32. Imaging evidence of: response 31: no change:46; progression 6. Analysis of this dataset informed consensus discussion and voting of representative cases for proposed trial criteria for observation, treatment and randomisation. RESULTS: Consensus on imaging and visual classification was achieved, including a schematic for recording patient, visual and imaging details. Criteria for case selection were: age, history of visual decline, presence of severe visual symptoms, unreliable visual assessment, proptosis and post-chiasmatic tumour involvement. A subsequent 19 case web-based questionnaire was completed by 15 workshop participants. The respondents allocated 8 cases to observation; 8 to immediate treatment and 3 for consideration for randomisation. CONCLUSION: A new consensus on selection criteria using a contemporary trial cohort was reached. We have piloted a web-based questionnaire to assess feasibility of a randomised trial.