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Zusammenfassung: Unterstützung bei der schulischen Reintegration wird als standard of care in der pädiatrischen Onkologie definiert. Ziel ist die Bereitstellung von Informationen und die Koordination der Kommunikation zwischen Patient_in/Familie, Schule und Krankenhaus. Dies ist von entscheidender Bedeutung für Schüler_innen mit Tumoren des Zentralnervensystems (ZNS), insbesondere in der Nachsorge, da sie eine Risikogruppe für Spätfolgen darstellen. Um die Kooperation zu verbessern, wurden mehrere praktische Unterstützungsmöglichkeiten eingeführt. Im Rahmen des vorgestellten Pilotprojekts wurde darüber hinaus ein Webinar konzipiert und evaluiert, das speziell auf die Fragen von externen Lehrer_innen eingeht. Die Ergebnisse zeigen, dass eine Online-Informationsveranstaltung das notwendige Wissen und die Zusammenarbeit verbessern kann, verdeutlichen gleichzeitig aber auch die Wichtigkeit der kontinuierlichen Unterstützung in Form von Expert_innen für schulische Reintegration, um Schüler_innen mit ZNS-Tumoren angemessen zu begleiten.

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.

Purpose The perioperative treatment of hydrocephalus in pediatric posterior fossa tumors with an external ventricular drain (EVD) is the treatment of choice in our center. We analyzed our experience in using EVD concerning safety and effectivity. Methods This is a single-center retrospective cohort study of 100 consecutive pediatric patients who underwent resection for a newly diagnosed tumor in the posterior fossa between 2011 and 2022. Results Of the 100 patients with posterior fossa tumors, 80 patients (80%) had radiological signs of hydrocephalus at presentation, 49 patients (49%) of whom underwent placement of an EVD. In 40 patients, the EVD was inserted at a mean of 2.25 days prior to the tumor resection; 9 had the EVD inserted during tumor resection (frontal trajectory in 7 patients, occipital trajectory in 2 patients). Histology revealed pilocytic astrocytoma in 48 patients, medulloblastoma in 32, ependymoma in 11, and other histologic entities in 9 patients. Gross total/near-total resection was achieved in 46 (95.83%) of the 48 pilocytic astrocytomas, 30 (93.75%) of the 32 medulloblastomas, and 11 (100%) of the 11 ependymomas. The mean number of total days with the EVD in place was 8.61 ± 3.82 (range 2–16 days). The mean number of days with an EVD after tumor resection was 6.35 ± 3.8 (range 0–16 days). EVD-associated complications were seen in 6 patients (12.24%) including one infection. None of these resulted in a worse clinical course or any long-term sequelae. Permanent CSF diversion at 6 months after surgery was necessary in 13 patients (13%), including two VP shunt, two SD-shunt, six endoscopic third ventriculostomy (ETV), and three combined VP shunt and ETV procedures. Patients with a medulloblastoma or ependymoma had a higher rate of permanent CSF diversion needed than the group of pilocytic astrocytoma patients (27.9% versus 2.13%, p p = 0.001). Conclusion The treatment of hydrocephalus in pediatric posterior fossa tumors with an EVD as a temporary measure is safe and effective, provided that a multi-professional understanding for its handling is given and there is no need for a long transport of the children.

Background A growing body of evidence has supported alternatives to sedation and general anesthesia for increasing treatment compliance of children during MRI examinations. Particularities in children with a brain tumor (frequency of examinations, neuropsychological deficits (attention, memory)) have a significant impact on methods and are given special consideration in this study. The aim of the present study was to (1) evaluate the effectiveness of an MRI training program and to investigate the moderating factors for successful MRI examination for a group of young patients with pediatric brain tumors and/or NF1 and (2) to examine the effect of the training on the patient’s well-being. Methods A total of 87 patients of the neuro-oncology unit (mean age: 6.83 years) underwent a two-step program to prepare children for MRI, including an in vitro strategy training inside the scanner and were recorded using a process-oriented screening (emotional wellbeing and level of information), which was developed for this purpose. All data was analyzed retrospectively and the data of a subgroup of 17 patients was also analyzed prospectively (ClinicalTrials.gov: NCT04474678). Results 81% of the children who had received MRI training managed to successfully undergo the MRI scan without sedation and/or anesthesia making the success rate almost five times as high as in the group that did not receive the intervention. Memory, attentional difficulties, and hyperactivity were significant neuropsychological moderators for successful or unsuccessful scanning. Furthermore, the training was effective in improving the psychological well-being of the patients. Conclusion Based on the results, the MRI training is an effective alternative to sedation of young patients for MRI examinations and a promising tool for improving patient well-being related to the diagnostic procedure. However, specialized psychological staff and an interdisciplinary approach are required to adapt the intervention to the children’s individual neuropsychological needs. Trial registration number: ClinicalTrials.gov Identifier: NCT04474678

To provide an effective alternative to sedation during MRI examinations in pediatric cancer and NF1 patients, the aims of the present study were to (1) exploratively evaluate a behavioral MRI training program, to (2) investigate potential moderators, as well as to (3) assess the patients’ well-being over the course of the intervention. A total of n = 87 patients of the neuro-oncology unit (mean age: 6.83 years) underwent a two-step MRI preparation program, including training inside the scanner, and were recorded using a process-oriented screening. In addition to the retrospective analysis of all data, a subset of 17 patients were also analyzed prospectively. Overall, 80% of the children receiving MRI preparation underwent the MRI scan without sedation, making the success rate almost five times higher than that of a group of 18 children that opted out of the training program. Memory, attentional difficulties, and hyperactivity were significant neuropsychological moderators for successful scanning. The training was associated with favorable psychological well-being. These findings suggest that our MRI preparation could present an alternative to sedation of young patients undergoing MRI examinations as well as a promising tool for improving patients’ treatment-related well-being.

BACKGROUND: Malignant brain tumors carry a high risk for leptomeningeal dissemination, but the CSF compartment is often not affected by systemic therapy. Intraventricular therapy via an Ommaya reservoir is one possibility to increase the cytotoxic drug concentration in the CSF. Unfortunately, the number of drugs that can be administered directly into the CSF is limited. We report on our experience with topotecan administered via an Ommaya reservoir. PATIENTS AND METHODS: Between 2015 and 2021, 50 patients aged 1 to 22 years (mean and median both 8 years) with various malignant brain tumors received intraventricular topotecan via an Ommaya reservoir. Topotecan was administered at 0.4mg twice a week (>1 and 2 and

PURPOSE: Advances in treatment have increased survival rates and quality of life of pediatric CNS tumor patients leading to a growing number of long-term survivors. However, there is sufficient clinical and scientific evidence for the need of a highly specialized lifelong follow-up care due to multidimensional late effects. Furthermore, adolescence and young adulthood are challenging age periods when patients frequently get lost to follow-up potentially having severe impact on health and well-being. Since 2020, we have established a structured transfer of long-term survivors older than 18 years to a newly founded highly specialized adult care follow-up setting for childhood cancer survivors (IONA). The aim of this study was to evaluate the current transition process. RESEARCH DESIGN: The standard of care transition process at the neuro-oncology unit of the MUV includes a joint appointment with the patient, a pediatric neuro-oncologist, psychologist and/or social worker and the team of the adult care facility (physician, psychologist). Different elements are used to end care safely in the pediatric structure and building trust in the upcoming out-patient-department at the same time. The transition process was evaluated statistically and analyzed qualitatively with regard to the factors that define a safe transition. RESULTS: After two years (01/2020-12/2021) 114 patients had a joint transition appointment, two patients contacted IONA directly. Shortly after the joint appointment all patients had a scheduled follow-up meeting at IONA. 102 patients (87.9%) showed up, seven patients (6%) already had a planned appointment, two patients (1.7%) were in contact with IONA but had no possibility to show up in person. Only five patients (4.3%) did not attend the appointment and were lost to follow-up. CONCLUSION: A structured interdisciplinary transition concept is a successful option to establish controlled and patient-safe transition from pediatric to adult care setting.

BACKGROUND Medulloblastoma represents the most common malignant pediatric brain tumor. Ophthalmic complications are possible sequelae. METHODS Pediatric medulloblastoma (MB) patients treated at the Medical University of Vienna from January 2012 to August 2021 were analyzed and their last ophthalmic assessment was reviewed. RESULTS Fifty-six MB patients could be included (71.4% non-WNT/non-SHH, 16.1% SHH-activated, 8.9% WNT-activated, 3.6% non-specified). Mean age at diagnosis was 7.2 years (range 0-19). Median follow-up to last ophthalmological assessment was 19.7 months (range 0.1-93.2). Thirty-four children underwent tumor resection at our hospital, their tumor localizations were: vermis (55.9%), floor of the 4th ventricle (26.5%), cerebellar hemispheres (11.8%), lateral recess (5.9%). Symptoms at presentation were evaluable for 51 children: 92.2% had symptoms of elevated intracranial pressure, 76.5% ataxia and 21.6% visual disturbances. Postoperative posterior fossa syndrome was observed in 11.1% of 54 children. 98.2% had chemotherapy as part of their initial treatment and all children older than four years (85.7%) received postoperative irradiation of the posterior fossa. In 13 (23.2%) intraventricular chemotherapy was applied. At the last follow-up 21 patients experienced relapse after primary treatment. At the final assessment, frequent neuro-ophthalmological abnormalities included: oculomotor disturbance (75%), esotropia (35.7%) including abducens palsy (12.5%), other cranial nerve palsies (21.4%), horizontal gaze-evoked nystagmus (51.8%), spontaneous nystagmus (16.1%), ocular tilt reaction (21.4%), and optic disc abnormalities (14.3%). Good visual acuity (≥20/25) was maintained in 62.5% patients. Visual field and optical coherence tomography was successfully performed in 75% and 66.1% of patients, respectively. Optic pathway lesions were detected in 4 patients (7.1%), including two cases with occipital metastases, one with optic nerve metastasis and one with leptomeningeal carcinomatosis. Orthoptic treatment with prisms and strabismus surgery was required in 14.3% and 7.7% of children, respectively. CONCLUSION Children with MB frequently suffer from neuro-ophthalmological late-effects. Regular monitoring is warranted to initiate appropriate management.

Pediatric high-grade glioma (pHGG) is an incurable disease with a median survival of less than 6 months post-progression and no effective targeted therapy. PDGFRA is commonly altered in pHGG, but targeting PDGFRA in this disease has been unsuccessful, likely due to poor central nervous system (CNS) penetrance. Avapritinib is a novel and CNS-penetrant PDGFRA/KIT inhibitor that is FDA-approved for adults with unresectable or metastatic PDGFRA exon 18-mutant gastrointestinal stromal tumor (GIST) and is being studied in CNS tumors. We performed a pre-clinical and clinical assessment to determine the potential suitability of avapritinib therapy in PDGFRA-driven glioma. A multi-institutional cohort genetic analysis revealed PDGFRA amplification and mutation in 10.2% and 6.1% of pHGG, respectively. Additionally, PDGFRA expression in the absence of genetic events was significantly increased in H3K27-altered diffuse midline glioma (DMG) compared to H3-wildtype pHGG. Avapritinib performed well in: (i) mutant PDGFRA enzyme inhibition and wildtype inhibition at high dose, (ii) minimal off-target kinase inhibition, (iii) brain penetration (peak 10 µM), and (iv) proliferation/pPDGFRA reduction in PDGFRA-amplified and mutant pHGG cell lines. Avapritinib treatment in an aggressive PDX model of pHGG resulted in significant survival benefit. We pursued treatment of eight pediatric and young adult HGG patients with avapritinib across seven institutions. Patients were a mixture of local (N = 4) and metastatic disease (N = 4); all patients were post-initial radiation, with 7/8 having progressed on prior treatment. 7/8 patients had PDGFRA amplifications or mutations, and 7/8 had H3K27M mutations. Therapy was generally well-tolerated. 4/8 patients showed radiographic response to avapritinib, with one patient demonstrating complete response of target lesion and remains on therapy. Avapritinib levels in patients’ CSF and brain tumor tissue reached micromolar levels. These results demonstrate that avapritinib is a potent, selective, and CNS-penetrant PDGFRA/KIT inhibitor that is promising for further study in pHGG with relevant alterations.

BACKGROUND: A growing body of evidence has supported alternatives to sedation and general anesthesia for increasing treatment compliance of children during MRI examinations. Particularities in children with a brain tumor (frequency of examinations, neuropsychological deficits (attention, memory)) have a significant impact on methods of treatment and are given special consideration in this study. OBJECTIVE: The aim of the present study was to (1) evaluate the effectiveness of an MRI training program and to investigate the moderating factors for successful MRI examination for a group of young patients with pediatric brain tumors and/or NF1 and (2) to examine the effect of the training on the patient’s well-being. METHODS: A total of 87 in the retrospective analyses (Study 1) and a subgroup of 17 patients in the prospective analyses (Study 2, ClinicalTrials.gov: NCT04474678) of the neuro-oncology unit with a mean age of 6.83 years underwent a two-step program to prepare children for MRI, including an in vitro strategy training inside the scanner and were recorded using a process-oriented screening. RESULTS: 81 % of the children who had received MRI training managed to successfully undergo the MRI scan. Hence, the rate of successful MRI examinations without anesthesia was almost five times as high in the group that received MRI training compared to the group that did not. Memory, attentional difficulties and hyperactivity were significant neuropsychological moderators for successful or unsuccessful scanning. Furthermore, the training was effective in improving the psychological well-being of the patients. CONCLUSION: Based on the results, the MRI training is an effective alternative to sedation of young patients for MRI examinations and a promising tool for improving patient well-being related to the diagnostic procedure. However, the intervention needs to be customized according to the children’s individual neuropsychological difficulties, which requires specialized psychological staff and an interdisciplinary approach.

OBJECTIVE: School reentry support focusing on providing information to schools and communication between patient/family-hospital-school is defined as a psychosocial standard of care in pediatric oncology (Thompson et al., 2015). This is critical for students with brain tumors (BT) - although it is not yet universally implemented - especially during follow-up, as they are a risk group for late effects. Due to long distances between family-hospital-school, limited personnel capacities and since 2020 Covid-19 restrictions, an online-event (OE) for teachers from external schools was designed, with the aim of: (1) strengthening cooperation, (2) breaking down barriers and (3) increasing level of knowledge. METHODS: 54 teachers participated in each of two OEs. Content was presented by an interdisciplinary team (clinician, clinical/neuropsychologist, social worker, teacher), followed by time for sharing experience. Two months after event 2, participants were asked to complete an evaluation in an anonymous online survey. Supportive and inhibiting factors for successful school reintegration were included in the survey and statistically analyzed. RESULTS: 54% of 23 respondents (70% teaching > 10 years) felt that their training before the event did not prepare them adequately for a teaching setting with seriously ill children (1-3 points on a 10-point Likert-scale). 92% rated their knowledge greater after the event. All interdisciplinary inputs were rated very useful and practical (79-88%: 8-10 points). 38% felt relieved to got to know contact persons. 33% rated teaching a student with BT as fundamentally challenging and felt more confident after the event. CONCLUSION: The results of this pilot project indicate that an online-information-event can increase knowledge and cooperation. Resulting promoting and inhibiting factors for school reintegration will be incorporated into future concept improvement. The findings further highlight the great importance of ongoing support in the form of a reintegration teacher and interdisciplinary input for schools to appropriately support students with BT.

H3K27M-mutated diffuse midline glioma (H3K27M DMG) are an almost universally fatal disease with a median survival of less than 6 months post progression and no effective therapy. PDGFRA-signaling has shown to promote and sustain a subset of oligodendrocyte precursor-like tumor cells that are responsible for tumor propagating potential and high proliferation rates. However, first attempts to target PDGFRA in adult glioblastoma with dasatinib/imatinib or pediatric refractory brain tumors with sunitinib were not successful. We report on the first experience in two patients receiving avapritinib, a highly potent, selective, brain penetrant PDGFRA/KIT inhibitor under a compassionate use program. Our first patient with spinal H3K27M DMG developed supratentorial metastases ten months after initial diagnosis. Molecular profiling revealed de novo PDGFRA and KIT amplifications and treatment with dasatinib was initiated. Due to disease progression and novel metastases, therapy was switched to avapritinib showing near complete resolution of the previously unirradiated frontal lesion with additional disease stabilization of other metastatic sites. Following re-resection and irradiation of progressing cerebellar lesions, the patient remains clinically stable on avapritinib therapy over 12 months. The second patient with diffuse intrinsic pontine glioma showed disease progression nine months after diagnosis and was treated with focal re-irradiation (30Gy). As the tumor harbored a PDGFRA R841del alteration, avapritinib was initiated seven weeks after radiation upon further tumor progression resulting in partial response. Pharmacokinetic sampling of cerebrospinal fluid (CSF) detected an increasing CSF/plasma ratio over time and up to 4 µM avapritinib in tumor tissue. Avapritinib CSF levels in both patients were distinctly higher than dasatinib levels. Avapritinib was generally well tolerated besides lower limb edema, elevated LDH and liver enzymes. Hence, effective CNS penetration of avapritinib at pharmacologically relevant brain tumor concentrations resulted in clinical response in two patients with rapidly progressive H3K27M DMG.