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Abstract Central nervous system germ cell tumors (CNS-GCT) are malignant neoplasms that arise predominantly during adolescence and young adulthood. These tumors are typically sensitive to treatment, but resulting long-term health deficits are common. Additional clinical challenges include surgical risks associated with tumor biopsy, and need to determine treatment response for adapting radiotherapy protocols. The aim of this study was to establish the detectability of circulating-tumor DNA (ctDNA) from cerebrospinal fluid (CSF) of children with CNS-GCT as a potential biomarker. We obtained CSF from patients with CNS-GCT by lumbar puncture or intra-operatively. Cell-free DNA (cfDNA) was extracted and subjected to low-pass whole genome sequencing (LP-WGS). Copy-number alterations (CNAs) were inferred and served as a marker of measurable residual disease (MRD). Comparisons with imaging findings and tumor marker levels were made. A total of 29 CSF samples from 21 patients (16 with germinoma, 5 with non-germinomatous GCT) were sequenced. Twenty samples from 19 patients were collected at diagnosis, and 9 samples from 7 patients were collected during or after therapy. Among the diagnostic samples, CNAs were detected in samples from 17/19 patients (89%), which included 8 with marker-negative tumors. Specific clinical scenarios suggested that serial cfDNA analysis may carry utility in tracking treatment responses as well as clarifying indeterminate imaging findings. Our results provide evidence for the high-sensitivity in detecting ctDNA from CSF of CNS-GCT patients using LP-WGS, with potential utility for non-invasive diagnosis and disease monitoring in upcoming CNS-GCT studies.

Background: The treatment of BRAF V600E gliomas with BRAF inhibitors (BRAFis) and MEK inhibitors (MEKis) has been increasingly integrated into clinical practice for pediatric low-grade gliomas (PLGGs) and pediatric high-grade gliomas (HGGs). However, some questions remain unanswered, such as the best time to start targeted therapy, duration of treatment, and discontinuation of therapy. Given that no clinical trial has been able to address these critical questions, we developed a Canadian Consensus statement for the treatment of BRAF V600E mutated pediatric as well as adolescent and young adult (AYA) gliomas. Methods: Canadian neuro-oncologists were invited to participate in the development of this consensus. The consensus was discussed during monthly web-based national meetings, and the algorithms were revised until a consensus was achieved. Results: A total of 26 participants were involved in the development of the algorithms. Two treatment algorithms are proposed, one for the initiation of treatment and one for the discontinuation of treatment. We suggest that most patients with BRAF V600E gliomas should be treated with BRAFis ± MEKis upfront. Discontinuation of treatment can be considered in certain circumstances, and we suggest a slow wean. Conclusions: Based on expert consensus in Canada, we developed algorithms for treatment initiation of children and AYA with BRAF V600E gliomas as well as a discontinuation algorithm.

IntroductionMost pediatric low-grade-gliomas (LGG) and some high-grade-gliomas (HGG) have alterations in the RAS/MAPK pathway. Promising high tumor response rates were achieved using BRAF/MEK inhibitors, however data on their use in low-middle-income-countries (LMICs) are limited.MethodsWe retrospectively reviewed our Jordanian experience of using compassionate BRAF/MEK inhibitors in treating children with gliomas. We reviewed patients’ clinical characteristics, tumor response, and side effects.ResultsTwenty patients (13 males, 7 females) were identified. Median age at diagnosis was 8.3 years (0.3-18.9years). There were fifteen LGGs, three HGGs and two grade-2 pleomorphic xanthoastrocytoma (PXA-2). Fifteen tumors were supratentorial, three posterior fossa/brainstem, one diffuse-glioneuronal tumor (DLGNT) and one spinal. Five tumors were metastatic. Except for one patient with neurofibromatosis, ten patients underwent partial resection and nine had biopsy. All patients, except three, received BRAF/MEK inhibitors after initial standard chemo/radiotherapy. Seven LGGs had BRAF-mutation, six had BRAF-fusion, and two were empirically treated (one neurofibromatosis and one DLGNT). Fourteen LGGs were treated with 1-4 chemotherapy regimens before BRAF/MEK inhibitors’ use; all had partial/stable response on targeted therapy at a median of 1.9 years (0.5-5.4years). Two patients with BRAFv600E-mutated/CDKN2A deleted PXA-2, had progression following resection, and experienced stable/partial response at 9 months of dabrafenib use. Two patients with HGGs had BRAFv600E-mutation, and one had an FGFR-mutation. All three patients with HGG had temporary stable/partial response, two with significant clinical improvement. At a median of 2.7 years (1.3-3.2years), all patients experienced tumor progression, and two died. Eight patients (40%) developed acneiform rash, three (15%) paronychia, and one had significant panniculitis and fatigue. Six patients (30%) needed dose-reduction. Nine patients had temporary drug interruptions [due to side effects (5) and drug shortage (4)]. Two patients who stopped trametinib due to side effects (significant acneiform rash/paronychia and intracranial bleeding) did not experience progression.ConclusionsOur experience with BRAF/MEK inhibitors’ use was positive achieving response in all LGGs and provided sustained response with good quality of life for patients with HGG. Cost effectiveness analyses and patients’ satisfaction comparisons with chemotherapy are needed to evaluate the routine use of these drugs in LMICs.

Improving cognitive sequelae in children treated for brain tumours (CTBT) requires accessible interventions. While instructor-led exercise in a hospital setting is efficacious, it is not extended to communities. Objectives We aimed to (i) develop a website with educational resources/tools for community health and fitness professionals (HFP) to deliver exercise for CTBT in community settings to improve cognition and (ii) assess its usability by community HFP. It was hypothesized that the website would be learnable, clear, satisfactory and efficient to deliver exercise. Methods A scoping review determined the state of eHealth resources to support exercise for CTBT and identified knowledge and resource gaps. Three focus groups with HFP who served cancer survivors in hospital or community settings ( n = 13) identified user needs; content analysis identified themes. Gaps from the scoping review and themes from focus groups informed website content. A questionnaire assessed its usability by community HFP ( n = 4). Descriptive statistics inferred the website's learnability, clarity, satisfaction and efficiency. Open-ended responses identified issues. Results The scoping review revealed a lack of eHealth resources supporting exercise to improve cognition in CTBT and education for HFP to deliver exercise. Six themes were identified in the focus groups. HFP rated the website as sufficiently learnable, clear, satisfactory and efficient. Two minor issues were reported and addressed. Conclusion The website marks one of the first eHealth resources to increase accessibility of intervention to improve cognitive sequelae and ultimately quality of life in CTBT. HFP also gain access to education and tools to deliver exercise in community settings.

BackgroundAccurate and precise diagnosis is central to treating central nervous system (CNS) tumors, yet tissue diagnosis is often a neglected focus in low- and middle-income countries (LMICs). Since 2016, the WHO classification of CNS tumors has increasingly incorporated molecular biomarkers into the diagnosis of CNS tumors. While this shift to precision diagnostics promises a high degree of diagnostic accuracy and prognostic precision, it has also resulted in increasing divergence in diagnostic and management practices between LMICs and high-income countries (HICs). Pathologists and laboratory professionals in LMICs lack the proper training and tools to join the molecular diagnostic revolution. We describe the impact of a 7-year long twinning program between Canada and Pakistan on pathology services.MethodsDuring the study period, 141 challenging cases of pediatric CNS tumors initially diagnosed at Aga Khan University Hospital (AKUH), Karachi, were sent to the Hospital for Sick Children in Toronto, Canada (SickKids), for a second opinion. Each case received histologic review and often immunohistochemical staining and relevant molecular testing. A monthly multidisciplinary online tumor board (MDTB) was conducted to discuss the results with pathologists from both institutions in attendance.ResultsDiagnostic discordance was seen in 30 cases. Expert review provided subclassification for 53 cases most notably for diffuse gliomas and medulloblastoma. Poorly differentiated tumors benefited the most from second review, mainly because of the resolving power of specialized immunohistochemical stains, NanoString, and targeted gene panel next-generation sequencing. Collaboration with expert neuropathologists led to validation of over half a dozen immunostains at AKUH facilitating diagnosis of CNS tumors.ConclusionsLMIC-HIC Institutional twinning provides much-needed training and mentorship to pathologists and can help in infrastructure development by adopting and validating new immunohistochemical stains. Persistent unresolved cases indicate that molecular techniques are indispensable in for diagnosis in a minority of cases. The development of affordable alternative molecular techniques may help with these histologically unresolved cases.

Optic pathway/hypothalamic gliomas (OP/HGs) are low-grade tumours that account for 3–5% of all pediatric CNS tumours. The majority of cases are diagnosed before the age of 20, and 75% before the age of 10 years. Presenting symptoms are essentially visual. Treatment is recommended when the tumour threatens the patient's vision. Even though they are low-grade tumours, their course can be unpredictable and their management is often challenging. As OP/HGs are generally not amenable to complete resection, surgery has a limited role in the management. Chemotherapy was essentially the treatment of choice in the past but in most series, the 5-year event-free survival was between 30 and 50%. Targeted therapies are starting to gain ground over recent years with a better understanding of the underlying molecular alterations.

IntroductionInitiated in June 2019, this collaborative effort involved 15 public and private sector hospitals in Pakistan. The primary objective was to enhance the capacity for pediatric neuro-oncology (PNO) care, supported by a My Child Matters/Foundation S grant.MethodsWe aimed to establish and operate Multidisciplinary Tumor Boards (MTBs) on a national scale, covering 76% of the population (185.7 million people). In response to the COVID-19 pandemic, MTBs transitioned to videoconferencing. Fifteen hospitals with essential infrastructure participated, holding monthly sessions addressing diagnostic and treatment challenges. Patient cases were anonymized for confidentiality. Educational initiatives, originally planned as in-person events, shifted to a virtual format, enabling continued implementation and collaboration despite pandemic constraints.ResultsA total of 124 meetings were conducted, addressing 545 cases. To augment knowledge, awareness, and expertise, over 40 longitudinal lectures were organized for healthcare professionals engaged in PNO care. Additionally, two symposia with international collaborators and keynote speakers were also held to raise national awareness. The project achieved significant milestones, including the development of standardized national treatment protocols for low-grade glioma, medulloblastoma, and high-grade glioma. Further protocols are currently under development. Notably, Pakistan's first pediatric neuro-oncology fellowship program was launched, producing two graduates and increasing the number of trained pediatric neuro-oncologists in the country to three.DiscussionThe initiative exemplifies the potential for capacity building in PNO within low-middle income countries. Success is attributed to intra-national twinning programs, emphasizing collaborative efforts. Efforts are underway to establish a national case registry for PNO, ensuring a comprehensive and organized approach to monitoring and managing cases. This collaborative initiative, supported by the My Child Matters/Foundation S grant, showcases the success of capacity building in pediatric neuro-oncology in low-middle income countries. The establishment of treatment protocols, fellowship programs, and regional tumor boards highlights the potential for sustainable improvements in PNO care.

IntroductionAdvances in molecular diagnostics led to improved targeted interventions in the treatment of pediatric CNS tumors. However, the capacity to test for these is limited in LMICs, and thus their value needs exploration.MethodsWe reviewed our experience with NGS testing (TruSight RNA Pan-Cancer-seq panel) for pediatric CNS tumors at KHCC/Jordan (March/2022–April/2023). Paraffin blocks’ scrolls were shipped to the SickKids laboratory based on the multidisciplinary clinic (MDC) recommendations. We reviewed the patients’ characteristics, the tumor types, and the NGS results’ impact on treatment.ResultsOf 237 patients discussed during the MDC meetings, 32 patients (14%) were included. They were 16 boys and 16 girls; the median age at time of testing was 9.5 years (range, 0.9–21.9 years). There were 21 samples sent at diagnosis and 11 upon tumor progression. The main diagnoses were low-grade-glioma (15), high-grade-glioma (10), and other histologies (7). Reasons to request NGS included searching for a targetable alteration (20) and to better characterize the tumor behavior (12). The median turnaround time from samples’ shipment to receiving the results was 23.5 days (range, 15–49 days) with a median laboratory processing time of 16 days (range, 8–39 days) at a cost of US$1,000/sample. There were 19 (59%) tumors that had targetable alterations (FGFR/MAPK pathway inhibitors (14), checkpoint inhibitors (2), NTRK inhibitors (2), and one with PI3K inhibitor or IDH1 inhibitor). Two rare BRAF mutations were identified (BRAFp.G469A, BRAFp.K601E). One tumor diagnosed initially as undifferentiated round cell sarcoma harbored NAB2::STAT6 fusion and was reclassified as an aggressive metastatic solitary fibrous tumor. Another tumor initially diagnosed as grade 2 astroblastoma grade 2 was reclassified as low-grade-glioma in the absence of MN1 alteration. NGS failed to help characterize a tumor that was diagnosed histologically as small round blue cell tumor. Nine patients received targeted therapy; dabrafenib/trametinib (6), pembrolizumab (2), and entrectinib (1), mostly upon tumor progression (7).ConclusionIn this highly selective cohort, a high percentage of targetable mutations was identified facilitating targeted therapies. Outsourcing of NGS testing was feasible; however, criteria for case selection are needed. In addition, local capacity-building in conducting the test, interpretation of the results, and access to “new drugs” continue to be a challenge in LMICs.

Elucidating how adaptive and maladaptive changes to the structural connectivity of brain networks influences neural synchrony, and how this structure–function coupling impacts cognition is an important question in human neuroscience. This study assesses these links in the default mode and executive control networks during resting state, a visual-motor task, and through computational modeling in the developing brain and in acquired brain injuries. Pediatric brain tumor survivors were used as an injury model as they are known to exhibit cognitive deficits, structural connectivity compromise, and perturbations in neural communication. Focusing on information processing speed to assess cognitive performance, we demonstrate that during the presence and absence of specific task demands, structural connectivity of these critical brain networks directly influences neural communication and information processing speed, and white matter compromise has an indirect adverse impact on reaction time via perturbed neural synchrony. Further, when our experimentally acquired structural connectomes simulated neural activity, the resulting functional simulations aligned with our empirical results and accurately predicted cognitive group differences. Overall, our synergistic findings further our understanding of the neural underpinnings of cognition and when it is perturbed. Further establishing alterations in structural–functional coupling as biomarkers of cognitive impairments could facilitate early intervention and monitoring of these deficits.

Abstract Chordomas are rare slow growing tumors, arising from embryonic remnants of notochord with a close predilection for the axial skeleton. Recurrence is common and no effective standard medical therapy exists. Thymidylate synthase (TS), an intracellular enzyme, is a key rate-limiting enzyme of DNA biosynthesis and repair which is primarily active in proliferating and metabolically active cells. Eighty-four percent of chordoma samples had loss of TS expression which may predict response to anti-folates. Pemetrexed suppresses tumor growth by inhibiting enzymes involved in folate metabolism, resulting in decreased availability of thymidine which is necessary for DNA synthesis. Pemetrexed inhibited growth in a preclinical mouse xenograft model of human chordoma. We report three cases of metastatic chordoma that had been heavily treated previously with a variety of standard therapies with poor response. In two cases, pemetrexed was added and objective responses were observed on imaging with one patient on continuous treatment for > 2 years with continued shrinkage. One case demonstrated tumor growth after treatment with pemetrexed. The two cases which had a favorable response had a loss of TS expression, whereas the one case with progressive disease had TS present. These results demonstrate the activity of pemetrexed in recurrent chordoma and warrant a prospective clinical trial which is ongoing (NCT03955042).

IntroductionAdvancements in genomic profiling led to the discovery of four major molecular subgroups in medulloblastoma (MB), which have now been incorporated into the World Health Organization classification of central nervous system tumors. The current study aimed to determine the prognostic significance of the MB molecular subgroups among children in Malaysia.MethodsWe assembled MB samples from children

The management of medulloblastoma in children has dramatically changed over the past four decades, with the development of chemotherapy protocols aiming at improving survival and reducing long-term toxicities of high-dose craniospinal radiotherapy. While the staging and treatment of medulloblastoma were until recently based on the modified Chang’s system, recent advances in the molecular biology of medulloblastoma have revolutionized approaches in the management of this increasingly complex disease. The evolution of systemic therapies is described in this review.

Abstract Background Treatment personalization via tumor molecular testing holds promise for improving outcomes for patients with pediatric low-grade glioma (PLGG). We evaluate the health economic impact of employing tumor molecular testing to guide treatment for patients diagnosed with PLGG, particularly the avoidance of radiation therapy (RT) for patients with BRAF-fusion. Methods We performed a model-based cost-utility analysis comparing two strategies: molecular testing to determine BRAF fusion status at diagnosis against no molecular testing. We developed a microsimulation to model the lifetime health and cost outcomes (in quality-adjusted life years (QALYs) and 2018 CAD, respectively) for a simulated cohort of 100,000 patients newly diagnosed with PLGG after their initial surgery. Results The life expectancy after diagnosis for individuals who did not receive molecular testing was 39.01 (95% Confidence Intervals (CI): 32.94;44.38) years and 40.08 (95% CI: 33.19;45.76) years for those who received testing. Our findings indicate that patients who received molecular testing at diagnosis experienced a 0.38 (95% CI: 0.08;0.77) gain in QALYs and $1384 (95% CI: $-3486; $1204) reduction in costs over their lifetime. Cost and QALY benefits were driven primarily by the avoidance of long-term adverse events (stroke, secondary neoplasms) associated with unnecessary use of radiation. Conclusions We demonstrate the clinical benefit and cost-effectiveness of molecular testing in guiding the decision to provide RT in PLGG. While our results do not consider the impact of targeted therapies, this work is an example of the value of simulation modeling in assessing the long-term costs and benefits of precision oncology interventions for childhood cancer, which can aid decision-making about health system reimbursement.

PURPOSEMedulloblastoma is composed of four clinically and prognostically distinct molecular subgroups (WNT, SHH, group 3, and group 4). However, the clinical implications of these subgroups in the context of the unique challenges of low- to middle-income countries are rarely reported.METHODSWe assembled an institutional cohort of children (3-18 years) diagnosed with medulloblastoma and treated in Jordan between 2003 and 2016. Tumors were subgrouped by NanoString and correlated with clinical and radiologic characteristics.RESULTSEighty-eight patients were identified (63% male); median age was 6.9 years (interquartile range 4.8-9.2) and median symptom duration was 6 weeks (interquartile range 4-11). Radiotherapy was implemented as standard-risk in 41 patients (47%) and high-risk in 47 patients (53%). Subgrouping revealed 17 WNT (19%), 22 SHH (25%), 21 group 3 (24%), and 28 group 4 tumors (32%). Median time between craniotomy and radiotherapy was 45 days (17-155); 44% of them > 49 days. Median duration of radiotherapy was 44 days (36-74). Seventy-two patients (82%) received chemotherapy afterward. With a median follow-up of 4.6 years (0.2-14.9), 5-year progression-free survival (PFS) and overall survival were 73.5% and 69.4%, respectively, with no statistically significant survival difference between standard-risk and high-risk patients. Metastasis was significant for overall survival (P = .011). Patients with SHH and group 4 tumors had very good PFS (83.4% and 87.0%, respectively) and those with group 3 tumors had dismal outcomes (PFS 44.9%), whereas WNT tumors had less-than expected PFS (70.5%). PFS was statistically significant in patients with nonmetastatic tumors receiving radiotherapy ≤ 49 days (P = .011), particularly group 3 tumors.CONCLUSIONPatients with SHH and group 4 medulloblastoma had excellent survival comparable with high-income countries. Compliance with treatment protocols and avoiding radiotherapy delays are important in achieving adequate survival in low- to middle-income country settings. Subgroup-driven treatment protocols should be considered in countries with limited resources.

Abstract Purpose We investigate the impact of severe sensorineural hearing loss (SNHL) and for the first time evaluate the effect of unilateral versus bilateral SNHL on intellectual outcome in a cohort of children with embryonal brain tumors treated with and without radiation. Methods Data were from 94 childhood survivors of posterior fossa (PF) embryonal brain tumors who were treated with either: (1) chemotherapy alone (n = 16, 7.11 [3.41] years, 11M/5F), (2) standard‐dose craniospinal irradiation (CSI) and/or large boost volumes (n = 44, 13.05 [3.26] years, 29M/15F), or (3) reduced‐dose CSI with a boost restricted to the tumor bed (n = 34, 11.07 [3.80] years, 19M/15F). We compared intellectual outcome between children who: (1) did and did not develop SNHL and (2) developed unilateral versus bilateral SNHL. A Chang grade of ≥2b that required the use of a hearing aid was considered severe SNHL. Comparisons were made overall and within each treatment group separately. Results Patients who developed SNHL had lower full scale IQ (p = 0.007), verbal comprehension (p = 0.003), and working memory (p = 0.02) than patients without SNHL. No differences were observed between patients who had unilateral versus bilateral SNHL (all p > 0.05). Patients treated with chemotherapy alone who developed SNHL had lower mean working memory (p = 0.03) than patients who did not develop SNHL. Among patients treated with CSI, no IQ indices differed between those with and without SNHL (all p > 0.05). Conclusions Children treated for embryonal brain tumors who develop severe SNHL have lower intellectual outcome than patients with preserved hearing: this association is especially profound in young children treated with radiation sparing approaches. We also demonstrate that intellectual outcome is similarly impaired in patients who develop unilateral versus bilateral SNHL. These findings suggest that early intervention to preserve hearing is critical.

PURPOSEPediatric CNS tumors are increasingly a priority, particularly with the WHO designation of low-grade glioma (LGG) as one of six index childhood cancers. There are currently limited data on outcomes of pediatric patients with LGGs in low- and middle-income countries (LMICs).METHODSTo better understand the outcomes of LGGs in LMICs, this systematic review interrogated nine literature databases.RESULTSThe search identified 14,977 publications. Sixteen studies from 19 countries met the selection criteria and were included for data abstraction and analysis. Eleven studies (69%) were retrospective reviews from single institutions, and one (6%) captured institutional data prospectively. The studies captured a total of 957 patients with a median of 49 patients per study. Seven (44%) of the studies described the treatment modalities used. Of 373 patients for whom there was information, 173 (46%) had a gross total or near total resection, 109 (29%) had a subtotal resection, and 91 (24%) had only a biopsy performed. Seven studies, with a total of 476 patients, described the frequency of use of radiotherapy and/or chemotherapy in the cohorts: 83 of these patients received radiotherapy and 76 received chemotherapy. The 5-year overall survival ranged from 69.2% to 93.5%, although lower survival rates were reported at earlier time points. We identified limitations in the published studies with respect to the cohort sizes and methodologies.CONCLUSIONThe included studies reported survival rates frequently exceeding 80%, although the ultimate number of studies was limited, pointing to the paucity of studies describing the outcomes of children with LGGs in LMICs. This study underscores the need for more robust data on outcomes in pediatric LGG.

Sonic Hedgehog medulloblastoma (Shh-MB) comprises four subtypes each with distinct clinical traits. Here the authors characterize the genome, transcriptome, and methylome of Shh-MB subtypes, revealing a complex fusion landscape and the molecular convergence of MYCN and cAMP signaling pathways.

IntroductionNeurofibromatosis type 1 (NF1) has an incidence of 1 in 2,000 to 3,000 individuals and in 15% is associated with optic pathway glioma (OPG). Given the variability in clinical presentation and related morbidity, a multidisciplinary approach for diagnosis and management of children with NF1 and OPG is required, but often lacks coordination and regular information exchange. Herein we summarize our experience and describe the care pathways/network provided by a multidisciplinary team. The role of the distinct team members is elucidated as well as the care amendments made over time.MethodsWe performed a retrospective single-center observational study, including children treated at our institution between 1990 and 2021. Inclusion criteria were clinical diagnosis of NF1, radiographic and/or histopathological diagnosis of OPG and age below 18 years. Patients being treated elsewhere were excluded from the study. Data was abstracted from each child’s health record using a standardized data collection form. Characteristics of children with NF1 and OPG were described using means (SD) and percentages. Outcomes were determined using Kaplan-Meier estimates.ResultsFrom 1990 to 2021, 1,337 children were followed in our institution. Of those, 195 were diagnosed with OPG (14.6%), including 94 (48.21%) females and 101 (51.79%) males. Comprehensive data were available in 150 patients. The mean (SD) age at diagnosis was 5.31(4.08) years (range: 0.8–17.04 years). Sixty-two (41.3%) patients remained stable and did not undergo treatment, whereas 88 (58.7%) patients required at least one treatment. The mean (SD) duration of follow up was 8.14 (5.46) years (range: 0.1–25.9 years; median 6.8 years). Overall survival was of 23.6 years (±1.08), comprising 5 deaths. A dedicated NF clinic, including pediatricians and a nurse, provides regular follow up and plays a central role in the management of children with NF1, identifying those at risk of OPG, coordinating referrals to Neuroradiology and other specialists as indicated. All children are assessed annually by Ophthalmology. Comprehensive care was provided by a multidisciplinary team consisting of Dermatology, Genetics, Neuro-oncology, Neuroradiology, Neurosurgery, Ophthalmology and Pediatrics.ConclusionsThe care of children with NF1 and OPG is optimized with a multidisciplinary team approach, coordinated by a central specialty clinic.

PURPOSE Adequate clinical services have yet to be established in the majority of African countries, where childhood cancer survival rates vary from 8.1% to 30.3%. The aim of this review is to describe the landscape of pediatric oncology trials in Africa, identify challenges, and offer future opportunities for research collaborations. METHODS The study includes data from the International Pediatric Oncology Society (SIOP) global mapping survey, meta-research identifying trials in Africa in ClinicalTrials.gov, and a literature overview of publications on the subject of pediatric oncology clinical research supported by expert opinions on the current situation and challenges. RESULTS The SIOP global mapping survey received responses from 47 of 54 African countries, of which 23 have active clinical research programs. A preliminary search of ClinicalTrials.gov showed that only 105 (12.1%) of 868 African oncology studies included children and adolescents. Of these, 53 (50.5%) were interventional trials according to the registry’s classification. The small number of African trials for children and adolescents included palliative care and leukemia trials. In African oncology journals and international pediatric oncology journals, < 1% of the pediatric oncology publications come from Africa. Services and research were strengthened by international collaboration. National studies focused on clinical needs, local challenges, or interventional priorities. Both the literature review and the expert opinions highlight the need to expand clinical research in Africa, despite ongoing regional instability and lack of resources. CONCLUSION While a low number of pediatric clinical treatment trials are open to African children and adolescents, clinical research of high quality is being done in Africa. Several initiatives are stimulating the development of the research capacity across the continent, which should increase the publication output.

Abstract Background Understanding the global impact of medulloblastoma on health related quality of life (HRQL) is critical to characterizing the broad impact of this disease and realizing the benefits of modern treatments. We evaluated HRQL in an international cohort of pediatric medulloblastoma patients. Methods Seventy‐six patients were selected from 10 sites across North America, Europe, and Asia, who participated in the Medulloblastoma Advanced Genomics International Consortium (MAGIC). The Health Utilities Index (HUI) was administered to patients and/or parents at each site. Responses were used to determine overall HRQL and attributes (ie specific subdomains). The impact of various demographic and medical variables on HRQL was considered—including molecular subgroup. Results The majority of patients reported having moderate or severe overall burden of morbidity for both the HUI2 and HUI3 (HUI2 = 60%; HUI3 = 72.1%) when proxy‐assessed. Self‐care in the HUI2 was rated as higher (ie better outcome) for patients from Western versus Eastern sites, P = .02. Patients with nonmetastatic status had higher values (ie better outcomes) for the HUI3 hearing, HUI3 pain, and HUI2 pain, all P

Background/Objectives: Visual field loss is frequent in patients with brain tumors, worsening their daily life and exacerbating the burden of disease, and no supportive care strategies exist. In this case series, we sought to characterize the feasibility and potential effectiveness of a home-based visual rehabilitation program in hemianopia patients using immersive virtual-reality stimulation.Subjects/Methods: Two patients, one with homonymous hemianopia and the other with bitemporal hemianopia, consecutive to pediatric brain tumors, with no prior visual rehabilitation performed 15 min of home-based audiovisual stimulation every 2 days for 6 weeks (case 2) and 7 weeks (case 1) between February and August 2020. Patients used a virtual-reality, stand-alone, and remotely controlled device loaded with a non-commercial audiovisual stimulation program managed in real time from the laboratory. Standard visual outcomes assessed in usual care in visual rehabilitation were measured at the clinic. Following a mixed method approach in this pragmatic study of two cases, we collected quantitative and qualitative data on feasibility and potential effectiveness and compared the results pre- and post-treatment.Results: Implementation and wireless delivery of the audiovisual stimulation, remote data collection, and analysis for cases 1 and 2 who completed 19/20 and 20/20 audiovisual stimulation sessions at home, respectively, altogether indicated feasibility. Contrast sensitivity increased in both eyes for cases 1 and 2. Visual fields, measured by binocular Esterman and monocular Humphrey full-field analyses, improved in case 1. A minor increase was observed in case 2. Cases 1 and 2 enhanced reading speed. Case 2 strongly improved quality of life scores.Conclusion: This is the first report of a home-based virtual-reality visual rehabilitation program for adult patients with hemianopia consecutive to a pediatric brain tumor. We show the feasibility in real-world conditions and potential effectiveness of such technology on visual perception and quality of life.

Infant gliomas behave differently to their childhood or adult counterparts. Here, the authors perform a large-scale genetic analysis of these tumours, revealing genetic alterations which may offer therapeutic opportunities.

Summary: Over the past decade, wingless-activated (WNT) medulloblastoma has been identified as a candidate for therapy de-escalation based on excellent survival; however, a paucity of relapses has precluded additional analyses of markers of relapse. To address this gap in knowledge, an international cohort of 93 molecularly confirmed WNT MB was assembled, where 5-year progression-free survival is 0.84 (95%, 0.763–0.925) with 15 relapsed individuals identified. Maintenance chemotherapy is identified as a strong predictor of relapse, with individuals receiving high doses of cyclophosphamide or ifosphamide having only one very late molecularly confirmed relapse (p = 0.032). The anatomical location of recurrence is metastatic in 12 of 15 relapses, with 8 of 12 metastatic relapses in the lateral ventricles. Maintenance chemotherapy, specifically cumulative cyclophosphamide doses, is a significant predictor of relapse across WNT MB. Future efforts to de-escalate therapy need to carefully consider not only the radiation dose but also the chemotherapy regimen and the propensity for metastatic relapses.

Abstract With improved survivorship in medulloblastoma, there has been an increasing incidence of late complications. To date, no studies have specifically addressed the risk of radiation-associated diffuse intrinsic pontine glioma (DIPG) in medulloblastoma survivors. Query of the International DIPG Registry identified six cases of DIPG with a history of medulloblastoma treated with radiotherapy. All patients underwent central radiologic review that confirmed a diagnosis of DIPG. Six additional cases were identified in reports from recent cooperative group medulloblastoma trials (total n = 12; ages 7 to 21 years). From these cases, molecular subgrouping of primary medulloblastomas with available tissue (n = 5) revealed only non-WNT, non-SHH subgroups (group 3 or 4). The estimated cumulative incidence of DIPG after post-treatment medulloblastoma ranged from 0.3–3.9%. Posterior fossa radiation exposure (including brainstem) was greater than 53.0 Gy in all cases with available details. Tumor/germline exome sequencing of three radiation-associated DIPGs revealed an H3 wild-type status and mutational signature distinct from primary DIPG with evidence of radiation-induced DNA damage. Mutations identified in the radiation-associated DIPGs had significant molecular overlap with recurrent drivers of adult glioblastoma (e.g. NRAS, EGFR, and PTEN), as opposed to epigenetic dysregulation in H3-driven primary DIPGs. Patients with radiation-associated DIPG had a significantly worse median overall survival (median 8 months; range 4–17 months) compared to patients with primary DIPG. Here, it is demonstrated that DIPG occurs as a not infrequent complication of radiation therapy in survivors of pediatric medulloblastoma and that radiation-associated DIPGs may present as a poorly-prognostic distinct molecular subgroup of H3 wild-type DIPG. Given the abysmal survival of these cases, these findings provide a compelling argument for efforts to reduce exposure of the brainstem in the treatment of medulloblastoma. Additionally, patients with radiation-associated DIPG may benefit from future therapies targeted to the molecular features of adult glioblastoma rather than primary DIPG.

There is growing evidence that exercise induced experience dependent plasticity may foster structural and functional recovery following brain injury. We examined the efficacy of exercise training for neural and cognitive recovery in long-term pediatric brain tumor survivors treated with radiation.We conducted a controlled clinical trial with crossover of exercise training (vs. no training) in a volunteer sample of 28 children treated with cranial radiation for brain tumors (mean age = 11.5 yrs.; mean time since diagnosis = 5.7 yrs). The endpoints were anatomical T1 MRI data and multiple behavioral outcomes presenting a broader analysis of structural MRI data across the entire brain. This included an analysis of changes in cortical thickness and brain volume using automated, user unbiased approaches. A series of general linear mixed effects models evaluating the effects of exercise training on cortical thickness were performed in a voxel and vertex-wise manner, as well as for specific regions of interest. In exploratory analyses, we evaluated the relationship between changes in cortical thickness after exercise with multiple behavioral outcomes, as well as the relation of these measures at baseline.Exercise was associated with increases in cortical thickness within the right pre and postcentral gyri. Other notable areas of increased thickness related to training were present in the left pre and postcentral gyri, left temporal pole, left superior temporal gyrus, and left parahippocampal gyrus. Further, we observed that compared to a separate cohort of healthy children, participants displayed multiple areas with a significantly thinner cortex prior to training and fewer differences following training, indicating amelioration of anatomical deficits. Partial least squares analysis (PLS) revealed specific patterns of relations between cortical thickness and various behavioral outcomes both after training and at baseline.Overall, our results indicate that exercise training in pediatric brain tumor patients treated with radiation has a beneficial impact on brain structure. We argue that exercise training should be incorporated into the development of neuro-rehabilitative treatments for long-term pediatric brain tumor survivors and other populations with acquired brain injury. (ClinicalTrials.gov, NCT01944761) Keywords: Brain recovery, Cranial radiation, Cortical thickness, Exercise, Neuroplasticity, Pediatric brain tumor

Purpose: Prospective and longitudinal neuroimaging studies of posterior fossa tumors are scarce. Here we evaluate the early changes in white matter and intellectual outcome up to 3 years after diagnosis. Patients and methods: Twenty-two children with posterior fossa tumors and 24 similarly-aged healthy children participated. Patients included: (a) 12 individuals who received surgery, cranial-spinal radiation (CSR), and focal radiation to the tumor bed (CSR group) and (b) 10 individuals who received local therapy, either surgery only or surgery and focal radiation to the tumor bed (Local group). Diffusion tensor imaging (DTI) and intelligence measures were obtained an average of 3 months after diagnosis and then at 12, 24, and 36 months later. DTI tractography and voxel-wise approaches were employed. The Neurological Predictor Scale was used to summarize the type and amount of treatment for PF tumor patients. Linear mixed modelling was used to evaluate group differences at baseline and changes over time in DTI metrics for both the specific white matter tracts and voxel-wise, as well as for intelligence measures. Results: Based on tractography, patients treated with CSR had significantly higher Axial and Mean diffusivity in the cortical-spinal tracts (CST) 3 month after diagnosis – particularly on the right side, p .10. Voxel-wise analyses revealed multiple areas of white matter compromise in both patients groups. Notably, both patient groups had lower scores on intelligence measures compared to the Control group: The CSR group displayed lower performance 3 months following diagnosis, ps 0.10, whereas the Local group displayed no differences at 3 months, ps> 0.10, but their performance declined over time, ps

Purpose: Consumption of medical opium for pain relief in India is low, despite the country being one of the main world producers of the substance. We investigated obstacles to opioid use and physician perceptions about optimal pain management in pediatric oncology patients in India. Methods: Semistructured interviews were conducted with oncologists who work in pediatric oncology settings. A mixed sampling strategy was used, including maximum variation and confirmation and disconfirmation of cases, as well as snowball sampling. Key informants were identified. Interviews were audio recorded, transcribed verbatim, and analyzed by thematic analysis methodology. Results: Twenty-three interviews were performed across 20 Indian institutions. The main obstacles identified were lack of financial resources, inadequate education of health care providers on pain management, insufficient human resources (particularly lack of dedicated trained oncology nurses), poor access to opioids, and cultural perceptions about pain. Children from rural areas, treated in public hospitals, and from lower socioeconomic classes appear disadvantaged. A significant equality gap exists between public institutions and private institutions, which provide state-of-the-art treatment. Conclusion: The study illuminates the complexity of pain management in pediatric oncology in India, where financial constraints, lack of education, and poor access to opioids play a dominant role, but lack of awareness and cultural perceptions about pain management among health care providers and parents emerged as important contributing factors. Urgent interventions are needed to optimize care in this vulnerable population.

Purpose: The management of central nervous system tumors is challenging in low- and middle-income countries. Little is known about applicability of twinning initiatives with high-income countries in neuro-oncology. In 2004, a monthly neuro-oncology video-teleconference program was started between King Hussein Cancer Center (Amman, Jordan) and the Hospital for Sick Children (Toronto, Ontario, Canada). More than 100 conferences were held and > 400 cases were discussed. The aim of this work was to assess the sustainability of such an initiative and the evolution of the impact over time. Methods: We divided the duration in to three eras according to the initial 2 to 3 years of work of three consecutive oncologists in charge of the neuro-oncology program at King Hussein Cancer Center. We retrospectively reviewed the written minutes and compared the preconference suggested plans with the postconference recommendations. Impact of changes on the patient care was recorded. Results: Thirty-three sets of written minutes (covering 161 cases) in the middle era and 32 sets of written minutes (covering 122 cases) in the last era were compared with the initial experience (20 meetings, 72 cases). Running costs of these conferences has dropped from $360/h to < $40/h. Important concepts were introduced, such as multidisciplinary teamwork, second-look surgery, and early referral. Suggestions for plan changes have decreased from 44% to 30% and 24% in the respective consecutive eras. Most recommendations involved alternative intervention modalities or pathology review. Most of these recommendations were followed. Conclusion: Video-teleconferencing in neuro-oncology is feasible and sustainable. With time, team experience is built while the percentage and the type of treatment modifications change. Commitment and motivation helped maintain this initiative rather than availability of financial resources. Improvement in patients’ care was achieved, in particular, with the implementation of a multidisciplinary team and the continuous effort to implement recommendations.

Purpose: Pediatric medulloblastoma (MB) treatment has evolved over the past few decades; however, treating children in countries with limited resources remains challenging. Until now, the literature regarding childhood MB in Malaysia has been nonexistent. Our objectives were to review the demographics and outcome of pediatric MB treated at the University Malaya Medical Center between January 1994 and December 2013 and describe the challenges encountered. Methods: Fifty-one patients with childhood MB were seen at University Malaya Medical Center. Data from 43 patients were analyzed; eight patients were excluded because their families refused treatment after surgery. Results: Headache and vomiting were the most common presenting symptoms, and the mean interval between symptom onset and diagnosis was 4 weeks. Fourteen patients presented with metastatic disease. Five-year progression-free survival (± SE) for patients ≥ 3 years old was 41.7% ± 14.2% (95% CI, 21.3% to 81.4%) in the high-risk group and 68.6% ± 18.6% (95% CI, 40.3% to 100%) in the average-risk group, and 5-year overall survival (± SE) in these two groups was 41.7% ± 14.2% (95% CI, 21.3% to 81.4%) and 58.3% ± 18.6% (95% CI, 31.3% to 100%), respectively. Children younger than 3 years old had 5-year progression-free and overall survival rates (± SE) of 47.6% ± 12.1% (95% CI, 28.9% to 78.4%) and 45.6% ± 11.7% (95% CI, 27.6% to 75.5%), respectively. Time to relapse ranged from 4 to 132 months. Most patients who experienced relapse died within 1 year. Febrile neutropenia, hearing loss, and endocrinopathy were the most common treatment-related complications. Conclusion: The survival rate of childhood MB in Malaysia is inferior to that usually reported in the literature. We postulate that the following factors contribute to this difference: lack of a multidisciplinary neuro-oncology team, limited health care facilities, inconsistent risk assessment, insufficient data in the National Cancer Registry and pathology reports, inadequate long-term follow-up, and cultural beliefs leading to treatment abandonment.

Facial emotion recognition (FER) deficits are evident and pervasive across neurodevelopmental, psychiatric, and acquired brain disorders in children, including children treated for brain tumours. Such deficits are thought to perpetuate challenges with social relationships and decrease quality of life. The present study combined eye-tracking, neuroimaging and cognitive assessments to evaluate if visual attention, brain structure, and general cognitive function contribute to FER in children treated for posterior fossa (PF) tumours (patients: n = 36) and typically developing children (controls: n = 18). To assess FER, all participants completed the Diagnostic Analysis of Nonverbal Accuracy (DANVA2), a computerized task that measures FER using photographs, while their eye-movements were recorded. Patients made more FER errors than controls (p

Spontaneous tumor regression is a unique feature of pediatric low-grade gliomas (PLGG). We speculated that lack of telomere maintenance is responsible for this behavior. We first looked for evidence of telomerase activity and alternative-lengthening telomeres (ALT) in 56 PLGG. Telomerase activity was observed in 0 of 11 PLGG in contrast to 10 of 13 high-grade pediatric brain tumors. There was no ALT in 45 of 45 samples. We applied Q-FISH to eight patients whose indolent PLGG underwent two metachronous biopsies over a lag of several years. Telomere shortening was observed in the second biopsy in all tumors but not in a normal brain control (P < .0001), indicating that lack of telomere maintenance is associated with continuous telomere erosion. Based on these observations, we observed that younger PLGG patients who exhibit more aggressive and frequently recurrent tumors had significantly longer telomeres than older ones (P = .00014). Tumors with a terminal restriction fragment length of 8.0) conferred a high likelihood of late recurrences in PLGG. Our findings provide a plausible biological mechanism to explain the tendency of PLGG to exhibit growth arrest and spontaneous regression. Telomere maintenance may therefore represent the first known biologic prognostic marker in PLGG.