LOGGIC/FIREFLY-2: a phase 3, randomized trial of tovorafenib vs. chemotherapy in pediatric and young adult patients with newly diagnosed low-grade glioma harboring an activating RAF alteration.

BACKGROUND: Pediatric low-grade glioma (pLGG) is essentially a single pathway disease, with most tumors driven by genomic alterations affecting the mitogen-activated protein kinase/ERK (MAPK) pathway, predominantly KIAA1549::BRAF fusions and BRAF V600E mutations. This makes pLGG an ideal candidate for MAPK pathway-targeted treatments. The type I BRAF inhibitor, dabrafenib, in combination with the MEK inhibitor, trametinib, has been approved by the United States Food and Drug Administration for the systemic treatment of BRAF V600E-mutated pLGG. However, this combination is not approved for the treatment of patients with tumors harboring BRAF fusions as type I RAF inhibitors are ineffective in this setting and may paradoxically enhance tumor growth. The type II RAF inhibitor, tovorafenib (formerly DAY101, TAK-580, MLN2480), has shown promising activity and good tolerability in patients with BRAF-altered pLGG in the phase 2 FIREFLY-1 study, with an objective response rate (ORR) per Response Assessment in Neuro-Oncology high-grade glioma (RANO-HGG) criteria of 67%. Tumor response was independent of histologic subtype, BRAF alteration type (fusion vs. mutation), number of prior lines of therapy, and prior MAPK-pathway inhibitor use. METHODS: LOGGIC/FIREFLY-2 is a two-arm, randomized, open-label, multicenter, global, phase 3 trial to evaluate the efficacy, safety, and tolerability of tovorafenib monotherapy vs. current standard of care (SoC) chemotherapy in patients < 25 years of age with pLGG harboring an activating RAF alteration who require first-line systemic therapy. Patients are randomized 1:1 to either tovorafenib, administered once weekly at 420 mg/m2 (not to exceed 600 mg), or investigator's choice of prespecified SoC chemotherapy regimens. The primary objective is to compare ORR between the two treatment arms, as assessed by independent review per RANO-LGG criteria. Secondary objectives include comparisons of progression-free survival, duration of response, safety, neurologic function, and clinical benefit rate. DISCUSSION: The promising tovorafenib activity data, CNS-penetration properties, strong scientific rationale combined with the manageable tolerability and safety profile seen in patients with pLGG led to the SIOPe-BTG-LGG working group to nominate tovorafenib for comparison with SoC chemotherapy in this first-line phase 3 trial. The efficacy, safety, and functional response data generated from the trial may define a new SoC treatment for newly diagnosed pLGG. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05566795. Registered on October 4, 2022.

Impact of trametinib on the neuropsychological profile of NF1 patients.

PURPOSE: The use of trametinib in the treatment of pediatric low-grade gliomas (PLGG) and plexiform neurofibroma (PN) is being investigated in an ongoing multicenter phase II trial (NCT03363217). Preliminary data shows potential benefits with significant response in the majority of PLGG and PN and an overall good tolerance. Moreover, possible benefits of MEK inhibitor therapy on cognitive functioning in neurofibromatosis type 1 (NF1) were recently shown which supports the need for further evaluation. METHODS: Thirty-six patients with NF1 (age range 3-19 years) enrolled in the phase II study of trametinib underwent a neurocognitive assessment at inclusion and at completion of the 72-week treatment. Age-appropriate Wechsler Intelligence Scales and the Trail Making Test (for children over 8 years old) were administered at each assessment. Paired t-tests and Reliable Change Index (RCI) analyses were performed to investigate change in neurocognitive outcomes. Regression analyses were used to investigate the contribution of age and baseline score in the prediction of change. RESULTS: Stable performance on neurocognitive tests was revealed at a group-level using paired t-tests. Clinically significant improvements were however found on specific indexes of the Wechsler intelligence scales and Trail Making Test, using RCI analyses. No significant impact of age on cognitive change was evidenced. However, lower initial cognitive performance was associated with increased odds of presenting clinically significant improvements on neurocognitive outcomes. CONCLUSION: These preliminary results show a potential positive effect of trametinib on cognition in patients with NF1. We observed significant improvements in processing speed, visuo-motor and verbal abilities. This study demonstrates the importance of including neuropsychological evaluations into clinical trial when using MEK inhibitors for patients with NF1.

Advances in pediatric gliomas: from molecular characterization to personalized treatments.

Pediatric gliomas, consisting of both pediatric low-grade (pLGG) and high-grade gliomas (pHGG), are the most frequently occurring brain tumors in children. Over the last decade, several milestone advancements in treatments have been achieved as a result of stronger understanding of the molecular biology behind these tumors. This review provides an overview of pLGG and pHGG highlighting their clinical presentation, molecular characteristics, and latest advancements in therapeutic treatments.  Conclusion: The increasing understanding of the molecular biology characterizing pediatric low and high grade gliomas has revolutionized treatment options for these patients, especially in pLGG. The implementation of next generation sequencing techniques for these tumors is crucial in obtaining less toxic and more efficacious treatments. What is Known: • Pediatric Gliomas are the most common brain tumour in children. They are responsible for significant morbidity and mortality in this population. What is New: • Over the last two decades, there has been a significant increase in our global understanding of the molecular background of pediatric low and high grade gliomas. • The implementation of next generation sequencing techniques for these tumors is crucial in obtaining less toxic and more efficacious treatments, with the ultimate goal of improving both the survival and the quality of life of these patients.

MRI Radiogenomics of Pediatric Medulloblastoma: A Multicenter Study.

Background Radiogenomics of pediatric medulloblastoma (MB) offers an opportunity for MB risk stratification, which may aid therapeutic decision making, family counseling, and selection of patient groups suitable for targeted genetic analysis. Purpose To develop machine learning strategies that identify the four clinically significant MB molecular subgroups. Materials and Methods In this retrospective study, consecutive pediatric patients with newly diagnosed MB at MRI at 12 international pediatric sites between July 1997 and May 2020 were identified. There were 1800 features extracted from T2- and contrast-enhanced T1-weighted preoperative MRI scans. A two-stage sequential classifier was designed-one that first identifies non-wingless (WNT) and non-sonic hedgehog (SHH) MB and then differentiates therapeutically relevant WNT from SHH. Further, a classifier that distinguishes high-risk group 3 from group 4 MB was developed. An independent, binary subgroup analysis was conducted to uncover radiomics features unique to infantile versus childhood SHH subgroups. The best-performing models from six candidate classifiers were selected, and performance was measured on holdout test sets. CIs were obtained by bootstrapping the test sets for 2000 random samples. Model accuracy score was compared with the no-information rate using the Wald test. Results The study cohort comprised 263 patients (mean age ± SD at diagnosis, 87 months ± 60; 166 boys). A two-stage classifier outperformed a single-stage multiclass classifier. The combined, sequential classifier achieved a microaveraged F1 score of 88% and a binary F1 score of 95% specifically for WNT. A group 3 versus group 4 classifier achieved an area under the receiver operating characteristic curve of 98%. Of the Image Biomarker Standardization Initiative features, texture and first-order intensity features were most contributory across the molecular subgroups. Conclusion An MRI-based machine learning decision path allowed identification of the four clinically relevant molecular pediatric medulloblastoma subgroups. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Chaudhary and Bapuraj in this issue.

Selumetinib for symptomatic, inoperable plexiform neurofibromas in children with neurofibromatosis type 1: A national real-world case series.

Neurofibromatosis type 1-associated plexiform neurofibromas can cause debilitating symptoms and be life threatening. Treatment options are limited, given their tendency to regrow following surgery and their propensity to transform into malignant tumours following radiation. Selumetinib is an oral selective inhibitor of RAS-mitogen-activated protein kinase (MAPK) 1 and 2, which has shown efficacy for tumour shrinkage/stabilisation and symptom improvement. We report a national case series of 19 children treated with selumetinib. All patients experienced symptom improvement or stabilisation with an acceptable toxicity profile, including those patients previously treated with trametinib. This real-world experience confirms previous trials showing significant clinical benefit for this patient population.

Validity and reliability of the French version of the Pediatric Quality of Life Inventory™ brain tumor module.

INTRODUCTION: Assessing health-related quality of life (HRQoL) is an increasingly important aspect of standard care in pediatric oncology. Currently, there is a gap in the availability of French questionnaires to assess the quality of life of French-speaking pediatric brain tumor (PBT) patients, which has important implications in the care of this population. The first aim of this study was to translate the original English Pediatric Quality of Life Inventory™ (PedsQL) brain tumor module version into French. The second aim was to describe the stability, repeatability and convergent validity of the French PedsQL brain tumor module. METHODS: A total of 61 PBT patients were included in this study. Among them, 15 children and 20 parents participated in the translation process. As part of the validation study, 48 children and 48 parents answered the PedsQL brain tumor module twice, and the PedsQL generic core scales and the patient-reported outcomes measurement information system (PROMIS-37 pediatric profile v2.0) questionnaire were administered once to the participants. The mean age of the 25 boys and 23 girls was 8.3 ± 4.8 years. For temporal stability, we used intraclass correlation coefficients (ICCs), for repeatability, we used the Bland and Altman method to assess the accuracy at a 1-week interval, and we used Pearson's correlation coefficients for convergent validity between the PedsQL brain tumor module, PedsQL general module and the PROMIS. RESULTS: Temporal stability for the parent proxy-reports (average ICC = 0.98) and the child self-reports (average ICC = 0.98) were excellent. There was a high absolute stability over a 1-week interval for the parent proxy-reports (ICC > 0.96) and child self-reports (ICC > 0.96). Convergent validity between parent proxy-reports and child self-reports was supported by positive correlations for five subscales. Children reported higher scores in cognitive problems and the movement and balance parameters than their parents and reported lower scores on the worry parameter than their parents. CONCLUSION: The strong psychometric properties of the French version of the PedsQL brain tumor module indicate that it is a validate and reliable questionnaire to measure HRQoL in PBT patients. The availability of a French version of the PedsQL brain tumor module supports the wider dissemination of the assessment of HRQOL in PBT patients.

Pediatric Hyperacute Arterial Ischemic Stroke Pathways at Canadian Tertiary Care Hospitals.

BACKGROUND: Childhood acute arterial ischemic stroke (AIS) is diagnosed at a median of 23 hours post-symptom onset, delaying treatment. Pediatric stroke pathways can expedite diagnosis. Our goal was to understand the similarities and differences between Canadian pediatric stroke protocols with the aim of optimizing AIS management. METHODS: We contacted neurologists at all 16 Canadian pediatric hospitals regarding AIS management. Established protocols were analyzed for similarities and differences in eight domains. RESULTS: Response rate was 100%. Seven (44%) centers have an established AIS protocol and two (13%) have a protocol under development. Seven centers do not have a protocol; two redirect patients to adult neurology, five rely on a case-by-case approach for management. Analysis of the seven protocols revealed differences in: 1) IV-tPA dosage: age-dependent 0.75-0.9 mg/kg (N = 1) versus age-independent 0.9 mg/kg (N = 6), with maximum doses of 75 mg (N = 1) or 90 mg (N = 6); 2) IV-tPA lower age cut-off: 2 years (N = 5) versus 3 or 10 years (each N = 1); 3) IV-tPA exclusion criteria: PedNIHSS score <4 (N = 3), <5 (N = 1), <6 (N = 3); 4) first choice of pre-treatment neuroimaging: computed tomography (CT) (N = 3), magnetic resonance imaging (MRI) (N = 2) or either (N = 2); 5) intra-arterial tPA use (N = 3) and; 6) mechanical thrombectomy timeframe: <6 hour (N = 3), <24 hour (N = 2), unspecified (N = 2). CONCLUSIONS: Although 44% of Canadian pediatric hospitals have established AIS management pathways, several differences remain among centers. Some criteria (dosage, imaging) reflect adult AIS literature. Canadian expert consensus regarding IV-tPA and endovascular treatment should be established to standardize and implement AIS protocols across Canada.

Pontine gliomas a 10-year population-based study: a report from The Canadian Paediatric Brain Tumour Consortium (CPBTC).

BACKGROUND: Diffuse intrinsic pontine gliomas (DIPG) are midline gliomas that arise from the pons and the majority are lethal within a few months after diagnosis. Due to the lack of histological diagnosis the epidemiology of DIPG is not completely understood. The aim of this report is to provide population-based data to characterize the descriptive epidemiology of this condition in Canadian children. PATIENTS AND METHODS: A national retrospective study of children and adolescents diagnosed with DIPG between 2000 and 2010 was undertaken. All cases underwent central review to determine clinical and radiological diagnostic characteristics. Crude incidence figures were calculated using age-adjusted (0-17 year) population data from Statistics Canada. Survival analyses were performed using the Kaplan-Meier method. RESULTS: A total of 163 patients with pontine lesions were identified. Central review determined one-hundred and forty-three patients who met clinical, radiological and/or histological criteria for diagnosis. We estimate an incidence rate of 1.9 DIPG/1,000,000 children/year in the Canadian population over a 10 years period. Median age at diagnosis was 6.8 years and 50.3% of patients were female. Most patients presented with cranial nerve palsies (76%) and ataxia (66%). Despite typical clinical and radiological characteristics, histological confirmation reported three lesions to be low-grade gliomas and three were diagnosed as CNS embryonal tumor not otherwise specified (NOS). CONCLUSIONS: Our study highlights the challenges associated with epidemiology studies on DIPG and the importance of central review for incidence rate estimations. It emphasizes that tissue biopsies are required for accurate histological and molecular diagnosis in patients presenting with pontine lesions and reinforces the limitations of radiological and clinical diagnosis in DIPG. Likewise, it underscores the urgent need to increase the availability and accessibility to clinical trials.

Correction: Expanding the clinical phenotype of individuals with a 3-bp in-frame deletion of the NF1 gene (c.2970_2972del): an update of genotype-phenotype correlation.

A correction has been published to this Article. The PDF and HTML have been updated accordingly.

Expanding the clinical phenotype of individuals with a 3-bp in-frame deletion of the NF1 gene (c.2970_2972del): an update of genotype-phenotype correlation.

PURPOSE: Neurofibromatosis type 1 (NF1) is characterized by a highly variable clinical presentation, but almost all NF1-affected adults present with cutaneous and/or subcutaneous neurofibromas. Exceptions are individuals heterozygous for the NF1 in-frame deletion, c.2970_2972del (p.Met992del), associated with a mild phenotype without any externally visible tumors. METHODS: A total of 135 individuals from 103 unrelated families, all carrying the constitutional NF1 p.Met992del pathogenic variant and clinically assessed using the same standardized phenotypic checklist form, were included in this study. RESULTS: None of the individuals had externally visible plexiform or histopathologically confirmed cutaneous or subcutaneous neurofibromas. We did not identify any complications, such as symptomatic optic pathway gliomas (OPGs) or symptomatic spinal neurofibromas; however, 4.8% of individuals had nonoptic brain tumors, mostly low-grade and asymptomatic, and 38.8% had cognitive impairment/learning disabilities. In an individual with the NF1 constitutional c.2970_2972del and three astrocytomas, we provided proof that all were NF1-associated tumors given loss of heterozygosity at three intragenic NF1 microsatellite markers and c.2970_2972del. CONCLUSION: We demonstrate that individuals with the NF1 p.Met992del pathogenic variant have a mild NF1 phenotype lacking clinically suspected plexiform, cutaneous, or subcutaneous neurofibromas. However, learning difficulties are clearly part of the phenotypic presentation in these individuals and will require specialized care.

A phase 2 study of trametinib for patients with pediatric glioma or plexiform neurofibroma with refractory tumor and activation of the MAPK/ERK pathway: TRAM-01.

BACKGROUND: Pediatric low-grade gliomas (PLGG) are the most frequent brain tumors in children. Up to 50% will be refractory to conventional chemotherapy. It is now known that the majority of PLGG have activation of the MAPK/ERK pathway. The same pathway is also activated in plexiform neurofibromas (PNs) which are low-grade tumors involving peripheral nerves in patients with neurofibromatosis type 1 (NF1). These lesions are known to be refractory to chemotherapy. Specific MEK inhibitors such as trametinib are now available and have been approved for other cancers harboring mutations in the MAPK/ERK pathway such as melanoma. We have observed significant responses to trametinib in patients with refractory PLGG in our institutions and results from the phase I study are promising. The treatment appears not only efficacious but is also usually well tolerated. We hypothesize that we will observe responses in the majority of refractory PLGG and PN treated with trametinib in this phase 2 study. METHODS: The primary objective is to determine the objective response rate of trametinib as a single agent for treatment of progressing/refractory tumors with MAPK/ERK pathway activation. The TRAM-01 study is a phase II multicentric open-label basket trial including four groups. Group 1 includes NF1 patients with progressing/refractory glioma. Group 2 includes NF1 patients with plexiform neurofibroma. Group 3 includes patients with progressing/refractory glioma with KIAA1549-BRAF fusion. Group 4 includes other patients with progressing/refractory glioma with activation of the MAPK/ERK pathway. Eligible patients for a given study group will receive daily oral trametinib at full dose for a total of 18 cycles of 28 days. A total of 150 patients will be enrolled in seven Canadian centers. Secondary objectives include the assessment of progression-free survival, overall survival, safety and tolerability of trametinib, serum levels of trametinib and evaluation of quality of life during treatment. DISCUSSION: Trametinib will allow us to target directly and specifically the MAPK/ERK pathway. We expect to observe a significant response in most patients. Following our study, trametinib could be integrated into standard treatment of PLGG and PN. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03363217 December 6, 2017.

Correction to: Efficacy of Dabrafenib for three children with brainstem BRAFV600E positive ganglioglioma.

In the original article, the author names were published incorrectly. The names are correct in this publication.

Central and peripheral steady-state visual evoked potentials in children with optic pathway gliomas.

PURPOSE: Treatment of optic pathway gliomas is prompted by neuroradiological evidence of tumor growth, usually associated with progressive visual loss. Despite therapy, approximately 40% will show visual deterioration. Treatment outcome is largely based on the preservation of vision. However, current visual function assessment is often unreliable in children with optic pathway gliomas who have limited collaboration. Thus, there is a need for new clinical tools to evaluate visual functions in these children. The aim of the study was to assess the value of steady-state visual evoked potentials as a tool to assess function in the central and peripheral visual fields of children with optic pathway gliomas. METHOD: Ten patients with optic pathway gliomas and 33 healthy controls (ages 3 to 18 years) were tested using steady-state visual evoked potentials. The dartboard stimulus consisted of one central circle alternating at 16 reversals/s and one peripheral hoop alternating at 14.4 reversals/s, separated by a hoop of gray space. It was presented monocularly at 30% and 96% contrasts. RESULTS: Results indicated that central signal-to-noise ratios were significantly lower in children with optic pathway gliomas compared to controls. However, no significant group difference was detected in the peripheral visual field. CONCLUSION: Steady-state visual evoked potentials could eventually be implemented in the clinical assessment and follow-up of central visual field deficits in uncooperative or nonverbal children but seem to have limited usefulness for evaluation of peripheral visual field deficits. Additional studies are needed to identify testing parameters for full visual field assessment.

Trametinib for progressive pediatric low-grade gliomas.

INTRODUCTION: Pediatric pilocytic astrocytomas (PAs) are low grade gliomas and the most common brain tumors in children. They often represent a therapeutic challenge when incompletely resected as they can recur and progress despite the use of several lines of chemotherapeutic agents or even radiation therapy. Genetic alterations leading to activation of the mitogen-activated-protein-kinase pathway are a hallmark of this disease and offer an interesting therapeutic alternative through the use of targeted inhibitors. METHODS: Here, we describe six children with sporadic PA who were treated with trametinib, a MEK inhibitor, following progression under conventional therapies. Retrospective chart review was performed. RESULTS: The median age at diagnosis was 2.3 years (y) old [range 11 months (m)-8.5 y old]. KIAA1549-BRAF fusion was identified in five cases, and hotspot FGFR1/NF1/PTPN11 mutations in one. All patients received at least one previous line of chemotherapy (range 1-4). The median time on treatment was 11 m (range 4-20). Overall, we observed two partial responses and three minor responses as best response; three of these patients are still on therapy. Treatment was discontinued in the patient with progressive disease. The most frequent toxicities were minor to moderately severe skin rash and gastro-intestinal symptoms. Two patients had dose reduction due to skin toxicity. Quality of life was excellent with decreased hospital visits and a close to normal life. CONCLUSION: Trametinib appears to be a suitable option for refractory pediatric low-grade glioma and warrants further investigations in case of progression.

Carboplatin and vincristine neurotoxicity in the treatment of pediatric low-grade gliomas.

BACKGROUND: Pediatric low-grade gliomas (LGG) represent 30-50% of central nervous system pediatric tumors. Over the last decades, the combination of carboplatin and vincristine (CV) has become the first line of treatment in most centers. In a large clinical trial where the efficacy of CV was compared to another regimen, 19% presented grade III neurotoxicity. Despite the fact that CV therapy is widely used for pediatric patients with LGG, no study has reported detailed neurological adverse events and outcome with this treatment regimen. The purpose of this retrospective study is to better understand neurotoxicity associated with CV. PROCEDURE: We conducted a retrospective study to better evaluate the incidence and evolution of neurotoxicity associated with CV in patients with LGG. RESULTS: Twenty-one pediatric patients were treated with CV at our single institution over 16 years. Most patients had optic glioma. Peripheral neuropathy was present in most patients (86%). Eight patients (38%) had a dose reduction of vincristine due to grade III toxicity (three motor neuropathies, three sensory neuropathies, one constipation, and one dysphagia). Most neurotoxicity occurred during induction or the first maintenance cycle. No ototoxicity was observed during treatment or follow-up. CONCLUSIONS: In our study, neurotoxicity with vincristine occurred two times more frequently than in previously published literature. Careful neurological assessment is important to detect neurotoxicity, especially during induction. The high incidence of neurotoxicity should be considered when selecting a chemotherapy regimen for pediatric LGG.

Survival in pediatric medulloblastoma: a population-based observational study to improve prognostication.

Medulloblastoma is the most common form of brain malignancy of childhood. The mainstay of epidemiological data regarding childhood medulloblastoma is derived from case series, hence population-based studies are warranted to improve the accuracy of survival estimates. To utilize a big-data approach to update survival estimates in a contemporary cohort of children with medulloblastoma. We performed a population-based retrospective observational cohort study utilizing the Surveillance, Epidemiology, and End Results Program database that captures all children, less than 20 years of age, between 1973 and 2012 in 18 geographical regions representing 28% of the US population. We included all participants with a presumed or histologically diagnosis of medulloblastoma. The main outcome of interest is survivors at 1, 5 and 10 years following diagnosis. A cohort of 1735 children with a median (interquartile range) age at diagnosis of 7 (4-11) years, with a diagnosis of medulloblastoma were identified. The incidence and prevalence of pediatric medulloblastoma has remained stable over the past 4 decades. There is a critical time point at 1990 when the overall survival has drastically improved. In the contemporary cohort (1990 onwards), the percentage of participants alive was 86, 70 and 63% at 1, 5 and 10 years, respectively. Multivariate Cox-Regression model demonstrated Radiation (HR 0.37; 95% CI 0.30-0.46, p < 0.001) and Surgery (HR 0.42; 95% CI 0.30-0.58, p < 0.001) independently predict survival. The probability of mortality from a neurological cause is <5% in patients who are alive 8 years following diagnosis. The SEER cohort analysis demonstrates significant improvements in pediatric medulloblastoma survival. In contrast to previous reports, the majority of patients survive in the modern era, and those alive 8 years following initial diagnosis are likely a long-term survivor. The importance of minimizing treatment-related toxicity is increasingly apparent given the likelihood of long-term survival.

Prognostic value of medulloblastoma extent of resection after accounting for molecular subgroup: a retrospective integrated clinical and molecular analysis.

BACKGROUND: Patients with incomplete surgical resection of medulloblastoma are controversially regarded as having a marker of high-risk disease, which leads to patients undergoing aggressive surgical resections, so-called second-look surgeries, and intensified chemoradiotherapy. All previous studies assessing the clinical importance of extent of resection have not accounted for molecular subgroup. We analysed the prognostic value of extent of resection in a subgroup-specific manner. METHODS: We retrospectively identified patients who had a histological diagnosis of medulloblastoma and complete data about extent of resection and survival from centres participating in the Medulloblastoma Advanced Genomics International Consortium. We collected from resections done between April, 1997, and February, 2013, at 35 international institutions. We established medulloblastoma subgroup affiliation by gene expression profiling on frozen or formalin-fixed paraffin-embedded tissues. We classified extent of resection on the basis of postoperative imaging as gross total resection (no residual tumour), near-total resection (<1·5 cm(2) tumour remaining), or sub-total resection (≥1·5 cm(2) tumour remaining). We did multivariable analyses of overall survival and progression-free survival using the variables molecular subgroup (WNT, SHH, group 4, and group 3), age (<3 vs ≥3 years old), metastatic status (metastases vs no metastases), geographical location of therapy (North America/Australia vs rest of the world), receipt of chemotherapy (yes vs no) and receipt of craniospinal irradiation (<30 Gy or >30 Gy vs no craniospinal irradiation). The primary analysis outcome was the effect of extent of resection by molecular subgroup and the effects of other clinical variables on overall and progression-free survival. FINDINGS: We included 787 patients with medulloblastoma (86 with WNT tumours, 242 with SHH tumours, 163 with group 3 tumours, and 296 with group 4 tumours) in our multivariable Cox models of progression-free and overall survival. We found that the prognostic benefit of increased extent of resection for patients with medulloblastoma is attenuated after molecular subgroup affiliation is taken into account. We identified a progression-free survival benefit for gross total resection over sub-total resection (hazard ratio [HR] 1·45, 95% CI 1·07-1·96, p=0·16) but no overall survival benefit (HR 1·23, 0·87-1·72, p=0·24). We saw no progression-free survival or overall survival benefit for gross total resection compared with near-total resection (HR 1·05, 0·71-1·53, p=0·8158 for progression-free survival and HR 1·14, 0·75-1·72, p=0·55 for overall survival). No significant survival benefit existed for greater extent of resection for patients with WNT, SHH, or group 3 tumours (HR 1·03, 0·67-1·58, p=0·89 for sub-total resection vs gross total resection). For patients with group 4 tumours, gross total resection conferred a benefit to progression-free survival compared with sub-total resection (HR 1·97, 1·22-3·17, p=0·0056), especially for those with metastatic disease (HR 2·22, 1·00-4·93, p=0·050). However, gross total resection had no effect on overall survival compared with sub-total resection in patients with group 4 tumours (HR 1·67, 0·93-2·99, p=0·084). INTERPRETATION: The prognostic benefit of increased extent of resection for patients with medulloblastoma is attenuated after molecular subgroup affiliation is taken into account. Although maximum safe surgical resection should remain the standard of care, surgical removal of small residual portions of medulloblastoma is not recommended when the likelihood of neurological morbidity is high because there is no definitive benefit to gross total resection compared with near-total resection. FUNDING: Canadian Cancer Society Research Institute, Terry Fox Research Institute, Canadian Institutes of Health Research, National Institutes of Health, Pediatric Brain Tumor Foundation, and the Garron Family Chair in Childhood Cancer Research.

Surveillance imaging in children with malignant CNS tumors: low yield of spine MRI.

Magnetic resonance imaging (MRI) is routinely obtained in patients with central nervous system (CNS) tumors, but few studies have been conducted to evaluate this practice. We assessed the benefits of surveillance MRI and more specifically spine MRI in a contemporary cohort. We evaluated MRI results of children diagnosed with CNS tumors from January 2000 to December 2011. Children with at least one surveillance MRI following the diagnosis of medulloblastoma (MB), atypical teratoid rhabdoid tumor (ATRT), pineoblastoma (PB), supratentorial primitive neuroectodermal tumor, supratentorial high-grade glioma (World Health Organization grade III-IV), CNS germ cell tumors or ependymoma were included. A total of 2,707 brain and 1,280 spine MRI scans were obtained in 258 patients. 97% of all relapses occurred in the brain and 3% were isolated to the spine. Relapse was identified in 226 (8%) brain and 48 (4%) spine MRI scans. The overall rate of detecting isolated spinal relapse was 9/1,000 and 7/1,000 for MB patients. MRI performed for PB showed the highest rate for detecting isolated spinal recurrence with 49/1,000. No initial isolated spinal relapse was identified in patients with glioma, supratentorial primitive neuroectodermal tumor and ATRT. Isolated spinal recurrences are infrequent in children with malignant CNS tumors and the yield of spine MRI is very low. Tailoring surveillance spine MRI to patients with higher spinal relapse risk such as PB, MB with metastatic disease and within 3 years of diagnosis could improve allocation of resources without compromising patient care.

Recurrence patterns across medulloblastoma subgroups: an integrated clinical and molecular analysis.

BACKGROUND: Recurrent medulloblastoma is a therapeutic challenge because it is almost always fatal. Studies have confirmed that medulloblastoma consists of at least four distinct subgroups. We sought to delineate subgroup-specific differences in medulloblastoma recurrence patterns. METHODS: We retrospectively identified a discovery cohort of all recurrent medulloblastomas at the Hospital for Sick Children (Toronto, ON, Canada) from 1994 to 2012 (cohort 1), and established molecular subgroups using a nanoString-based assay on formalin-fixed paraffin-embedded tissues or frozen tissue. The anatomical site of recurrence (local tumour bed or leptomeningeal metastasis), time to recurrence, and survival after recurrence were assessed in a subgroup-specific manner. Two independent, non-overlapping cohorts (cohort 2: samples from patients with recurrent medulloblastomas from 13 centres worldwide, obtained between 1991 and 2012; cohort 3: samples from patients with recurrent medulloblastoma obtained at the NN Burdenko Neurosurgical Institute [Moscow, Russia] between 1994 and 2011) were analysed to confirm and validate observations. When possible, molecular subgrouping was done on tissue obtained from both the initial surgery and at recurrence. RESULTS: Cohort 1 consisted of 30 patients with recurrent medulloblastomas; nine with local recurrences, and 21 with metastatic recurrences. Cohort 2 consisted of 77 patients and cohort 3 of 96 patients with recurrent medulloblastoma. Subgroup affiliation remained stable at recurrence in all 34 cases with available matched primary and recurrent pairs (five pairs from cohort 1 and 29 pairs from cohort 2 [15 SHH, five group 3, 14 group 4]). This finding was validated in 17 pairs from cohort 3. When analysed in a subgroup-specific manner, local recurrences in cohort 1 were more frequent in SHH tumours (eight of nine [89%]) and metastatic recurrences were more common in group 3 and group 4 tumours (17 of 20 [85%] with one WNT, p=0·0014, local vs metastatic recurrence, SHH vs group 3 vs group 4). The subgroup-specific location of recurrence was confirmed in cohort 2 (p=0·0013 for local vs metastatic recurrence, SHH vs group 3 vs group 4,), and cohort 3 (p<0·0001). Treatment with craniospinal irradiation at diagnosis was not significantly associated with the anatomical pattern of recurrence. Survival after recurrence was significantly longer in patients with group 4 tumours in cohort 1 (p=0·013) than with other subgroups, which was confirmed in cohort 2 (p=0·0075), but not cohort 3 (p=0·70). INTERPRETATION: Medulloblastoma does not change subgroup at the time of recurrence, reinforcing the stability of the four main medulloblastoma subgroups. Significant differences in the location and timing of recurrence across medulloblastoma subgroups have potential treatment ramifications. Specifically, intensified local (posterior fossa) therapy should be tested in the initial treatment of patients with SHH tumours. Refinement of therapy for patients with group 3 or group 4 tumours should focus on metastases.

Epidemiology of Pediatric Tumors in Quebec: A 17-Year Report of Cancer in Young People in the Canada Registry.

BACKGROUND: Cancer is the leading cause of disease-related death among children of more than 1 year of age. However, childhood cancer risk factors and etiology are yet to be fully understood. The goal of this study is to identify geographic variation among children and adolescents diagnosed with pediatric tumors between 2001 and 2018 in the province of Quebec. METHODS: We analyzed pediatric patients less than 15 years of age from the Cancer in Young People in Canada (CYP-C) surveillance system who were diagnosed between 2001 and 2018 with cancer in the province of Quebec. The age-standardized age-adjusted incidence rates (AAIR) per 100,000 person years were calculated for all childhood cancers by cancer subgroups, Quebec Health regions, and age groups. RESULTS: Overall, 3904 pediatric patients less than 15 years old were diagnosed with cancer in the province of Quebec in 2001-2018. The overall incidence rate (IR) in the province of Quebec was 16.14 (95%CL [15.56-16.73]) per 100,000 person years. For childhood cancers, regions that presented a higher AAIR were Chaudière-Appalaches and Capitale-Nationale with 18.2 and 17.5 per 100,000 person years, respectively. The incidence rates (IRs) in Chaudière-Appalaches (95% CI 1.0439-1.3532) and in Capitale-Nationale (95% CI 1.0124-1.2942) were statistically higher than the incidence in the province of Quebec (p = 0.0090 and p = 0.0310, respectively). When comparing the AAIR of the CNS tumor subgroup in Chaudière-Appalaches and in Capitale-Nationale, with the provincial average, we noticed a statistically higher incidence in Chaudière-Appalaches and a trend for Capitale-Nationale (p < 0.0001 and p = 0.0602, respectively). CONCLUSION: There is evidence of spatial clusters in Chaudière-Appalaches and Capitale-Nationale as areas for all childhood cancers. Further studies should be performed to investigate potential risk factors in these regions.