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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.

Background: Low- and middle-income countries sustain the majority of pediatric cancer burden, with significantly poorer survival rates compared to high-income countries. Collaboration between institutions in low- and middle-income countries and high-income countries is one of the ways to improve cancer outcomes., Methods: Patient characteristics and effects of a pediatric neuro-oncology twinning program between the Hospital for Sick Children in Toronto, Canada and several hospitals in Karachi, Pakistan over 7 years are described in this article., Results: A total of 460 patients were included in the study. The most common primary central nervous system tumors were low-grade gliomas (26.7%), followed by medulloblastomas (18%), high-grade gliomas (15%), ependymomas (11%), and craniopharyngiomas (11.7%). Changes to the proposed management plans were made in consultation with expert physicians from the Hospital for Sick Children in Toronto, Canada. On average, 24% of the discussed cases required a change in the original management plan over the course of the twinning program. However, a decreasing trend in change in management plans was observed, from 36% during the first 3.5 years to 16% in the last 3 years. This program also led to the launch of a national pediatric neuro-oncology telemedicine program in Pakistan., Conclusions: Multidisciplinary and collaborative efforts by experts from across the world have aided in the correct diagnosis and treatment of children with brain tumors and helped establish local treatment protocols. This experience may be a model for other low- and middle-income countries that are planning on creating similar programs., (© 2022 Wiley Periodicals LLC.)

Background: The COVID-19 pandemic has had a major impact on access to health care resources. Our objective was to estimate the impact of the COVID-19 pandemic on the incidence of childhood cancer in Canada. We also aimed to compare the proportion of patients who enrolled in clinical trials at diagnosis, presented with metastatic disease or had an early death during the first 9 months of the COVID-19 pandemic compared with previous years., Methods: We conducted an observational study that included children younger than 15 years with a new diagnosis of cancer between March 2016 and November 2020 at 1 of 17 Canadian pediatric oncology centres. Our primary outcome was the monthly age-standardized incidence rates (ASIRs) of cancers. We evaluated level and trend changes using interventional autoregressive integrated moving average models. Secondary outcomes were the proportion of patients who were enrolled in a clinical trial, who had metastatic or advanced disease and who died within 30 days. We compared the baseline and pandemic periods using rate ratios (RRs) and 95% confidence intervals (CIs)., Results: Age-standardized incidence rates during COVID-19 quarters were 157.7, 164.6, and 148.0 per million, respectively, whereas quarterly baseline ASIRs ranged between 150.3 and 175.1 per million (incidence RR 0.93 [95% CI 0.78 to 1.12] to incidence RR 1.04 [95% CI 0.87 to 1.24]). We found no statistically significant level or slope changes between the projected and observed ASIRs for all new cancers (parameter estimate [β], level 4.98, 95% CI -15.1 to 25.04, p = 0.25), or when stratified by cancer type or by geographic area. Clinical trial enrolment rate was stable or increased during the pandemic compared with baseline (RR 1.22 [95% CI 0.70 to 2.13] to RR 1.71 [95% CI 1.01 to 2.89]). There was no difference in the proportion of patients with metastatic disease (RR 0.84 [95% CI 0.55 to 1.29] to RR 1.22 [0.84 to 1.79]), or who died within 30 days (RR 0.16 [95% CI 0.01 to 3.04] to RR 1.73 [95% CI 0.38 to 15.2])., Interpretation: We did not observe a statistically significant change in the incidence of childhood cancer, or in the proportion of children enrolling in a clinical trial, presenting with metastatic disease or who died early during the first 9 months of the COVID-19 pandemic, which suggests that access to health care in pediatric oncology was not reduced substantially in Canada., Competing Interests: Competing interests: None declared., (© 2021 CMA Joule Inc. or its licensors.)

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.

Introduction: The study objectives were to describe patterns of practice for intracranial germ cell tumors (IGCT) in adolescents and young adults (AYA) and to determine factors associated with practice patterns., Methods: A survey was written containing questions on the management of two 17-year old males, one with localized pineal germinoma and the other with localized pineal non-germinomatous germ cell tumor (NGGCT). An invitation to participate anonymously in the survey was e-mailed to 119 oncologists who treat brain tumors across Canada., Results: Seventy-two (61%) of the 119 oncologists participated in the study. For the germinoma case, the most common treatment approaches were whole ventricular radiotherapy (WVRT) and chemotherapy (CH) (56%), WVRT alone (15%), and craniospinal radiotherapy (CSRT) alone (10%); for physicians recommending WVRT + CH, most frequently selected whole ventricular doses were 24 Gy (57%) and 18 Gy (20%). Chemotherapy was included in the treatment of germinoma by 96% of pediatric physicians vs. 54% of adult physicians (P = 0.001). The most common treatment approaches for NGGCT were CSRT + CH (44%), WVRT + CH (21%), and pineal gland RT + CH (15%). The selection of craniospinal vs. smaller-volume RT was not associated with the physicians' specialty, percentage of practice treating brain tumors, number of IGCTs seen, or size of institution., Conclusions: There is wide variation in the management of IGCT in AYA across Canada. A 17-year old male with a localized pineal germinoma is highly likely to receive chemotherapy if managed by a pediatric oncologist, while the same patient is much less likely to receive chemotherapy if managed by an adult oncologist.

Combining mammalian target of rapamycin (mTOR) inhibitors and vinca alkaloids has shown therapeutic synergy in xenograft models of pediatric cancers. This phase I study assessed safety and toxicity of temsirolimus in combination with vinblastine in children., Procedure: Patients ≥ 1 and ≤ 18 years with recurrent/refractory solid or CNS tumors were eligible. Vinblastine (4 mg/m 2 ) and temsirolimus (15 mg/m 2 ) were administered i.v. weekly, with planned dose escalation of vinblastine using a rolling six phase I design. Pharmacokinetic and pharmacodynamic data were collected., Results: Seven patients with median age 12 years (range, 8-18 years) were enrolled; all were evaluable for toxicity and six for response. At dose level 1, four of six patients developed grade 3 mucositis, of which one met duration criteria for dose-limiting toxicity (DLT). Four patients required dose omissions for grade 3 or 4 hematologic toxicity, including one prolonged neutropenia DLT. A subsequent patient was enrolled on dose level -2 (temsirolimus 10 mg/m 2 , vinblastine 4 mg/m 2 ) with no protocol-related toxicity > grade 1, except grade 2 neutropenia. Two serious adverse events (SAE) occurred-an allergic reaction to temsirolimus (grade 2) and an intracranial hemorrhage in a CNS tumor patient (grade 3)-unlikely related to study therapy. Soluble VEGFR2 was reduced at cycle 1, day 36 in keeping with inhibition of angiogenesis. Four patients achieved prolonged stable disease for a median of 5.0 months (range, 3.1-8.3 months)., Conclusion: The combination of weekly temsirolimus (15 mg/m 2 ) and vinblastine (4 mg/m 2 ) exceeds the maximum tolerated dose in children, with frequent oral mucositis and hematologic toxicity., (© 2018 Wiley Periodicals, Inc.)

Background: Lack of pediatric palliative care (PPC) training impedes successful integration of PPC principles into pediatric oncology., Objectives: We examined the impact of an enhanced implementation of the Education in Palliative and End-of-Life Care for Pediatrics (EPEC ® -Pediatrics) curriculum on the following: (1) knowledge dissemination; (2) health professionals' knowledge; (3) practice change; and (4) quality of PPC., Design: An integrated knowledge translation approach was used with pre-/posttest evaluation of care quality. Setting/Subjects/Measurements: Regional Teams of 3-6 health professionals based at 15 pediatric oncology programs in Canada became EPEC-Pediatrics Trainers who taught the curriculum to health professionals (learners) and implemented quality improvement (QI) projects. Trainers recorded the number of learners at each education session and progress on QI goals. Learners completed knowledge surveys. Care quality was assessed through surveys with a cross-sectional sample of children with cancer and their parents about symptoms, quality of life, and care quality plus reviews of deceased patients' health records., Results: Seventy-two Trainers taught 3475 learners; the majority (96.7%) agreed that their PPC knowledge improved. In addition, 10/15 sites achieved practice change QI goals. The only improvements in care quality were an increased number of days from referral to PPC teams until death by a factor of 1.54 (95% confidence interval [CI] = 1.17-2.03) and from first documentation of advance care planning until death by a factor of 1.50 (95% CI = 1.06-2.11), after adjusting for background variables., Conclusion: While improvements in care quality were only seen in two areas, our approach was highly effective in achieving knowledge dissemination, knowledge improvement, and practice change goals.

Objective: Clinical trials have failed to demonstrate a survival benefit of adjuvant chemotherapy in diffuse intrinsic pontine gliomas (DIPG). Radiation therapy (RT) is the only effective treatment thus far and reirradiation (rRT) has become an option at the time of progression. The aim of this study was to review the Canadian experience of DIPG rRT with a focus on the safety and possible efficacy of this approach., Method: We retrospectively reviewed the demographic, clinical, and RT data of patients with DIPG treated in Canada with rRT., Results: Since January 2011, we identified 16 patients with progressive DIPG who received rRT. Median time from diagnosis to progression was 10.5 months (range, 4-37 months). rRT was given focally in 14 patients at a dose ranging from 21.6 to 36 Gy. rRT was well tolerated by all children but one. All but three patients showed neurological improvement. With a median follow-up from original diagnosis of 19.2 months, all patients died, with a median time from rRT to death of 6.48 months (range, 3.83-13.26 months). When compared to a historic cohort of 46 consecutive patients, the median time from progression to death was 92 days in the non-reirradiated patients versus 218 days in the reirradiated ones (P = 0.0001)., Conclusion: In this limited experience, rRT was safe and feasible in patients with progressive DIPG, providing neurological improvement and a prolonged life span in most patients. Prospective Canadian rRT protocols are ongoing to further assess the benefit of this approach, including quality of life assessment., (© 2018 Wiley Periodicals, Inc.)

Medulloblastoma is the most common malignant brain tumor in children. Published survival rates for this tumor are ∼70%; however, there is limited published information on outcome after disease recurrence. This was an observational study which included all persons under the age of 18 years diagnosed with medulloblastoma from 1990 to 2009 inclusive in Canada. Data collected included date of diagnosis, age at diagnosis, sex, stage, pathology, treatment, recurrence, and current status. Survival rates were determined. In total, 550 cases were ascertained meeting the study criteria. The overall survival rate at 1 year was 83.6%±1.7%, at 3 years 77.2%±1.9%, and at 5 years 72.5%±20%. The progression-free survival rates were 78%±1.9%, 70%±2.1%, and 69±2.1% at 1, 3, and 5 years from initial diagnosis. In total, 173 (31.2%) were reported to have had tumor recurrence and 23 (11.4%) of them were alive at the time of survey with an overall survival rate at 1 year of 38.3%±4%, at 2 years of 16.9%±3.3%, and at 5 years of 12.4%±2.8%. Our data confirm that children with recurrent medulloblastoma have a poor prognosis, supporting the need for novel treatment approaches for this group.

OBJECT Primary CNS sarcomas are very rare pediatric tumors with no defined standard of care. METHODS This study was a retrospective review of children diagnosed with a primary CNS sarcoma and treated at 2 Canadian tertiary care centers between 1995 and 2012. This report focuses on patients with cerebral hemispheric tumor location due to their specific clinical presentation. RESULTS Fourteen patients with nonmetastatic primary CNS sarcoma were identified; in 9 patients, tumors were located in the cerebral hemisphere and 7 of these patients presented with intratumoral hemorrhage. One infant who died of progressive disease postoperatively before receiving any adjuvant therapy was not included in this study. The final cohort therefore included 8 patients (4 males). Median patient age at diagnosis was 11.8 years (range 5.8-17 years). All tumors were located in the right hemisphere. Duration of symptoms prior to diagnosis was very short with a median of 2 days (range 3-7 days), except for 1 patient. Three (37.5%) patients had an underlying diagnosis of neurofibromatosis Type 1 (NF1). Gross-total resection was achieved in 5 patients. The dose of focal radiation therapy (RT) ranged between 54 Gy and 60 Gy. Concomitant etoposide was administered during RT. ICE (ifosfamide, carboplatin, etoposide) chemotherapy was administered prior to and after RT for a total of 6-8 cycles. Seven of the 8 patients were alive at a median time of 4.9 years (range 1.9-17.9 years) after treatment. CONCLUSIONS In this retrospective series, patients with primary CNS sarcomas located in the cerebral hemisphere most commonly presented with symptomatic acute intratumoral hemorrhage. Patients with NF1 were overrepresented. The combination of adjuvant ICE chemotherapy and focal RT provided encouraging outcomes.

Background: There are identified gaps in the care provided to children with cancer based on the self-identified lack of education for health care professionals in pediatric palliative care and in the perceptions of bereaved parents who describe suboptimal care. In order to address these gaps, we will implement and evaluate a national roll-out of Education in Palliative and End-of-Life Care for Pediatrics (EPEC®-Pediatrics), using a 'Train-the-Trainer' model., Methods/design: In this study we are using a pre- post-test design and an integrated knowledge translation approach to assess the impact of the educational roll-out in four areas: 1) self-assessed knowledge of health professionals; 2) knowledge dissemination outcomes; 3) practice change outcomes; and 4) quality of palliative care. The quality of palliative care will be assessed using data from three sources: a) parent and child surveys about symptoms, quality of life and care provided; b) health record reviews of deceased patients; and c) bereaved parent surveys about end-of-life and bereavement care. After being trained in EPEC®-Pediatrics, 'Master Facilitators' will train 'Regional Teams' affiliated with 16 pediatric oncology programs in Canada. Each team will consist of three to five health professionals representing oncology, palliative care, and the community. Each team member will complete online modules and attend one of two face-to-face conferences, where they will receive training and materials to teach the EPEC®-Pediatrics curriculum to 'End-Users' in their region. Regional Teams will also choose a Tailored Implementation of Practice Standards (TIPS) Kit to guide implementation of a quality improvement project in their region; support will be provided via quarterly meetings with Co-Leads and via a listserv and webinars with other teams., Discussion: Through this study we aim to raise the level of pediatric palliative care education amongst health care professionals in Canada. Our study will be a significant step forward in evaluation of the impact of EPEC®-Pediatrics both on dissemination outcomes and on care quality at a national level. Based on the anticipated success of our project we hope to expand the EPEC®-Pediatrics roll-out to health professionals who care for children with non-oncological life-threatening conditions.

The treatment of medulloblastoma, the most common malignant brain tumor in children, has evolved over the last few decades. The objectives of this paper were to determine the survival of pediatric medulloblastoma in Canada, to determine if there has been an improvement in the survival rates between the years of 1990 and 2009, inclusive, and to determine prognostic factors for survival. All patients under the age of 18 years diagnosed with medulloblastoma from 1990 to 2009, inclusive, in Canada were included. Data collected included date of diagnosis, age at diagnosis, gender, stage, pathology, treatment, recurrence and current status. From these, survival rates were determined. Data were obtained on 628 eligible patients. The overall 5-year survival rate for the study time period was 69.2 ± 3.3 %. The survival rate increased during the interval of 1996-2000, then remained stable; 1990-1994: 60.2 ± 4.3 %; 1995-1999: 73.2 ± 3.5 %; 2000-2004: 68.8 ± 3.7 %; and 2005-2009: 72.1 ± 4.9 %, p = 0.05. Children over 14 years of age had a significantly better overall survival than those age 5-14 and those under 5 (85.7 ± 5.5 % vs 76.1 ± 2.7 % and 60.8 ± 3 % respectively, p = 0.001). Histologic medulloblastoma subtype and M stage of disease did not result in significant differences in survival. Despite changes in approaches to therapy, we demonstrate a steady survival rate for children with medulloblastoma after 1996. In our analyses, age over 14 years was associated with a higher survival rate.

In children under the age of 3 years, the most common solid tumors are brain tumors. Low grade astrocytomas represent 30-40 % of brain tumours in this age group. This study reviewed the incidence, characteristics, therapy, and outcome of children less than 36 months of age diagnosed with a low grade astrocytoma from 1990 to 2005 in Canada. A data bank was established using data collected from Canadian pediatric oncology centers on children less than age 3 diagnosed with brain tumors between 1990 and 2005. Cases of low grade astrocytoma were extracted from this data bank and their characteristics summarized. From the 579 cases in the data bank, 153 cases of low grade astrocytoma (26 %) were identified. The mean duration of symptoms prior to presentation was 13 weeks, and 53 % of patients underwent a greater than 90 % resection of their tumor, while 30 % underwent 10-90 % resection. Seventy-one percent of patients received no further therapy after surgery and of the 45 who received therapy following surgery, 43 received chemotherapy, and 5 received radiation therapy. Sixty-eight patients had recurrence or progression of their tumor. Eighty-seven percent of patients were alive at the time of the survey with a 2 year survival rate of 95.3 ± 1.8 %, 5 year survival rate of 93.1 ± 2.1 % and 10 year survival rate of 89.1 ± 2.8 %. The 5 year survival rate for Canadian children less than 36 months of age with a low grade astrocytoma was 93.0 ± 2.8 % which is similar to that for older children with this tumor.

Background: Because atypical teratoid rhabdoid tumor(ATRT) is a rare disease of infancy carrying a grim prognosis, focus on long-term outcome, especially neurocognitive remained very limited. With new era of multimodality therapy, an increasing proportion of patients are now long-term survivors., Procedure: Retrospective review of neuropsychological (NP) status of survivors from the Canadian ATRT registry., Results: Among 77 patients diagnosed between 1995-2012, 16(22%) were survivors. Formal NP assessments were available in eight patients. Partial information on academic achievement was available on three additional patients. There were four girls and seven boys diagnosed at a median age of 27.5 months. Seven patients underwent complete resection and three had metastatic disease. All but one received sequential high dose chemotherapy. Five patients received intrathecal chemotherapy. Three patients underwent radiation. Median age at time of formal NP assessment was 7.6 years (3.9-9.8). Full Scale Intellectual Quotient (FSIQ) ranged from less than 50-119 (mean 78). Simple expressive and receptive language appeared relatively preserved. Three recently diagnosed patients (median time assessment from diagnosis 2.6 years (1.6-4.7)) had average to high average FSIQ, academic and visual spatial skills, visual, and verbal memory. Five other patients diagnosed earlier and tested at a median time of 4.9 years (3.3-8.3) post-diagnosis had a FSIQ ranging from <50 to 71. Approximately 50% of their scores were in the impaired range., Conclusion: Overall this cohort appears significantly impaired at school age despite the absence of systematic radiotherapy. Larger series focusing on neurocognitive outcome are needed in the current context where treatment strategies include adjuvant radiation., (© 2015 Wiley Periodicals, Inc.)

Medulloblastoma is the most common malignant brain tumor in children. There was a perception of pediatric neuro-oncologists that the incidence had declined in Canada. An epidemiological survey was undertaken to determine the incidence of this tumor in Canada and if a change had indeed occurred. All patients 14 years and under diagnosed with medulloblastoma from 1990 to 2009 inclusive in Canada were included. Data collected included date of diagnosis, age at diagnosis, gender, stage, pathology, treatment, recurrence and current status. Data were analysed for change in incidence over time. Data were obtained on 574 eligible patients. The mean overall incidence per 1,000,000 persons was 4.82 (95 % CI 4.28-5.35) for the study time period. The mean age at diagnosis was 5.8 years, and there was a male predominance. Although there was an increase in incidence over the first three time periods (24 % for 1990-1994, 27.5 % for 1995-1999, 27.7 % for 2000-2004), the most recent time period (2005-2009) showed a decrease (21 %). This was true for male children while the incidence was stable for females. The mean incidence rate was double for children under the age of 5 years (7.92 per million) compared to those over 5 years (3.64 per million).This study showed that from 1990 to 2009 the incidence of medulloblastoma was relatively stable, with a slight decrease in the last five-year time period.

Purpose: We describe parental attitudes toward the return of targeted and incidental genomic research results in the setting of high-risk pediatric cancer and inherited childhood diseases., Methods: A validated 36-item questionnaire was mailed to participants in three large-scale genome research consortia examining attitudes toward receipt of genomic research results and the influence of certainty, severity, and onset of the condition, in addition to responsibilities to extended family and provision of results even after death of the proband., Results: Of the 563 participants who were sent questionnaires, 362 (64%) responded. Most of them stated a positive right to receive results related to the target condition (97%) or to incidental findings (86%); no difference was found in results between participants with cancer and those with orphan diseases. Furthermore, 92% indicated that genomic research for childhood-onset conditions should occur. The majority wanted incidental results predicting susceptibility even to untreatable fatal conditions (83%), to multiple conditions (87%), or to those with uncertain impact (70%). Most felt sibling genomic results showing serious conditions, whether treatable (93%) or not (88%), and/or results discovered after death of the proband should be shared with family (74%)., Conclusion: Many parents of children in pediatric genomic research indicated a strong desire to receive a broader range of results than is described in consensus recommendations. Clear delineation of what will be offered should be established at the time of consent.

The determination of optimal therapy for ependymoma (EP) in infants is ongoing. We describe the incidence, management and outcomes of Canadian infants with EP to discern potential future research questions. Of 579 cases registered in a national database of children <36 months of age diagnosed with a brain tumor from 1990 to 2005, inclusive, 75 (13 %) were EP. These cases were analyzed. A mean annual age-adjusted incidence rate of 4.6 per 100,000 children years was calculated. The male:female ratio was 1.77. Of the tumors, 80 % were infratentorial in location, 67 % were WHO grade II histology, and 29 % were metastatic at diagnosis. All patients underwent a surgical procedure. A complete resection of the tumor was achieved in 56 % of the cases; 43 % of these patients survive while 36 % of the patients with tumors less than completely resected survive. Initial therapy consisted of surgery alone in 23 % of patients, or surgery plus chemotherapy (37 %), radiation therapy (RT; 19 %), or both (21 %). Any use of RT increased with patient age. The 5-year EFS rates for patients in each of the four treatment groups was 22, 11.5, 46.2 and 64.8 %, respectively. For all patients the median survival was 63 ± 6 months and 5-year overall survival was 55 ± 6 %. Patients treated with surgery and chemotherapy alone were younger and had a lower rate of survival than older patients who were more often treated with radiation therapy containing regimens. Further study is needed to determine which patients are optimally served with these treatment modalities.

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., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Purpose: The purpose of this study was to explore the attitudes of genomics researchers in a pediatric setting in the context of regulatory guidance recommending the disclosure of clinically significant research findings., Methods: A validated 32-item questionnaire was sent to 107 researchers with two large-scale projects (the Canadian Pediatric Cancer Genome Consortium and the Finding of Rare Genes Canada Consortium). We examined researchers' attitudes toward obligations to offer genomic research results (including if the participant was deceased, a relative, or a child), influence of the certainty/severity of the condition on this obligation, and personal experiences., Results: Of the 107 researchers, 74 (69%) responded. Researchers did not feel a strong responsibility to look for meaningful incidental results in the research genomic data set (n = 27, 37%). However, once identified, they felt participants had a strong right to receive them, irrespective of being incidental (n = 50, 68%) or primary targets (n = 64, 87%). There was a high degree of support for informing siblings of genomic results (n = 46, 62%), especially for treatable conditions (n = 56, 76%). Less than half of the participants indicated that their research ethics board required an offer of results (n = 34, 46%) or provided a detailed process (n = 16, 22%)., Conclusion: Researchers strongly support the offer of targeted and incidental genomic research results to participants. Greater regulatory guidance is needed for a consistent approach.

Background: Atypical teratoid rhabdoid tumours (ATRT) are aggressive brain tumours mostly occurring in early childhood. Largest published series arise from registries and institutional experiences (1-4). The aim of this report is to provide population-based data to further characterise this rare entity and to delineate prognostic factors., Patients and Methods: A national retrospective study of children ⩽18years diagnosed with a central nervous system (CNS) ATRT between 1995 and 2007 was undertaken. All cases underwent central pathology review., Results: There were 50 patients (31 males; median age at diagnosis of 16.7months). Twelve patients were >36months. Infratentorial location accounted for 52% of all cases. Nineteen patients (38%) had metastatic disease. Fifteen (30%) underwent gross total resection (GTR). Ten patients (20%) underwent palliation. Among the 40 remaining patients, 22 received conventional chemotherapy and 18 received high dose chemotherapy regimens (HDC); nine received intrathecal chemotherapy and 15 received adjuvant radiation. Thirty of the 40 treated patients relapsed/progressed at a median time of 5.5months (0-32). The median survival time of the entire cohort was 13.5months (1-117.5months). Age, tumour location and metastatic status were not prognostic. Patients with GTR had a better survival (2years overall survival (OS): 60%±12.6 versus 21.7%±8.5, p=0.03). HDC conferred better outcome (2years OS 47.9%±12.1 versus 27.3%±9.5, p=0.036). Upfront radiation did not provide survival benefit. Six of the 12 survivors (50%) did not receive radiation., Conclusion: The outcome of CNS ATRT remains poor. However, the use of HDC provides encouraging results. GTR is a significant prognostic factor. The role of adjuvant radiation remains unclear., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

This study explored impacts of an online support network for fathers of a child with a brain tumor. Evaluation comprised pre/post-intervention questionnaires, content analysis of online network postings, and post-intervention qualitative interviews. Findings suggest that this intervention was beneficial to fathers. Positive effects on paternal coping were demonstrated, as were opportunities to grapple with difficult issues related to having a child with a brain tumor. Fathers recommended a combined resource of online and face-to-support, including the development of a support network with a larger participant base. Implications for practice are examined.

Background: Tumors of the spinal cord are exceedingly rare in infancy and only a paucity of literature exists describing the spectrum of this disease and its management. The objectives of our study were to describe the demographic characteristics of spinal cord tumors (SCT) in children less than 3 years of age at diagnosis and to review their treatment and outcome., Methods: A national retrospective chart review was conducted on patients under the age of 3 years diagnosed with a primary tumor of the central nervous system (CNS) between 1990 and 2005 across Canada. Inclusion criteria were: age ≤ 3 years, histologic confirmation of the diagnosis, and residency in Canada. A centralized database was created and information regarding SCT was extracted., Results: Twenty-five of five hundred seventy-nine patients (4.3%) in the data bank had a SCT. The majority of tumors were low-grade astrocytomas (14/25). Leptomeningeal dissemination based on neuroradiologic imaging and/or cerebrospinal fluid cytology was present in five (20%) patients. The majority of patients underwent an incomplete surgical resection (52%). Most patients (64%) did not receive postoperative radiotherapy or chemotherapy. Seventy-two percent (18/25) developed recurrent/progression of disease. Overall 2- and 5-year survival for low- and high-grade malignancies was 93 ± 6.4% and 37.5 ± 17.1% respectively. Significant predictors of survival included mean duration of symptoms prior to initial diagnosis and recurrence/progression of disease., Conclusions: Relapse/progression of disease in infant SCT is frequent. Prolonged survival of low-grade tumors is possible with further therapy; however, the prognosis of high-grade malignancies remains poor.

Background: Choroid plexus tumors (CPT) are rare pediatric tumors. A population-based study on choroid plexus carcinoma (CPC) and choroid plexus papilloma (CPP) was carried out to describe the incidence, demographic, and outcome data and to identify potential prognostic factors., Methods: The CPT population from the Canadian databank of CNS tumor in children ≤ 36 months diagnosed between 1990 and 2005 was reviewed, Results: Out of the 579 reported cases of CNS tumors, 37 were CPT. The annual age-adjusted incidence rate was 0.22 + 0.12 (95% CI 0.16-0.28)/100,000 children < 3 years. There were 21 (56.7%) CPP and 16 (43.3.5%) CPC. Twenty patients (54%) were males. Median age at diagnosis was 7 months(range 0-30). Ten patients(62.5%) with CPC and one with CPP were metastatic at diagnosis. Twenty patients with CPP (95%) had a complete resection, whereas 6/16 CPC (37.5%) achieved a resection >90%. Fourteen CPC patients received adjuvant chemotherapy. None of the 37 patients received adjuvant radiation. At completion of survey, all CPP and five CPC were alive. Median survival time for CPC patients was 15 months (0-120). One death was related to intraoperative hemorrhage, another to chemotherapy-induced toxicity, and one to secondary AML. Age at diagnosis, degree of resection and metastatic status were not significant prognostic factors for CPC., Conclusion: By contrast to CPC, CPP have an excellent prognosis following surgery alone. Survival of CPC remains poor. However, these data may suggest adjuvant chemotherapy can alter the aggressive natural history of CPC. As with other rare CNS tumors, international collaboration is required to identify optimal therapy.

Purpose: To evaluate the safety, efficacy and pharmacokinetics of imatinib in children with recurrent or refractory central nervous system (CNS) tumours expressing KIT and/or PDGFRA., Methods: Nineteen patients aged 2-18 years, with recurrent or refractory CNS tumours expressing either of the target receptors KIT and/or PDGFRA (by immunohistochemistry) were eligible. Participants received imatinib orally at a dose of 440 mg/m(2)/day and toxicities and tumour responses were monitored. Serial blood and cerebrospinal fluid samples for pharmacokinetics were obtained in a subset of consenting patients. Frozen tumour samples were analysed retrospectively for KIT and PDGFRA gene amplification in a subset of patients for whom samples were available., Results: Common toxicities were lymphopaenia, neutropaenia, leucopaenia, elevated serum transaminases and vomiting. No intratumoural haemorrhages were observed. Although there were no objective responses to imatinib, four patients had long-term stable disease (SD) (38-104 weeks). Our results suggest a possible relationship between KIT expression and maintenance of SD with imatinib treatment; KIT immunopositivity was seen in only 58% (11/19) of study participants overall, but in 100% of patients with SD at 38 weeks. All patient tumours showed PDGFRA expression. Pharmacokinetic data showed a high interpatient variability, but corresponded with previously reported values., Conclusions: Imatinib at 440 mg/m(2)/day is relatively safe in children with recurrent CNS tumours, but induced no objective responses. Demonstration of SD in previously progressing patients (KIT-expressing) suggests cytostatic activity of imatinib.

Children under the age of 3 with medulloblastoma have an inferior survival to older children with this disease. This study reviewed the incidence, characteristics, therapy, and outcome of children less than 36 months of age diagnosed with medulloblastoma from 1990 to 2005 in Canada. Ninety-six cases were identified with a median age at diagnosis of 19.5 months. Forty-seven percent of patients had a complete resection, 25% a 90-95% near complete resection, 20% an incomplete (10-90%) resection, and 3% biopsy only. Therapy consisted of chemotherapy (90%), high dose chemotherapy with stem cell rescue (13%), and radiation therapy (21%). The median survival time was 45 +/- 13.82 months. There was no significant difference in survival when comparing patients with <90% resection versus >90% resection, nor when comparing the presence of metastases versus their absence. There was a significant increase in survival time in patients who received radiation therapy compared to those who were not treated with this modality, as well as for those who were over 18 months at diagnosis compared to those under 18 months.

Background: Carboplatin-based regimens have demonstrated activity in pediatric patients with low-grade glioma (LGG). However, carboplatin hypersensitivity reaction (Cb HSR) represents a common and limiting factor for the continuation of therapy., Methods: The objectives of this study were to describe the prevalence, characteristics, and management of Cb HSR and to detail their impact on outcome. The authors conducted a comprehensive, national, retrospective review of children who were diagnosed with LGG between 1985 and 2004 and received treatment with carboplatin., Results: One hundred five patients from 10 Canadian centers were included. The median patient age at diagnosis was 3.5 years (range, 0.3-16.8 years), and 33 patients (31.4%) had neurofibromatosis type 1. Carboplatin was administered monthly in 46 children and weekly in 59 children. Forty-four patients (41.9%) developed Cb HSR after a median of 10.5 infusions (range, 3-39 infusions). Cb HSR occurred significantly earlier among children on the weekly schedule (4.4 months vs 9.1 months; P = .02). The first allergic reaction was grade I or II in 36 patients (82%). The cumulative incidence of Cb HSR increased with the number of infusions, and there was no evidence of a plateau. The only predictive factor was being a girl rather than a boy (P = .02). Thirty-four of 44 patients with Cb HSR were re-exposed to carboplatin, and 24 of 34 patients (70.5%) had recurrent Cb HSR. A desensitization approach did not provide any advantage compared with premedication alone for altering Cb HSR. The median number of additional Cb infusions delivered was 4 (range, 0.5-34 infusions). The effect of Cb HSR on the 5-year progression-free survival rate was not statistically significant (P = .1)., Conclusions: Forty-two percent of children with LGG who received carboplatin regimens experienced Cb HSR. Most rechallenged children had recurrent Cb HSR despite Cb HSR-altering regimens. Cb HSR did not have an impact on progression-free survival., (Cancer 2008. (c) 2007 American Cancer Society.)

Introduction: Supratentorial primitive neuroectodermal tumors (SPNET) are rare tumors accounting for only 2.5% of childhood brain tumors. The purpose of this study was to describe the range of treatment regimens used to treat pediatric SPNET in Canada and to identify prognostic factors for overall survival in this population., Methods: This study was a retrospective clinical analysis of SPNET patients treated over the last 10 years in Canada. A questionnaire was developed and distributed to all institutions in Canada who treat pediatric patients. Data were collected for patients <19 years of age who were diagnosed and treated for SPNET between 1995 and 2005., Results: Data were obtained for 48 eligible patients. The stages of patients for whom complete data were provided were 80, 3, and 16% for metastatic stage M0, M1, and M2/3, respectively. The best responses to therapy included complete response in 44%, partial response in 8%, still on therapy in 2%, progressive disease in 31%, toxic death in 2%, and no therapy given in 12%. The 4-year survival was 37.7 +/- 7.6%. The factors associated with an increase in survival were the use of radiation therapy and chemotherapy, and age >2 years. Overall survival was not affected by metastatic disease at diagnosis, tumor site, or degree of initial resection., Conclusions: Survival is poor in SPNET patients but highest in those who received chemotherapy and radiation therapy. Further studies are needed to improve the survival of these patients.

Objectives: To determine the incidence and characteristics of pediatric patients with central nervous system (CNS) germ cell tumors (GCT) in Canada., Method: A national retrospective review of hospital charts was done on all patients with CNS GCT diagnosed between 1990 and 2004. Patients had to be under age 18 years at the time of diagnosis of a CNS germ cell tumor and be a resident of Canada. Information extracted included age and year of diagnosis, pathological diagnosis, location of tumor, evidence of disseminated disease at time of diagnosis and biological markers., Results: One hundred and twenty-one cases were identified (83 germinoma; 38 non-germinoma germ cell tumor). The mean annual incidence of CNS GCT was 1.06 per million children (0.7 per million for germinoma; 0.3 per million for NGGCT). Though yearly incidences varied, there was no clear trend to increased incidence. Male predominance was noted (2.4:1 for germinoma; 11:1 for NGGCT). The primary locations were the pineal and suprasellar regions. At the time of diagnosis, disseminated disease was not uncommon (22% germinoma; 32% NGGCT). Beta human gonadotrophin was elevated in the serum, cerebrospinal fluid (CSF) or both in 7% of patients with germinoma and 36% of patients with NGGCT. Elevation of alpha-fetoprotein in serum, CSF or both was seen in 34% of patients with NGGCT., Conclusion: The incidence of CNS germ cell tumors in Canadian children is similar to that observed in other Western countries.

Background and Purpose: Reports of secondary high-grade glioma (HGG) in survivors of childhood cancer are scarce. The aim of this study was to review the pattern of diagnosis, the treatment, and outcome of secondary pediatric HGG., Patients and Methods: We performed a multi-center retrospective study among the 17 paediatric institutions participating in the Canadian Pediatric Brain Tumour Consortium (CPBTC)., Results: We report on 18 patients (14 males, 4 females) treated in childhood for a primary cancer, who subsequently developed a HGG as a second malignancy. All patients had previously received radiation therapy +/- chemotherapy for either acute lymphoblastic leukaemia (n=9) or solid tumour (n=9). All HGG occurred within the previous radiation fields. At the last follow-up, 17 patients have died and the median survival time is 9.75 months., Conclusion: Although aggressive treatment seems to provide sustained remissions in some patients, the optimal management is still to be defined. Further documentation of such cases is necessary in order to better understand the pathogenesis, the natural history and the prevention of these tumours.

Malignancy is considered a contra-indication to organ donation, with a few possible exceptions. We present the case of a child with fatal intracranial hemorrhage from a primary brain tumor (PBT) whose organs were denied for transplant after recovery. We review the literature of organ donors with PBTs in the context of the current organ shortage and discuss the implications for the practicing oncologist. Transmission of donor brain tumor to organ recipients has been documented but the incidence appears to be very low. Risk factors for tumor transmission include underlying donor tumor histology, history of craniotomy and/or shunt placement, use of systemic chemotherapy and radiation therapy, and duration of disease prior to donation. Ongoing data collection by national registries will provide more information on the potential risk to organ recipients. It may be appropriate to expand the donor pool to include donors with PBTs in certain situations. The transplantation team ultimately decides upon the use of organs from specific donors. Many families will appreciate the opportunity to donate specific tissues even if solid organ transplantation is prohibited., (Copyright 2004 Wiley-Liss, Inc.)