Medulloblastoma (MB) is the most common malignant pediatric brain tumour, and is categorized into four molecular subgroups, with Group 3 MB having the worst prognosis due to the highest rate of metastatic dissemination and relapse. In this work, we describe the epigenetic regulator Bmi1 as a novel therapeutic target for treatment of recurrent Group 3 MB. Through comparative profiling of primary and recurrent MB, we show that Bmi1 defines a treatment-refractory cell population that is uniquely targetable by a novel class of small molecule inhibitors. We have optimized an in vivo mouse-adapted therapy model that has the advantage of generating recurrent, human, treatment-refractory MBs. Our preliminary studies showed that although chemoradiotherapy administered to mice engrafted with human MB showed reduction in tumour size, Bmi1 expression was enriched in the post-treatment residual tumour. Furthermore, we found that knockdown of Bmi1 in human recurrent MB cells decreases proliferation and self-renewing capacities of MB cells in vitro as well as both tumour size and extent of spinal leptomeningeal metastases in vivo. Oral administration of a potent Bmi1 inhibitor, PTC 028, resulted in a marked reduction in tumour burden and an increased survival in treatment cohort. Bmi1 inhibitors showed high specificity for MB cells and spared normal human neural stem cells, when treated with doses relevant for MB cells. As Group 3 medulloblastoma is often metastatic and uniformly fatal at recurrence, with no current or planned trials of targeted therapy, an efficacious agent such as Bmi1 inhibitor could be rapidly transitioned to clinical trials.

Background: Ataluren is the first drug to treat the underlying cause of nmDMD. Methods: ACT DMD is a Phase 3, randomized, double-blind study. Males 7-16 years with nmDMD and a screening six-minute walk distance (6MWD) ≥150 m and <80%-predicted were randomized to ataluren 40 mg/kg/day or placebo for 48 weeks. A pre-specified subgroup included patients with baseline 6MWD 300-400 m. A meta-analysis of the overall ACT DMD population and the ‘ambulatory decline phase’ subgroup of the Phase 2b study (those patients meeting ACT DMD entry criteria) was pre-specified in the statistical plan. Results: In the overall ACT DMD population (N=228), changes in TFTs favored ataluren over placebo: 10-meter walk/run, -1.2s (p=0.117); 4-stair climb, -1.8s (p=0.058); 4-stair descend, -1.8s (p=0.012). In the pre-specified subgroup (n=99), these differences increased to -2.1s, -3.6s, and -4.3s, respectively, and were statistically significant (p<0.01) for 4-stair climb and descend. Results are supported by the meta-analysis (N=291), which demonstrated significant differences (p<0.05) in 10-meter walk/run, 4-stair climb, 4-stair descend. Conclusions: TFT results showed a benefit for ataluren in ACT DMD, and a larger treatment effect in the pre-specified baseline 6MWD 300-400 m subgroup as well as the pre-specified meta-analysis of ACT DMD and the Phase 2b study decline subgroup.

Supported By: PTC Therapeutics Inc.

Brain tumors are the most common solid tumors in children in Canada. While technological advances have increased their survival rates, survivors of childhood brain tumors (SCBT) often develop obesity, which can reduce lifespan and quality of life. While adiposity is a known factor for cardiometabolic disorders in the general population, adiposity patterns in SCBT have not been determined. This study aims to investigate how adiposity patterns differ between SCBT and non-cancer controls, and how lifestyle and treatment factors may contribute to these patterns. Methods: Fifty-nine SCBT and 108 non-cancer controls were recruited from the clinics at McMaster Children’s Hospital. Sociodemographic and lifestyle details were collected using standardized tools to assess diet, physical activity, and sleep. Brain tumor type, location and treatment details were obtained from medical records. Total and visceral adiposity were determined by total fat mass (FM) as well as waist-to-hip (WHR) and waist-to-height ratio (WHTR). Results: SCBT have higher total and visceral adiposity, while BMI is similar to controls. Female SCBT who received radiotherapy and/or chemotherapy have higher adiposity. A dietary pattern of white bread and fried foods with low dark bread was positively associated with adiposity. Lower physical activity levels, but not sleep durations, were associated with higher adiposity. Conclusion: SCBT have higher visceral and total adiposity than non-cancer controls. Sex, chemoradiotherapy, high fat diet, and physical inactivity, can contribute to these adiposity patterns. These results provide multiple points of entry to design interventions that reduce adiposity, and may improve long-term outcomes in SCBT.

Background: Improved respiratory care of Duchenne muscular dystrophy (DMD) patients has unmasked cardiomyopathy as a major source of morbidity and mortality. There is currently no consensus regarding the management of DMD-associated cardiomyopathy (DMD-CM). The objective of this systematic review was to evaluate the efficacy of pharmacological therapies for prevention and management of DMD-CM, and determine the optimal timing to commence these interventions. Methods: A systematic search was conducted in October 2015 and updated in January 2016 using MEDLINE, EMBASE and CINAHL databases and 9 grey literature sources for studies evaluating the use of angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARB), beta-blockers (BB) or aldosterone antagonists (AA) in DMD patients. References of retrieved records were searched. Quality assessment was conducted using the Downs and Black Quality Assessment Checklist. PRISMA reporting guidelines were used. Results: The 11 included studies were of low methodological quality. However, the use of an ACEi, ARB, BB and AA tended to improve or preserve left ventricular systolic function and delay the progression of cardiomyopathy. Conclusions: While there is evidence supporting the use of heart failure medication in patients with DMD-CM, data regarding these interventions for delaying the onset of DMD-CM and when to initiate therapy is lacking.

To describe the epidemiology of children under age 3 diagnosed with central nervous system tumors in Canada. Case ascertainment: Retrospective observation study of children under age 3 diagnosed with neoplasm involving the central nervous system between 1990 and 2005 at 13 of the Canadian pediatric oncology centres. Results: Case ascertainment was 573 persons. Below 6 months of age at diagnosis, no gender difference was seen and the commonest location of tumor was supratentorial. Embryonal tumors were the commonest, increased head circumference and vomiting were the commonest presenting symptom and survival rates were poor. Over 6 months of age at diagnosis, male predominance occurred and commonest location of tumor was the cerebellum. The commonest tumor was astrocytic, vomiting was the commonest presenting symptom and survival was better than in the under 6-month age group. Conclusion: Over the study period, the incidence rate and degree of resection remained stable. A trend to increased survival in children with ependymal tumors occurred; while, with medulloblastoma, survival decreased.

Background: Acute flaccid paralysis (AFP) is notifiable in Canada with a differential diagnosis that includes a number of conditions. This analysis describes the epidemiology of AFP in Canadian youth less than 15 years old. Methods: Monthly active surveillance for AFP was conducted as part of the Canadian AFP Surveillance System. Results: From 1996 to 2014, 850 cases of AFP were reported, representing an average annual crude incidence rate of 0.77 cases per 100,000 youth less than 15 years old. The mean age of cases was 6.8 years (median 5.9 years). Nine percent had an abnormal neurological history and 53% had an acute respiratory illness within 30 days of onset. Fever occurred in 23% of cases, 96% experienced bilateral weakness, 21% had respiratory muscle involvement, and 26% had cranial nerve involvement. The average hospital length of stay was 13.5 days. The most common diagnoses were Guillain-Barré Syndrome (GBS) or a variant (70%), and transverse myelitis (TM, 14%). At the time of the initial report, 14% had fully recovered. Conclusions: Our AFP surveillance system provides a baseline for AFP and its causes in the Canadian paediatric population. While rare, AFP is associated with severe morbidity in youth. GBS and TM were the most common diagnoses.

Proton beam therapy (PBT) offers compelling advantages in physical dose distribution compared to photon therapy. There are increasing numbers of gantry-based proton facilities worldwide but no such facilities exist in Canada. To access PBT, Canadian patients must travel abroad for treatment at high cost. In the face of limited access, this report seeks to provide recommendations for the selection of patients most likely to benefit from PBT and suggests an out-of-country referral process. METHODS: A systematic literature search for studies between January 1990 and May 2014 evaluating clinical outcomes after PBT. A draft report was developed through review of evidence, externally reviewed, and approved by the Alberta Health Services Cancer Care Proton Therapy Guidelines steering committee. RESULTS: Proton therapy is often used to treat tumours close to radiosensitive tissues, and children at risk of developing significant late effects of radiation therapy (RT). Local control rates with PBT appear similar to or, in some cases, higher than photon RT in uncontrolled and retrospective studies. Randomized trials comparing equivalent doses of PBT and photon RT are not available. SUMMARY: Referral for PBT is recommended for patients being treated with curative intent, with an expectation for long-term survival, and who are able and willing to travel abroad to a proton facility. Commonly accepted indications for referral include chordoma and chondrosarcoma, intraocular melanoma, and solid tumours in children and adolescents occurring in patients with greatest risk of long-term sequelae. Current data do not provide sufficient evidence to recommend routine referral of patients with most head and neck, breast, lung, gastrointestinal tract, and pelvic cancers including prostate cancer. It is recommended that all referrals be considered by a multidisciplinary team to select appropriate cases.

Background: Cerebral Palsy (CP) is a neurological condition arising from a perinatal or intra-uterine stroke. In the past 25 years there has been a revolution in neonatal care. For over 40 years children with CP in and around Saskatoon have been treated through the Kinsman Childrens’ Centre (KCC). This is a unique population database covering all CP patients in the region. We analyzed the KCC database to determine if the recent changes in neonatal care were correlated with the incidence of CP co-morbidities. Methods: A retrospective study using a Saskatchewan database of cerebral palsy data from the last four decades. Results: Over the last 40 years the incidence of visual disturbance and diagnoses of epilepsy in children with CP have remained stable regardless of advances in neonatal care. However, incidences of spine and hip issues requiring orthopedic intervention have halved. Conclusions: We hypothesize that advances in neonatal care have been successful in decreasing the incidence of gross motor impairments however have yet to significantly impact impairments relating to cortical network function. Although improvements in care have resulted in a decreased burden of disability, there remains opportunity for further improvements, especially in the settings of epilepsy and long-term visual function.

Background: Stroke leads to a substantial societal economic burden. We aimed to characterize productivity and factors associated with employability in Canadian stroke survivors. Methods: We used the Canadian Community Health Survey (CCHS) 2010-2011 to identify stroke survivors and employment status. We used multivariable models to determine the impact of stroke on employment and factors associated with employability. We used the Heckman model to estimate the effect of stroke on productivity (number of hours worked/week and hourly wages). Results: We included data from 91,633 respondents between 18 and 70 years and identified 923 (1%) stroke survivors. Stroke survivors were less likely to be employed (adjusted Odds Ratio 0.39, 95% CI 0.33 to 0.46) and had hourly wages 17.7% (95% CI 8.3% to 27.1%) lower compared to the general population, although there was no association between work hours and being a stroke survivor. Older age, being single and having medical comorbidities were associated with lower odds of employment in stroke survivors. Conclusions: Stroke survivors are less likely to be employed and earn a lower hourly wage than the general population. Interventions such as dedicated vocational rehabilitation and policies around return to work could be considered to address this lost productivity among stroke survivors.