Chris Fryer

Age is the major determinant of recurrence in pediatric differentiated thyroid carcinoma

BACKGROUND A relationship between young age and increased risk of recurrence of pediatric differentiated thyroid carcinoma has been suggested; however, no attempts have been made to assess the prognostic factors or efficacy of treatment in very young children with this malignancy. The objectives of this study were to evaluate the association of age with outcome in pediatric differentiated thyroid carcinoma and to compare the clinical, pathologic, prognostic, and treatment variables between younger and older children with this disease. PROCEDURE A retrospective review of all patients presenting to the British Columbias Childrens Hospital or British Columbia Cancer Agency <17 years of age at diagnosis with differentiated thyroid carcinoma between January, 1955, and December, 1996, was completed. RESULTS Thirty-eight patients were identified, 12 of whom were </=10 years of age. The overall and relapse-free survivals at 20 years were 100% and 32.2%, respectively. Age at diagnosis was the only determinant of time to recurrence on univariate and multivariate regression analysis of prognostic factors (P = 0.022). The 20 year relapse-free survival for children < or =10 years of age was 10.1% vs. 48.3% for children >10 years. An association between young age and extrathyroidal tumor invasion was identified (P = 0.016); however, the latter factor did not independently predict outcome. There was a trend for suppressive doses of thyroid hormone to improve outcome, particularly with increasing age at diagnosis, but this was not statistically significant. CONCLUSIONS Age is the major determinant of recurrence in pediatric differentiated thyroid carcinoma. The results suggest different tumor biology in young children requiring novel approaches to therapy to decrease recurrence rates.

Intratumoral therapy with bleomycin for cystic craniopharyngiomas in children.

Surgical removal of cystic craniopharyngiomas in children is associated with significant operative morbidity and recurrence rates. The purpose of this study was to review our experience with a less invasive therapy, namely, intratumoral bleomycin, in the treatment of predominantly cystic craniopharyngiomas. All children with craniopharyngiomas treated at a tertiary care pediatric neurosurgical center since 1994, when bleomycin was first used, were reviewed retrospectively. Seven patients received intratumoral bleomycin therapy. Patients received 2–5 mg bleomycin per dose, 3 times per week, for 3–5 weeks as an initial course. Mean follow-up of these patients was 3 years. In 4 patients, treatment resulted in a significant decrease (>50%) in tumor size, which has remained stable. Two patients’ tumors progressed and underwent resection, and 1 patient had surgical removal because of persistent headaches, although no growth of residual tumor had been noted. One patient developed peritumoral edema as a result of bleomycin therapy. Intratumoral bleomycin is a useful alternative therapy for cystic craniopharyngiomas, and may control tumor growth and delay potentially harmful resection and/or radiotherapy in young children.

Molecular subgroups of atypical teratoid rhabdoid tumours in children: an integrated genomic and clinicopathological analysis

BACKGROUND Rhabdoid brain tumours, also called atypical teratoid rhabdoid tumours, are lethal childhood cancers with characteristic genetic alterations of SMARCB1/hSNF5. Lack of biological understanding of the substantial clinical heterogeneity of these tumours restricts therapeutic advances. We integrated genomic and clinicopathological analyses of a cohort of patients with atypical teratoid rhabdoid tumours to find out the molecular basis for clinical heterogeneity in these tumours. METHODS We obtained 259 rhabdoid tumours from 37 international institutions and assessed transcriptional profiles in 43 primary tumours and copy number profiles in 38 primary tumours to discover molecular subgroups of atypical teratoid rhabdoid tumours. We used gene and pathway enrichment analyses to discover group-specific molecular markers and did immunohistochemical analyses on 125 primary tumours to evaluate clinicopathological significance of molecular subgroup and ASCL1-NOTCH signalling. FINDINGS Transcriptional analyses identified two atypical teratoid rhabdoid tumour subgroups with differential enrichment of genetic pathways, and distinct clinicopathological and survival features. Expression of ASCL1, a regulator of NOTCH signalling, correlated with supratentorial location (p=0·004) and superior 5-year overall survival (35%, 95% CI 13-57, and 20%, 6-34, for ASCL1-positive and ASCL1-negative tumours, respectively; p=0·033) in 70 patients who received multimodal treatment. ASCL1 expression also correlated with superior 5-year overall survival (34%, 7-61, and 9%, 0-21, for ASCL1-positive and ASCL1-negative tumours, respectively; p=0·001) in 39 patients who received only chemotherapy without radiation. Cox hazard ratios for overall survival in patients with differential ASCL1 enrichment treated with chemotherapy with or without radiation were 2·02 (95% CI 1·04-3·85; p=0·038) and 3·98 (1·71-9·26; p=0·001). Integrated analyses of molecular subgroupings with clinical prognostic factors showed three distinct clinical risk groups of tumours with different therapeutic outcomes. INTERPRETATION An integration of clinical risk factors and tumour molecular groups can be used to identify patients who are likely to have improved long-term radiation-free survival and might help therapeutic stratification of patients with atypical teratoid rhabdoid tumours. FUNDING C17 Research Network, Genome Canada, b.r.a.i.n.child, Mitchell Duckman, Tal Doron and Suri Boon foundations.

A Canadian paediatric brain tumour consortium (CPBTC) phase II molecularly targeted study of imatinib in recurrent and refractory paediatric central nervous system tumours

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.

Childhood craniopharyngioma: Vancouver experience

ObjectiveTo present our institution’s experience in the management of childhood craniopharyngioma since 1982.MethodsWe retrospectively reviewed the records of all children diagnosed with craniopharyngioma at our children’s hospital from its opening in 1982 through to 2003. One neuroradiologist systematically reviewed the neuroimaging. Kaplan–Meier curves were used to analyze the progression-free survival and the overall survival from the time of the first definitive intervention.ConclusionsMost children diagnosed with craniopharyngioma are long-term survivors. Survivors suffer from multiple deficits in the long term. A conservative surgical and radiotherapeutic approach and avoiding interventions that are known to cause severe morbidity may minimize these. The use of intracystic bleomycin is a strategy that allows the delay of more aggressive therapies in select patients.

White and Gray Matter Abnormalities After Cranial Radiation in Children and Mice.

PURPOSE Pediatric patients treated with cranial radiation are at high risk of developing lasting cognitive impairments. We sought to identify anatomical changes in both gray matter (GM) and white matter (WM) in radiation-treated patients and in mice, in which the effect of radiation can be isolated from other factors, the time course of anatomical change can be established, and the effect of treatment age can be more fully characterized. Anatomical results were compared between species. METHODS AND MATERIALS Patients were imaged with T1-weighted magnetic resonance imaging (MRI) after radiation treatment. Nineteen radiation-treated patients were divided into groups of 7 years of age and younger (7-) and 8 years and older (8+) and were compared to 41 controls. C57BL6 mice were treated with radiation (n=52) or sham treated (n=52) between postnatal days 16 and 36 and then assessed with in vivo and/or ex vivo MRI. In both cases, measurements of WM and GM volume, cortical thickness, area and volume, and hippocampal volume were compared between groups. RESULTS WM volume was significantly decreased following treatment in 7- and 8+ treatment groups. GM volume was unchanged overall, but cortical thickness was slightly increased in the 7- group. Results in mice mostly mirrored these changes and provided a time course of change, showing early volume loss and normal growth. Hippocampal volume showed a decreasing trend with age in patients, an effect not observed in the mouse hippocampus but present in the olfactory bulb. CONCLUSIONS Changes in mice treated with cranial radiation are similar to those in humans, including significant WM and GM alterations. Because mice did not receive any other treatment, the similarity across species supports the expectation that radiation is causative and suggests mice provide a representative model for studying impaired brain development after cranial radiation and testing novel treatments.

De-escalation of therapy for pediatric medulloblastoma: trade-offs between quality of life and survival.

Treatment intensity for pediatric medulloblastoma may vary depending on the type of medulloblastoma. In some cases, the dose of radiation may be reduced or eliminated. Correspondingly, there may be trade‐offs between quality of life and survival. In this study, focus groups were conducted with parents and clinicians to explore their opinions about these trade‐offs as well as the alignment/misalignment between parents and clinicians regarding the trade‐offs.

White matter compromise predicts poor intellectual outcome in survivors of pediatric low-grade glioma

BACKGROUND While the impact of cranial radiation on white matter following treatment for pediatric brain tumor has been the focus of many recent studies, the effect of treatment in the absence of radiation has received little attention. The relations between white matter and cognitive outcome have not been explored in patients who have undergone radiation-free treatment. As most patients treated without cranial radiation survive long after their diagnosis, it is critical to identify factors that may impact structural and neurocognitive outcomes. METHODS Using diffusion tensor imaging, we examined white matter structure in 32 patients with pediatric low-grade glioma (PLGG) (19 with subtentorial location and 13 with supratentorial location) and 32 healthy participants. Indices of intellectual functioning were also evaluated. Radiation was not used to treat this cohort, aged 8-19 years. RESULTS We detected evidence of deficits in IQ and compromised supra- and subtentorial white matter in patients relative to healthy children (P < .05). Compromise of supratentorial white matter mediated the impact of treatment for PLGG on IQ. Greater white matter compromise was observed in patients who presented without multiple symptoms, were treated with biopsy/no surgery, had positive neurofibromatosis 1 status, were younger age at diagnosis, and whose parents had lower levels of education (P < .05). CONCLUSIONS Our findings provide evidence of increased risk of intellectual and white matter compromise in patients treated for PLGG without radiation. We identify a neural origin of cognitive deficit useful for predicting outcome and mitigating long-term adverse effects in pediatric brain tumor patients treated without cranial radiation.

Neurocognitive evaluation of long term survivors of atypical teratoid rhabdoid tumors (ATRT): The Canadian registry experience

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.

Survival Following Tumor Recurrence in Children With Medulloblastoma

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.