Beverly Wilson

Advanced Vertebral Fracture among Newly Diagnosed Children with Acute Lymphoblastic Leukemia: Results of the Canadian STeroid-associated Osteoporosis in the Pediatric Population (STOPP) Research Program

Vertebral compression is a serious complication of childhood acute lymphoblastic leukemia (ALL). The prevalence and pattern of vertebral fractures, as well as their relationship to BMD and other clinical indices, have not been systematically studied. We evaluated spine health in 186 newly diagnosed children (median age, 5.3 yr; 108 boys) with ALL (precursor B cell: N = 167; T cell: N = 19) who were enrolled in a national bone health research program. Patients were assessed within 30 days of diagnosis by lateral thoraco‐lumbar spine radiograph, bone age (also used for metacarpal morphometry), and BMD. Vertebral morphometry was carried out by the Genant semiquantitative method. Twenty‐nine patients (16%) had a total of 75 grade 1 or higher prevalent vertebral compression fractures (53 thoracic, 71%; 22 lumbar). Grade 1 fractures as the worst grade were present in 14 children (48%), 9 patients (31%) had grade 2 fractures, and 6 children (21%) had grade 3 fractures. The distribution of spine fracture was bimodal, with most occurring in the midthoracic and thoraco‐lumbar regions. Children with grade 1 or higher vertebral compression had reduced lumbar spine (LS) areal BMD Z‐scores compared with those without (mean ± SD, −2.1 ± 1.5 versus −1.1 ± 1.2; p < 0.001). LS BMD Z‐score, second metacarpal percent cortical area Z‐score, and back pain were associated with increased odds for fracture. For every 1 SD reduction in LS BMD Z‐score, the odds for fracture increased by 80% (95% CI: 10–193%); the presence of back pain had an OR of 4.7 (95% CI: 1.5–14.5). These results show that vertebral compression is an under‐recognized complication of newly diagnosed ALL. Whether the fractures will resolve through bone growth during or after leukemia chemotherapy remains to be determined.

Phase II Study of Weekly Vinblastine in Recurrent or Refractory Pediatric Low-Grade Glioma

PURPOSEnTo evaluate the efficacy of single-agent vinblastine in pediatric patients with recurrent or refractory low-grade glioma.nnnPATIENTS AND METHODSnPatients were eligible if they had experienced previous treatment failure (chemotherapy and/or radiation) for incompletely resected or unresectable low-grade glioma (LGG). Vinblastine (6 mg/m(2)) was administered weekly for 1 year unless unacceptable toxicity or progression (confirmed on two consecutive imaging studies) occurred.nnnRESULTSnFifty-one patients (age range, 1.4 to 18.2 years; median age, 7.2 years) were prospectively enrolled onto this phase II study. Fifty patients had previously received at least one prior regimen of chemotherapy, and 10 patients had previously received radiation treatment. Fifty patients were evaluable for response; 18 patients (36%) had a complete, partial, or minor response, and 31 patients completed 1 year of treatment. At a median follow-up of 67 months, 23 patients had not experienced progression; three patients have died. Five-year overall survival was 93.2% ± 3.8%, and 5-year progression-free survival was 42.3% ± 7.2%. Toxicity was manageable and mostly hematologic, although a few patients needed transfusions.nnnCONCLUSIONnWeekly vinblastine seems to be a reasonable alternative to radiation for pediatric patients with LGG who have experienced treatment failure with first-line chemotherapy. The 5-year progression-free survival observed in this phase II trial is comparable to results observed with first-line chemotherapy in chemotherapy-naive patients. The role of single-agent vinblastine and other vinca alkaloid in the management of pediatric LGGs deserves further investigation.

Central nervous system atypical teratoid rhabdoid tumours: The Canadian Paediatric Brain Tumour Consortium experience

BACKGROUNDnAtypical 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.nnnPATIENTS AND METHODSnA 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.nnnRESULTSnThere 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.nnnCONCLUSIONnThe 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.

High Incidence of Vertebral Fractures in Children With Acute Lymphoblastic Leukemia 12 Months After the Initiation of Therapy

PURPOSEnVertebral fractures due to osteoporosis are a potential complication of childhood acute lymphoblastic leukemia (ALL). To date, the incidence of vertebral fractures during ALL treatment has not been reported.nnnPATIENT AND METHODSnWe prospectively evaluated 155 children with ALL during the first 12 months of leukemia therapy. Lateral thoracolumbar spine radiographs were obtained at baseline and 12 months. Vertebral bodies were assessed for incident vertebral fractures using the Genant semiquantitative method, and relevant clinical indices such as spine bone mineral density (BMD), back pain, and the presence of vertebral fractures at baseline were analyzed for association with incident vertebral fractures.nnnRESULTSnOf the 155 children, 25 (16%; 95% CI, 11% to 23%) had a total of 61 incident vertebral fractures, of which 32 (52%) were moderate or severe. Thirteen (52%) of the 25 children with incident vertebral fractures also had fractures at baseline. Vertebral fractures at baseline increased the odds of an incident fracture at 12 months by an odds ratio of 7.3 (95% CI, 2.3 to 23.1; P = .001). In addition, for every one standard deviation reduction in spine BMD Z-score at baseline, there was 1.8-fold increased odds of incident vertebral fracture at 12 months (95% CI, 1.2 to 2.7; P = .006).nnnCONCLUSIONnChildren with ALL have a high incidence of vertebral fractures after 12 months of chemotherapy, and the presence of vertebral fractures and reductions in spine BMD Z-scores at baseline are highly associated clinical features.

Supratentorial primitive neuroectodermal tumors: a Canadian pediatric brain tumor consortium report

AbstractIntroduction 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 10xa0years in Canada. A questionnaire was developed and distributed to all institutions in Canada who treat pediatric patients. Data were collected for patients <19xa0years 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 37.7xa0±xa07.6%. The factors associated with an increase in survival were the use of radiation therapy and chemotherapy, and age >2xa0years. Overall survival was not affected by metastatic disease at diagnosis, tumor site, or degree of ninitial 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.

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

BACKGROUNDnRhabdoid 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.nnnMETHODSnWe 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.nnnFINDINGSnTranscriptional 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.nnnINTERPRETATIONnAn 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.nnnFUNDINGnC17 Research Network, Genome Canada, b.r.a.i.n.child, Mitchell Duckman, Tal Doron and Suri Boon foundations.

Carboplatin Hypersensitivity Reaction in Pediatric Patients With Low-grade Glioma : A Canadian Pediatric Brain Tumor Consortium Experience

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.

Epidemiological survey of central nervous system germ cell tumors in Canadian children

ObjectivesTo determine the incidence and characteristics of pediatric patients with central nervous system (CNS) germ cell tumors (GCT) in Canada.MethodA 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 18xa0years 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.ResultsOne 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). β 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 α-fetoprotein in serum, CSF or both was seen in 34% of patients with NGGCT.ConclusionThe incidence of CNS germ cell tumors in Canadian children is similar to that observed in other Western countries.

Choroid plexus tumors in children less than 36 months: the Canadian Pediatric Brain Tumor Consortium (CPBTC) experience

BackgroundChoroid 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.MethodsThe CPT population from the Canadian databank of CNS tumor in children ≤36xa0months diagnosed between 1990 and 2005 was reviewedResultsOut of the 579 reported cases of CNS tumors, 37 were CPT. The annual age-adjusted incidence rate was 0.22u2009+u20090.12 (95% CI 0.16–0.28)/100,000 children <3xa0years. There were 21 (56.7%) CPP and 16 (43.3.5%) CPC. Twenty patients (54%) were males. Median age at diagnosis was 7xa0months(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 15xa0months (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.ConclusionBy 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.

Medulloblastoma in children under the age of three years: a retrospective Canadian review

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 36xa0months of age diagnosed with medulloblastoma from 1990 to 2005 in Canada. Ninety-six cases were identified with a median age at diagnosis of 19.5xa0months. 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 45xa0±xa013.82xa0months. 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 18xa0months at diagnosis compared to those under 18xa0months.