Pediatric pineoblastoma: A pooled outcome study of North American and Australian therapeutic data.

Background: Pineoblastoma is a rare brain tumor usually diagnosed in children. Given its rarity, no pineoblastoma-specific trials have been conducted. Studies have included pineoblastoma accruing for other embryonal tumors over the past 30 years. These included only occasional children with pineoblastoma, making clinical features difficult to interpret and determinants of outcome difficult to ascertain. Patients and Methods: Centrally or independently reviewed series with treatment and survival data from North American and Australian cases were pooled. To investigate associations between variables, Fisher's exact tests, Wilcoxon-Mann-Whitney tests, and Spearman correlations were used. Kaplan-Meier plots, log-rank tests, and Cox proportional hazards models were used in survival analyses. Results: We describe a pooled cohort of 178 pineoblastoma cases from Children's Oncology Group (n = 82) and institutional series (n = 96) over 30 years. Children <3 years of age have significantly worse survival compared to older children, with 5-year progression-free survival (PFS) and overall survival (OS) estimates of 13.5 ± 5.1% and 16.2 ± 5.3%, respectively, compared with 60.8 ± 5.6% and 67.3 ± 5.0% for ≥3 years old (both P < .0001). Multivariable analysis showed male sex was associated with worse PFS in children <3 years of age (hazard ratio [HR] 3.93, 95% CI 1.80-8.55; P = .0006), suggestive of sex-specific risks needing future validation. For children ≥3 years of age, disseminated disease at diagnosis was significantly associated with an inferior 5-year PFS of 39.2 ± 9.7% (HR 2.88, 95% CI 1.52-5.45; P = .0012) and 5-year OS of 49.8 ± 9.1% (HR 2.87, 95% CI 1.49-5.53; P = .0016). Conclusion: Given the rarity of this tumor, prospective, collaborative international studies will be vital to improving the long-term survival of these patients.

Germline-driven replication repair-deficient high-grade gliomas exhibit unique hypomethylation patterns.

Replication repair deficiency (RRD) leading to hypermutation is an important driving mechanism of high-grade glioma (HGG) occurring predominantly in the context of germline mutations in RRD-associated genes. Although HGG presents specific patterns of DNA methylation corresponding to oncogenic mutations, this has not been well studied in replication repair-deficient tumors. We analyzed 51 HGG arising in the background of gene mutations in RRD utilizing either 450 k or 850 k methylation arrays. These were compared with HGG not known to be from patients with RRD. RRD HGG harboring secondary mutations in glioma genes such as IDH1 and H3F3A displayed a methylation pattern corresponding to these methylation subgroups. Strikingly, RRD HGG lacking these known secondary mutations clustered together with an incompletely described group of HGG previously labeled "Wild type-C" or "Paediatric RTK 1". Independent analysis of two comparator HGG cohorts showed that other RRD/hypermutant tumors clustered within these subgroups, suggesting that undiagnosed RRD may be driving some HGG clustering in this location. RRD HGG displayed a unique CpG Island Demethylator Phenotype in contrast to the CpG Island Methylator Phenotype described in other cancers. Hypomethylation was enriched at gene promoters with prominent demethylation in genes and pathways critical to cellular survival including cell cycle, gene expression, cellular metabolism, and organization. These data suggest that methylation arrays may provide diagnostic information for the detection of RRD HGG. Furthermore, our findings highlight the unique natural selection pressures in these highly dysregulated, hypermutant cancers and provide the novel impact of hypermutation and RRD on the cancer epigenome.

Cystatin C Based Equation Accurately Estimates Glomerular Filtration Rate in Children With Solid and Central Nervous System Tumours: Enough Evidence to Change Practice?

BACKGROUND: Assessing the glomerular filtration rate (GFR) of paediatric patients receiving nephrotoxic chemotherapy is a vital element of clinical practice. Isotopically measured GFR is the gold standard in terms of accuracy but requires injection of tracer followed by several hours of blood tests. Estimation of GFR using creatinine is widely used but inaccurate, and there is increasing concern regarding its usage for paediatric oncology patients. Cystatin C (CysC) based equations are increasingly used in other paediatric specialities to estimate GFR, and their usefulness in paediatric oncology practice is becoming evident. METHODS: We assessed the renal function of children with solid tumours and CNS tumours receiving nephrotoxic chemotherapy over a 1-year period using paired CysC and isotopic GFR. RESULTS: Fifty-six sets of measurements were reviewed with estimated GFR predicted using CysC-based and creatinine-based equations. The best performing equation was the 'new CKiD' equation, which estimated GFR within 30% of the measured GFR on 86% of occasions, outperforming the Schwartz equation. If estimated GFR using this equation was >100 ml/min/1.73 m(2) , all values of measured GFR were normal at >90 ml/min/1.73 m(2) , a category containing two-thirds of all measurements. CONCLUSIONS: The new CKiD equation predicts GFR in paediatric oncology patients with more accuracy than creatinine-based equations. When the estimated GFR is >100 ml/min/1.73 m(2) , isotopic GFR can be safely omitted.

Pediatric Pleomorphic Xanthoastrocytoma Treated With Surgical Resection Alone: Clinicopathologic Features.

Pleomorphic xanthoastrocytoma (PXA) is a rare brain tumor that usually occurs in children and young adults. It has characteristic histologic features and is regarded as a WHO grade II lesion. Overall survival is reported to be >60%, but published series usually consist of a range of ages and treatment modalities. Gross total resection is associated with superior survival but recurrence rates after gross total resection are not well described, particularly in a pediatric population. We describe 16 cases over 20 years at our institution of pediatric PXA treated with surgical resection alone with a 5-year relapse-free survival of 40% (95% confidence interval, 20%-82%) and overall survival of 76% (95% confidence interval, 55%-100%). Gross total resection was associated with superior relapse-free survival (P<0.05). Some cases have a very long period between symptom onset or radiologic detection and resection, but neither length of symptoms nor radiologic signs of slow growth were associated with survival. PXA is a rare and unusual entity with unpredictable behavior. Complete surgical resection is optimal but does not guarantee relapse-free survival. We propose separation of PXA from other low-grade gliomas in childhood given differing biology and behavior.

Disseminated glioneuronal tumors occurring in childhood: treatment outcomes and BRAF alterations including V600E mutation.

Disseminated glioneuronal tumors of childhood are rare. We present a retrospective IRB-approved review of the clinical course and frequency of BRAF mutations in disseminated glioneuronal tumors at two institutions. Defining features of our cohort include diffuse leptomeningeal-spread, often with a discrete spinal cord nodule and oligodendroglioma-like histologic features. Patients were identified through a pathology database search of all cases with disseminated low-grade neoplasms with an oligodendroglioma-like component. De-identified clinical information was collected by chart review and all imaging was reviewed. We retrieved the results of targeted genomic analyses for alterations in BRAF. Ten patients (aged 2-14 years) were identified from the Dana-Farber/Boston Children's Hospital and the Royal Children's Hospital, Melbourne pathology databases. Nine patients received chemotherapy. Eight patients are alive, although three have had episodes of progressive disease. We identified genomic alterations affecting the MAPK pathway in six patients. One patient had a germline RAF1 mutation and a clinical diagnosis of cardio-facio-cutaneous syndrome. BRAF duplications were identified in four and BRAF V600E mutation was identified in one. These data support the presence of targetable genomic alterations in this disease.

Low rates of recurrence and slow progression of pediatric pilocytic astrocytoma after gross-total resection: justification for reducing surveillance imaging.

OBJECTIVE Pilocytic astrocytomas (PAs) are common brain tumors in children. Optimal management of PA is gross-total resection (GTR), after which event-free survival (EFS) is excellent. The tempo of recurrences, when they do occur, is relatively sparsely reported, and there is no agreed upon surveillance recommendation for patients in this category. It has been suggested that surveillance MRI is performed too frequently and could be safely reduced in both frequency and duration. The authors conducted a retrospective review of pediatric patients with PA who underwent GTR at a single institution over an 18-year period and who had documented recurrences. METHODS All patients under 18 years of age who had undergone GTR of a PA between 1996 and 2013 were included in the study. Clinical, radiological, and tumor characteristics were recorded. RESULTS Sixty-seven patients met the criteria for GTR over the period studied. The 5-year EFS rate was 95% (95% CI 89%-100%) and overall survival was 100%. Recurrences showed a nonsignificant trend of occurring more commonly in patients with persistent nonenhancing FLAIR abnormalities after surgery, but there was no difference with regard to tumor location. All recurrences occurred before 3 years postresection, all were asymptomatic, and all patients were observed for at least one additional scan after the initial detection during routine surveillance MRI before further therapy was undertaken. CONCLUSIONS EFS and overall survival are excellent after GTR in this population with PAs. Progression after recurrence occurs slowly and is asymptomatic. A less intensive schedule of MRI surveillance in this group of patients would result in time and cost savings, without compromising safety. The authors suggest a schedule of 6 MRI scans to be obtained postoperatively, at 3-6 months, then at 1, 2, 3.5, and 5 years.

Biallelic FANCD1/BRCA2 mutations predisposing to glioblastoma multiforme with multiple oncogenic amplifications.

Fanconi anaemia (FA) caused by biallelic mutation in FANCD1/BRCA2 is rare but carries a high risk of early onset cancer. Medulloblastoma is well described in this cohort but reports of other brain tumours are uncommon. The molecular profile of tumours from FA patients is not well reported. A glioblastoma multiforme (GBM) from a 3-year-old patient with FA and confirmed biallelic BRCA2 mutations was submitted for methylation analysis. This revealed strong clustering with the K27 mutation subgroup and copy number analysis showed gains of chromosomes 1q, 4q, part of 7q, part of 8q and 17q with resultant amplifications of MDM4, CDK6, MET, MYC and PPM1D (WIP1). We also describe for the first time the germline mutation in BRCA2 c.8057T > C resulting in p.Leu2686Pro in our patient with confirmed FA. Biallelic BRCA2 mutations have predisposed to an aggressive and universally fatal subtype of childhood GBM in our patient. Copy number alterations and multiple oncogenic amplifications may be secondary to inherent chromosomal instability and this raises the question of what role BRCA2 may play in the development of GBM in children without FA.

Carboplatin Hypersensitivity Reactions in Pediatric Low Grade Glioma Are Protocol Specific and Desensitization Shows Poor Efficacy.

BACKGROUND: The use of carboplatin for the treatment of pediatric low grade gliomas (PLGG) is often limited by the development of carboplatin hypersensitivity. Reported rates of carboplatin hypersensitivity reactions vary between 6% and 32% in these patients. Here we report the frequency of carboplatin hypersensitivity reactions depending on the treatment regimen used, and outcomes of carboplatin desensitization. METHODS: The records of all patients in a single institution who were treated with carboplatin for PLGG were accessed and all patients receiving more than one dose of carboplatin are reported. RESULTS: Thirty four patients with PLGG were treated with carboplatin according to one of the two different regimens. Carboplatin hypersensitivity was documented in 47% of patients, but the frequency differed by treatment protocol. Those patients treated with 4-weekly single agent carboplatin had carboplatin allergy in 8% of cases whereas 68% of those treated with combined carboplatin and vincristine (every three weeks, according to the SIOP 2004 low grade glioma protocol) had carboplatin reactions (OR 23.6, P < 0.01). Desensitization was only successful in two out of 10 patients in whom it was attempted. CONCLUSIONS: Hypersensitivity reactions to carboplatin are more common in this cohort than previously reported and rates are protocol-dependent. Desensitization showed limited effectiveness in this cohort.

Single agent carboplatin for pediatric low-grade glioma: A retrospective analysis shows equivalent efficacy to multiagent chemotherapy.

Pediatric low-grade gliomas (LGG) that are unresectable often require adjuvant chemotherapy such as carboplatin/vincristine. Small Phase II studies have suggested equivalent efficacy of single agent 4-weekly carboplatin. A single-institution retrospective review captured all patients aged 0 to 18 years diagnosed with LGG between 1996 and 2013 and treated with carboplatin monotherapy. The response and survival according to tumor site was compared to published results for multiagent chemotherapy. Of 268 children diagnosed with LGG diagnosed in this period, 117 received chemotherapy and 104 children received single agent carboplatin as first line chemotherapy. All patients received carboplatin at 560 mg/m(2), four-weekly for a median of 12 courses. The mean age at diagnosis was 5.8 years (range 3m-16y) and 32% had neurofibromatosis type 1. With a mean followup of 54 months, 86% of patients achieved stabilisation or better (SD/PR/CR). 3-year progression free survival (PFS) 66% (95% CI 57-76%), and 5-year PFS was 51% (95% CI 41-63%). 5-year overall survival was 97%. Multivariate analysis showed poorer PFS for those with chiasmatic/hypothalamic tumors. In this retrospective analysis single agent carboplatin shows comparable efficacy to historical multiagent chemotherapy for the treatment of patients with unresectable LGG. Equivalent outcomes are achieved with less chemotherapy, reduced side effects and fewer hospital visits. Further research is required to establish the place of this simplified regimen in the up-front treatment of unresectable LGG.

Long-term visual outcome after chemotherapy for optic pathway glioma in children: Site and age are strongly predictive.

BACKGROUND: Optic pathway gliomas (OPGs) are commonly noted in pediatric oncology services. Radiotherapy is effective at controlling tumors, but has many undesirable late effects, especially in patients with neurofibromatosis. Chemotherapy is commonly used to preserve vision and delay or eliminate the need for radiotherapy. Despite visual threat being a common reason to initiate chemotherapy in patients with OPG, reports of visual outcome after chemotherapy are not common and reports of long-term visual outcome are even scarcer. METHODS: In a single institution, all patients with OPG who had received chemotherapy or radiotherapy between 1996 and 2013 were identified from hospital databases. Visual, treatment, and radiological data were recorded. Categorized visual acuity was the primary outcome measure. RESULTS: Of 43 patients identified, visual data were available for 42 patients. Approximately 14% of patients experienced an improvement in visual acuity during therapy, 9% of patients experienced a deterioration, and the remainder were stable. At a mean follow-up of 78 months, 26% of patients were legally blind. Children aged <2 years and patients with a chiasmatic/hypothalamic tumor site were overrepresented in this category. An intraconal location was predictive of poor visual outcome for that eye but was unilateral with normal vision in the contralateral eye. CONCLUSIONS: Risk factors for long-term visual deterioration are young age, chiasmatic/hypothalamic tumor site, and intraconal tumor site for the involved eye. The most common visual outcome for children with OPG after treatment with chemotherapy is stability. This stability is maintained over the long term for >90% of children without these risk factors.

Enrollment in clinical cancer trials: how are we doing and what are the obstacles to improving enrollment rates? A 2-year retrospective review of pediatric cancer trial enrollment in New Zealand.

Clinical trials contribute to the establishment of the best therapy for children with cancer. This study looks at rates of enrollment in therapeutic clinical trials over a 2-year period in New Zealand and examines the reasons for nonenrollment. All new diagnoses of cancer in children aged 16 or younger over the period of 1 January, 2009 to 31 December, 2010 were identified through the New Zealand Child Cancer Registry. Clinical trial enrollment status was identified from the medical records. For those not enrolled, the reason for nonenrollment was ascertained. A total of 28% of children diagnosed with cancer who received chemotherapy with curative intent in this time period were enrolled on clinical trials. The 2 most common reasons for nonenrollment in this study were that no study was open locally in which to enroll children (27%) or that previously open-clinical trials were closed to accrual at the time of the child's diagnosis (20%). In New Zealand, enrollment rates on clinical trials for children with cancer are lower than expected.

Population-based cases control study of inflammatory bowel disease risk factors.

BACKGROUND AND AIM: The rapid increase in inflammatory bowel disease (IBD) incidence confirms the importance of environment in its etiology. We aimed to assess the role of childhood and other environmental risk factors in IBD. METHODS: A population-based case-control study was carried out in Canterbury, New Zealand. Participants comprised 638 prevalent Crohn's disease (CD) cases, 653 prevalent ulcerative colitis (UC) cases and 600 randomly-selected sex and age matched controls. Exposure rates to environmental risk factors were compared. Unadjusted and adjusted odds ratios (OR) with 95% confidence intervals (CI) are presented. RESULTS: A family history of IBD (CD OR 3.06 [2.18-4.30], UC OR 2.52 [1.90-3.54]), cigarette smoking at diagnosis (CD OR 1.99 [1.48-2.68], UC OR 0.67 [0.48-0.94]), high social class at birth (CD and UC trend, P < 0.001) and Caucasian ethnicity (CD OR 2.04 [1.05-4.38], UC OR 1.47 [1.01-2.14]) were significantly associated with IBD. City living was associated with CD (P < 0.01). Being a migrant was associated with UC (UC OR 1.40 [1.14-2.01]). Having a childhood vegetable garden was protective against IBD (CD OR 0.52 [0.36-0.76], UC OR 0.65 [0.45-0.94]) as was having been breast-fed (CD OR 0.55 [0.41-0.74], UC OR 0.71 [0.52-0.96]) with a duration-response effect. Appendicectomy, tonsillectomy, infectious mononucleosis and asthma were more common in CD patients than controls (P < 0.01). CONCLUSIONS: The importance of childhood factors in the development of IBD is confirmed. The duration-response protective association between breast-feeding and subsequent development of IBD requires further evaluation, as does the protective effect associated with a childhood vegetable garden.