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Purpose: The outcome of recurrent ependymoma in children is dismal. Reirradiation has been proposed as an effective modality for ependymoma at relapse. However, the toxicity and outcome benefits of this approach have not been well established. Methods and Materials: We conducted a retrospective population-based study of all patients with recurrent ependymoma treated between 1986 and 2010 in our institution. Demographic, treatment, and outcome data were analyzed for the entire cohort. Results: Of 113 patients with intracranial ependymoma, 47 patients relapsed. At the time of relapse, 29 patients were treated with surgical resection and/or chemotherapy, and 18 patients received full-dose (≥54 Gy focal and/or craniospinal) reirradiation with or without surgery at recurrence. Reirradiation was tolerated well with no severe acute complications noticed. Three-year overall survival was 7% ± 6% and 81% ± 12% for nonreirradiated and reirradiated patients, respectively (p < 0.0001). Time to second progression after reirradiation was significantly longer than time to first progression. This surprising phenomenon was associated with improved progression-free survival for tumors with evidence of DNA damage (n = 15; p = 0.002). At a mean follow-up of 3.73 years, only 2/18 patients had endocrine dysfunction, and 1 patient required special education support. However, a decline in intellectual function from pre- to postreirradiation assessment was observed. Conclusions: Reirradiation is an effective treatment that may change the natural history of recurrent ependymoma in children. However, this change may be associated with increased neurocognitive toxicity. Additional follow-up is needed to determine the risk of late recurrence, secondary radiation-induced tumors, and long-term functional outcome of these patients. [ABSTRACT FROM AUTHOR]

We describe a 31-year-old male who presented with progressive myelopathy from a thoracic pilocytic astrocytoma (PA). Following multiple recurrences and resections, 10 years after his index surgery, pathology revealed diffuse leptomeningeal glioneuronal tumor (DLGNT) with high-grade features. We discuss his clinical course, management, histopathological findings, and present a comprehensive review of spinal PA undergoing malignant transformation in adults and adult-onset spinal DLGNT. To our knowledge, we present the first reported case of adult-onset spinal PA malignant transformation to DLGNT. Our case adds to the paucity of clinical data characterizing such transformations and highlights the importance of developing novel management paradigms. [ABSTRACT FROM AUTHOR]

Objectives: In precision medicine, where oncologic management is tailored to the individual's clinical and genetic profiles, advanced diagnostic testing provides prognostic information and guides management in a growing number of malignancies. There is a need to capture the work pathologists perform to meet this demand by providing medically relevant, timely, and accurate testing results. This work includes not only direct patient consults (interpretation of results and issuing reports) but the administrative and medical oversight as well as the research needed to provide the necessary quality assurance, quality control, direction, and framework for the laboratory.Methods: An expert panel of Canadian pathologists involved in advanced diagnostics was convened to establish and beta test a model for workload assessment in advanced diagnostics.Results: All aspects of the advanced diagnostics workload were detailed and applied to models based on members' experience, including medical oversight, administration, and the introduction of new testing and platforms. Models for biomarker testing were developed for simple and complex or multiplexed assays, and a detailed model was developed to assess the workload for next-generation sequencing-based assays.Conclusions: This paper provides the first detailed proposal for capturing an advanced diagnostic workload to enable appropriate pathologist allotment for performing all the steps required to run an advanced diagnostic service. [ABSTRACT FROM AUTHOR]

Diffusely infiltrating astrocytomas include diffuse astrocytomas WHO grade II and anaplastic astrocytomas WHO grade III and are classified under astrocytic tumours according to the current WHO Classification. Although the patients generally have longer survival as compared to those with glioblastoma, the timing of inevitable malignant progression ultimately determines the prognosis. Recent advances in molecular genetics have uncovered that histopathologically diagnosed astrocytomas may consist of two genetically different groups of tumours. The majority of diffusely infiltrating astrocytomas regardless of WHO grade have concurrent mutations of IDH1 or IDH2, TP53 and ATRX. Among these astrocytomas, no other genetic markers that may distinguish grade II and grade III tumours have been identified. Those astrocytomas without IDH mutation tend to have a distinct genotype and a poor prognosis comparable to that of glioblastomas. On the other hand, diffuse astrocytomas that arise in children do not harbour IDH/ TP53 mutations, but instead display mutations of BRAF or structural alterations involving MYB/ MYBL1 or FGFR1. A molecular classification may thus help delineate diffusely infiltrating astrocytomas into distinct pathogenic and prognostic groups, which could aid in determining individualised therapeutic strategies. [ABSTRACT FROM AUTHOR]

We performed genome‐wide methylation analysis on 136 pediatric low‐grade gliomas, identifying a unique cluster consisting of three tumors with oligodendroglioma‐like histology, BRAF p.V600E mutations and recurrent whole chromosome gains of 7 and loss of 10. Morphologically, all showed similar features, including a diffusely infiltrative glioma composed of round nuclei with perinuclear halos, a chicken‐wire pattern of branching capillaries and microcalcification. None showed astrocytic features or characteristics suggestive of high‐grade tumors including necrosis or mitotic figures. All tumors harbored multiple chromosomal copy number abnormalities (>10 chromosomes altered), but none showed 1p/19q co‐deletion or IDH1 p.R132H mutation. Hierarchical clustering and t‐stochastic neighbor embedding analyses from DNA methylation data cluster them more closely to previously described pediatric‐type low‐grade gliomas and separate from adult gliomas. These tumors exhibit distinct clinical features; they are temporal lobe lesions occurring in adolescents and young adults with a prolonged history of seizures and all are alive with no recurrence (follow‐up 3.2 to 13.2 years). We encountered another young adult case with quite similar pathological appearance and molecular status except for TERT promoter mutation. Although the series is small, these may represent a new category of IDH wild‐type low‐grade gliomas which may be confused with "molecular GBM." Further, they highlight the heterogeneity of IDH wild‐type gliomas and the relatively indolent behavior of "pediatric‐type" gliomas. [ABSTRACT FROM AUTHOR]

Background: Thalamic gliomas are rare. The natural history is unpredictable, and the optimal management of these tumors in children is poorly defined. The aim was to identify outcomes, prognostic factors, and response to various modalities of treatment in a relatively large population of pediatric thalamic tumors from many centers within a fairly homogeneous health care system. Methods: We performed a Canadian multicenter retrospective review of pediatric thalamic tumors presenting during the MRI era (1989-2012). Radiology and pathology were reviewed by central independent reviewers. Paraffin shavings for RNA extraction were taken and tested for fusion events involving KIAA1549:BRAF. Tumors were classified as unilateral or bithalamic based on their origin on imaging. Univariate and multivariate analyses on factors influencing survival were performed. Results: Seventy-two thalamic tumors were identified from 11 institutions. Females represented 53 % of the study population, and the mean age at presentation was 8.9 years. Sixty-two tumors were unilateral and 10 bithalamic. Unilateral tumors had a greater propensity to grow inferiorly towards the brainstem. These tumors were predominantly low grade in comparison to bithalamic tumors which were high-grade astrocytomas. The 5-year overall survival was 61 ± 13 % for unithalamic tumors compared to 37 ± 32 % for bithalamic tumors ( p = 0.097). Multivariate analysis indicated tumor grade as the only significant prognostic factor for unithalamic tumors. Six unilateral tumors, all low grade, were BRAF fusion positive. Conclusion: Unilateral and bilateral thalamic tumors behave differently. Surgical resection is an appropriate treatment option in unilateral tumors, most of which are low grade, but outcome is not related to extent of resection (EOR). Bilateral thalamic tumors have a poorer prognosis, but the occasional patient does remarkably well. The efficacy of chemotherapy and radiotherapy has not been clearly demonstrated. Novel therapeutic approaches are required to improve the prognosis for malignant unilateral thalamic tumors and bilateral thalamic tumors. [ABSTRACT FROM AUTHOR]

Purpose: Gross total resection (GTR) of intracranial ependymoma is an accepted goal. More controversial is radiotherapy deferral. This study reports on children treated with gross total resection who did not receive upfront adjuvant radiotherapy. Methods: We conducted a retrospective review of children with intracranial ependymoma in 12 Canadian centers. Patients who had GTR of their tumor and no upfront radiotherapy were identified. Immunostaining was performed for Ki-67, epidermal growth factor receptor (EGFR), and EZH2 on archived tissue. The Kaplan-Meier survival analysis was performed and compared with those who had GTR followed by radiation. Results: Twenty-six children were identified treated with GTR alone at diagnosis; 12 posterior fossa ependymoma (PFE) WHO grade II, and 14 supratentorial ependymoma (STE). Progression-free survival (PFS) in ependymoma treated with GTR alone at diagnosis was inferior in those with high Ki-67 or positive EZH2 immunostaining. Survival was inferior for patients less than 2 years old at diagnosis ( p = 0.002). Survival was comparable to PFE WHO grade II and STE who had GTR followed by radiation ( p = 0.62). Five-year PFS and overall survival (OS) of those treated with GTR alone were 60 and 70 % respectively for PFE and 45 and 70 % respectively for STE ( p = 0.2; 0.55). Conclusions: This study suggests that there is a subset of children with certain biologic features who, in the setting of a prospective clinical trial, might be candidates for observation following GTR. Good risk factors for this approach include age of 2 years or older, low Ki-67, and negative EZH2. If relapse occurs, it may be confined to the primary site, allowing for possible salvage with GTR followed by XRT. [ABSTRACT FROM AUTHOR]

Major discoveries in the biology of nervous system tumors have raised the question of how non-histological data such as molecular information can be incorporated into the next World Health Organization ( WHO) classification of central nervous system tumors. To address this question, a meeting of neuropathologists with expertise in molecular diagnosis was held in Haarlem, the Netherlands, under the sponsorship of the International Society of Neuropathology ( ISN). Prior to the meeting, participants solicited input from clinical colleagues in diverse neuro-oncological specialties. The present 'white paper' catalogs the recommendations of the meeting, at which a consensus was reached that incorporation of molecular information into the next WHO classification should follow a set of provided ' ISN- Haarlem' guidelines. Salient recommendations include that (i) diagnostic entities should be defined as narrowly as possible to optimize interobserver reproducibility, clinicopathological predictions and therapeutic planning; (ii) diagnoses should be 'layered' with histologic classification, WHO grade and molecular information listed below an 'integrated diagnosis'; (iii) determinations should be made for each tumor entity as to whether molecular information is required, suggested or not needed for its definition; (iv) some pediatric entities should be separated from their adult counterparts; (v) input for guiding decisions regarding tumor classification should be solicited from experts in complementary disciplines of neuro-oncology; and (iv) entity-specific molecular testing and reporting formats should be followed in diagnostic reports. It is hoped that these guidelines will facilitate the forthcoming update of the fourth edition of the WHO classification of central nervous system tumors. [ABSTRACT FROM AUTHOR]

The author discusses the publication of the "2016 World Health Organization Classification of Tumors of the Central Nervous System" (2016 CNS WHO) which represents the advancement of the classification of human brain tumors and facilitates a precise diagnosis of well-understood entities.

Spontaneous tumor regression is a unique feature of pediatric low-grade gliomas (PLGG). We speculated that lack of telomere maintenance is responsible for this behavior. We first looked for evidence of telomerase activity and alternative-lengthening telomeres (ALT) in 56 PLGG. Telomerase activity was observed in 0 of 11 PLGG in contrast to 10 of 13 high-grade pediatric brain tumors. There was no ALT in 45 of 45 samples. We applied Q-FISH to eight patients whose indolent PLGG underwent two metachronous biopsies over a lag of several years. Telomere shortening was observed in the second biopsy in all tumors but not in a normal brain control (P < .0001), indicating that lack of telomere maintenance is associated with continuous telomere erosion. Based on these observations, we observed that younger PLGG patients who exhibit more aggressive and frequently recurrent tumors had significantly longer telomeres than older ones (P = .00014). Tumors with a terminal restriction fragment length of <7.5 did not recur, whereas the presence of longer telomeres (>8.0) conferred a high likelihood of late recurrences in PLGG. Our findings provide a plausible biological mechanism to explain the tendency of PLGG to exhibit growth arrest and spontaneous regression. Telomere maintenance may therefore represent the first known biologic prognostic marker in PLGG. [ABSTRACT FROM AUTHOR]

After publication of the original article [1], authors have requested to add a 'J' as middle name for Richard Gilbertson. Hence, full name should be Richard J Gilbertson. [ABSTRACT FROM AUTHOR]

Background: Histological grading of choroid plexus tumors (CPTs) remains the best prognostic tool to distinguish between aggressive choroid plexus carcinoma (CPC) and the more benign choroid plexus papilloma (CPP) or atypical choroid plexus papilloma (aCPP); however, these distinctions can be challenging. Standard treatment of CPC is very aggressive and often leads to severe damage to the young child's brain. Therefore, it is crucial to distinguish between CPC and less aggressive entities (CPP or aCPP) to avoid unnecessary exposure of the young patient to neurotoxic therapy. To better stratify CPTs, we utilized DNA methylation (DNAm) to identify prognostic epigenetic biomarkers for CPCs. Methods: We obtained DNA methylation profiles of 34 CPTs using the HumanMethylation450 BeadChip from Illumina, and the data was analyzed using the Illumina Genome Studio analysis software. Validation of differentially methylated CpG sites chosen as biomarkers was performed using pyrosequencing analysis on additional 22 CPTs. Sensitivity testing of the CPC DNAm signature was performed on a replication cohort of 61 CPT tumors obtained from Neuropathology, University Hospital Münster, Germany. Results: Generated genome-wide DNAm profiles of CPTs showed significant differences in DNAm between CPCs and the CPPs or aCPPs. The prediction of clinical outcome could be improved by combining the DNAm profile with the mutational status of TP53. CPCs with homozygous TP53 mutations clustered as a group separate from those carrying a heterozygous TP53 mutation or CPCs with wild type TP53 (TP53-wt) and showed the worst survival outcome. Specific DNAm signatures for CPCs revealed AK1, PER2, and PLSCR4 as potential biomarkers for CPC that can be used to improve molecular stratification for diagnosis and treatment. Conclusions: We demonstrate that combining specific DNAm signature for CPCs with histological approaches better differentiate aggressive tumors from those that are not life threatening. These findings have important implications for future prognostic risk prediction in clinical disease management. [ABSTRACT FROM AUTHOR]