Of nine ependymoma molecular groups detected by DNA methylation profiling, the posterior fossa type A (PFA) is most prevalent. We used DNA methylation profiling to look for further molecular heterogeneity among 675 PFA ependymomas. Two major subgroups, PFA-1 and PFA-2, and nine minor subtypes were discovered. Transcriptome profiling suggested a distinct histogenesis for PFA-1 and PFA-2, but their clinical parameters were similar. In contrast, PFA subtypes differed with respect to age at diagnosis, gender ratio, outcome, and frequencies of genetic alterations. One subtype, PFA-1c, was enriched for 1q gain and had a relatively poor outcome, while patients with PFA-2c ependymomas showed an overall survival at 5 years of > 90%. Unlike other ependymomas, PFA-2c tumors express high levels of OTX2, a potential biomarker for this ependymoma subtype with a good prognosis. We also discovered recurrent mutations among PFA ependymomas. H3 K27M mutations were present in 4.2%, occurring only in PFA-1 tumors, and missense mutations in an uncharacterized gene, CXorf67, were found in 9.4% of PFA ependymomas, but not in other groups. We detected high levels of wildtype or mutant CXorf67 expression in all PFA subtypes except PFA-1f, which is enriched for H3 K27M mutations. PFA ependymomas are characterized by lack of H3 K27 trimethylation (H3 K27-me3), and we tested the hypothesis that CXorf67 binds to PRC2 and can modulate levels of H3 K27-me3. Immunoprecipitation/mass spectrometry detected EZH2, SUZ12, and EED, core components of the PRC2 complex, bound to CXorf67 in the Daoy cell line, which shows high levels of CXorf67 and no expression of H3 K27-me3. Enforced reduction of CXorf67 in Daoy cells restored H3 K27-me3 levels, while enforced expression of CXorf67 in HEK293T and neural stem cells reduced H3 K27-me3 levels. Our data suggest that heterogeneity among PFA ependymomas could have clinicopathologic utility and that CXorf67 may have a functional role in these tumors.

MTX-related clinical neurotoxicity is transient, and most patients can receive subsequent MTX without recurrence of acute or subacute symptoms. All symptomatic patients and one in five asymptomatic patients develop leukoencephalopathy that can persist until the end of therapy. Polymorphisms in genes related to neurogenesis may contribute to susceptibility to MTX-related neurotoxicity.

American Lebanese Syrian Associated Charities, St Jude Children's Research Hospital, NCI Cancer Center, Alexander and Margaret Stewart Trust, Sontag Foundation, and American Association for Cancer Research.

Characterization of toxicity associated with cancer and its treatment is essential to quantify risk, inform optimization of therapeutic approaches for newly diagnosed patients, and guide health surveillance recommendations for long-term survivors. The National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) provides a common rubric for grading severity of adverse outcomes in cancer patients that is widely used in clinical trials. The CTCAE has also been used to assess late cancer treatment-related morbidity, but is not fully representative of the spectrum of events experienced by pediatric and aging adult survivors of childhood cancer. Also, CTCAE characterization does not routinely integrate detailed patient-reported and medical outcomes data available from clinically assessed cohorts. To address these deficiencies, we standardized the severity grading of long-term and late-onset health events applicable to childhood cancer survivors across their lifespan by modifying the existing CTCAEv4.03 criteria and aligning grading rubrics from other sources for chronic conditions not included or optimally addressed in the CTCAEv4.03. This manuscript describes the methods of late toxicity assessment used in the St. Jude Lifetime Cohort (SJLIFE) Study, a clinically assessed cohort in which data from multiple diagnostic modalities and patient-reported outcomes are ascertained.

PURPOSE The Children's Oncology Group trial ACNS0121 estimated event-free survival (EFS) and overall survival for children with intracranial ependymoma treated with surgery, radiation therapy, and-selectivelywith chemotherapy. Treatment was administered according to tumor location, histologic grade, and extent of resection. The impacts of histologic grade, focal copy number gain on chromosome 1q, and DNA methylation profiles were studied for those undergoing surgery and immediate postoperative conformal radiation therapy (CRT).METHODS ACNS0121 included 356 newly diagnosed patients (ages 1 to 21 years). Patients with classic supratentorial ependymoma were observed after gross total resection (GTR). Those undergoing subtotal resection received chemotherapy, second surgery, and CRT. The remaining patients received immediate postoperative CRT after near-total resection or GTR. CRT was administered with a 1.0-cm clinical target volume margin. The cumulative total dose was 59.4 Gy, except for patients who underwent GTR and were younger than age 18 months (who received 54 Gy). Patients were enrolled between October 2003 and September 2007 and were observed for 5 years. Supratentorial tumors were evaluated for RELA fusion; infratentorial tumors, for chromosome 1q gain. Classification of posterior fossa groups A and B was made by methylation profiles. RESULTSThe 5-year EFS rates were 61.4% (95% CI, 34.5% to 89.6%), 37.2% (95% CI, 24.8% to 49.6%), and 68.5% (95% CI, 62.8% to 74.2%) for observation, subtotal resection, and near-total resection/GTR groups given immediate postoperative CRT, respectively. The 5-year EFS rates differed significantly by tumor grade (P = .0044) but not by age, location, RELA fusion status, or posterior fossa A/posterior fossa B grouping. EFS was higher for patients with infratentorial tumors without 1q gain than with 1q gain (82.8% [95% CI, 74.4% to 91.2%] v 47.4% [95% CI, 26.0% to 68.8%]; P = .0013).CONCLUSION The EFS for patients with ependymoma younger than 3 years of age who received immediate postoperative CRT and for older patients is similar. Irradiation should remain the mainstay of care for most subtypes. 5 year, 82.8% (95% CI 74.4 to 91.2) 5 year, 47.4% (95% CI, 26.0 to 68.8) FIG 4. Event-free survival (EFS) for patients treated with immediate postoperative radiation therapy (strata 3 and 4) according to 1q gain status.6

A B S T R A C T PurposeLong-term survivors of childhood Hodgkin lymphoma (HL) are at risk for cardiopulmonary complications and CNS stroke, although neurocognitive function has not been previously examined. The aim of this study was to examine neurocognitive and brain imaging outcomes in adult survivors of childhood HL. Patients and MethodsIn all, 62 adult survivors (mean age, 42.2 years; standard deviation [SD], 4.77; mean age at diagnosis, 15.1 years; SD, 3.30) were identified by stratified random selection from a large cohort treated with either high-dose (Ն 30 Gy) thoracic radiation (n ϭ 38) or lower-dose (Ͻ 30 Gy) thoracic radiation combined with anthracycline (n ϭ 24). Patients underwent neurocognitive evaluations, brain magnetic resonance imaging (MRI), echocardiograms, pulmonary function tests, and physical examinations. ResultsCompared with national age-adjusted norms, HL survivors demonstrated lower performance on sustained attention (P ϭ .004), short-term memory (P ϭ .001), long-term memory (P ϭ .006), working memory (P Ͻ .001), naming speed (P Ͻ .001), and cognitive fluency (P ϭ .007). MRI revealed leukoencephalopathy in 53% of survivors, and 37% had evidence of cerebrovascular injury. Higher thoracic radiation dose was associated with impaired cardiac diastolic function (E/EЈ; ratio of peak mitral flow velocity of early rapid filling [E] to early diastolic velocity of the mitral annulus [EЈ]; P ϭ .003), impaired pulmonary function (diffusing capacity of lungs for carbon monoxide [DL co corr ; P ϭ .04), and leukoencephalopathy (P ϭ .02). Survivors with leukoencephalopathy demonstrated reduced cognitive fluency (P ϭ .001). Working memory impairment was associated with E/EЈ, although impaired sustained attention and naming speed were associated with DL co corr . Neurocognitive performance was associated with academic and vocational functioning. ConclusionThese results suggest that adult long-term survivors of childhood HL are at risk for neurocognitive impairment, which is associated with radiologic indices suggestive of reduced brain integrity and which occurs in the presence of symptoms of cardiopulmonary dysfunction.

Background Leukoencephalopathy is observed in some children undergoing chemotherapy for acute lymphoblastic leukemia (ALL), though its impact on long-term outcomes is unknown. This study examines associations between acute leukoencephalopathy, and neurobehavioral, neurocognitive and brain white matter imaging outcomes in long-term survivors of ALL treated with chemotherapy without cranial radiation. Methods During active therapy, 190 survivors (mean[SD] age 13·7[4·4] years, 7·7[1·7] years post-diagnosis) had brain magnetic resonance imaging (MRI’s), which were systematically coded for leukoencephalopathy using Common Terminology Criteria for Adverse Event v4. At ≥5 years post-diagnosis, survivors completed neurocognitive testing, another brain MRI, and their parents completed neurobehavioral ratings. Follow-up MRI included diffusion tensor imaging to assess white matter integrity, with indices of fractional anisotropy (FA), axial diffusivity (AD) and radial diffusivity (RD) from frontal and parietal lobes, and within the frontostriatal tract, an axonal fiber bundle associated with executive function. Findings Compared to population norms, survivors were reported to demonstrate more problems with Working Memory, Organization, Initiation and Planning (all p’s<0·001). The 51/190 survivors (27%) with a history of acute leukoencephalopathy displayed more problems than survivors with no history of leukoencephalopathy on Organization and Initiation. Survivors with acute leukoencephalopathy also had reduced white matter integrity within the frontostriatal tract at follow-up: lower FA (p=0·069), higher AD (p=0·020) and higher RD (p=0·0077). A one-unit change in the RD index corresponded to a 15·0, 30·3 and 28·0 increase in raw score points on Initiation, Planning and Working Memory, respectively (all p’s<0·050). Interpretation Acute leukoencephalopathy during chemotherapy treatment without cranial radiation for childhood ALL predicted higher risk for long-term neurobehavioral problems and reduced white matter integrity in frontal brain regions. Survivors of ALL may benefit from preventative cognitive and/or behavioral interventions, particularly those who develop acute leukoencephalopathy.

Survivors of childhood acute lymphoblastic leukaemia are at risk for neurocognitive impairment, though little information is available on its association with brain integrity, particularly for survivors treated without cranial radiation therapy. This study compares neurocognitive function and brain morphology in long-term adult survivors of childhood acute lymphoblastic leukaemia treated with chemotherapy alone (n = 36) to those treated with cranial radiation therapy (n = 39) and to healthy control subjects (n = 23). Mean (standard deviation) age at evaluation was 24.9 (3.6) years for the chemotherapy group and 26.7 (3.4) years for the cranial radiation therapy group, while time since diagnosis was 15.0 (1.7) and 23.9 (3.1) years, respectively. Brain grey and white matter volume and diffusion tensor imaging was compared between survivor groups and to 23 healthy controls with a mean (standard deviation) age of 23.1 (2.6) years. Survivors treated with chemotherapy alone had higher fractional anisotropy in fibre tracts within the left (P < 0.05), but not in the right, hemisphere when compared to controls. Survivors of acute lymphoblastic leukaemia, regardless of treatment, had a lower ratio of white matter to intracranial volume in frontal and temporal lobes (P < 0.05) compared with control subjects. Survivors of acute lymphoblastic leukaemia treated with chemotherapy alone performed worse in processing speed (P < 0.001), verbal selective reminding (P = 0.01), and academics (P < 0.05) compared to population norms and performed better than survivors treated with cranial radiation therapy on verbal selective reminding (P = 0.02), processing speed (P = 0.05) and memory span (P = 0.009). There were significant associations between neurocognitive performance and brain imaging, particularly for frontal and temporal white and grey matter volume. Survivors of acute lymphoblastic leukaemia treated with chemotherapy alone demonstrated significant long-term differences in neurocognitive function and altered neuroanatomical integrity. These results suggest substantial region-specific white matter alterations in survivors of acute lymphoblastic leukaemia possibly resulting in restricted radial diffusion due to the compaction of neuronal fibres.