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Few reports exist about reirradiation (RT2) for recurrent brain tumors in pediatric patients.A monocentric retrospective analysis of 22 patients with reirradiated CNS neoplasms was conducted with the objective to describe clinical outcomes and toxicities associated with RT2. Median age at diagnosis and RT2 was 8.5 years and 11.5 years respectively. Primary diagnoses included ependymoma (n=7, 32%), medulloblastoma (n=5, 23%), DIPG (n=4, 18%), glioblastoma (N=2, 9%), and others (N=4, 18%). The median interval between the first radiotherapy and RT2 was 16.5 months. Two patients underwent in-field RT2 for a secondary tumor. RT2 was administered with a curative intent in 13 patients, with a palliative-only treatment in the remaining 9. Sixteen patients received brain RT2 and 3 patients spine RT2, with a median cumulative dose of 19.9 Gy and 30 Gy respectively. Three patients received combined RT2. Volumetric Modulated Arc Therapy(VMAT) was the most frequent technique used (60%). Eight patients showed neurological symptoms before RT2, 6 had clinical benefit with RT2. Among patients who were asymptomatic before RT2, 5 later showed progressive neurological symptoms (at least partly attributable to RT2). Radionecrosis was radiologically detected in 6 patients, but accompanied by symptoms only in 3. Median event-free survival (EFS) and overall survival(OS) after RT2 was 4.7 and 8.7 months respectively, similarly to previous results. One-year EFS and OS was 13% and 36% respectively. As previously reported, OS appeared to be longer for patients with >12 months elapsed time between first irradiation and RT2 (1-year OS=45% versus 0%, p=0.07). In our cohort RT2 appeared feasible and provided short-term disease control with tolerable short-term toxicity, while providing relief in most symptomatic patients. Larger prospective studies are needed to understand which subsets of patients may benefit from either curative or palliative reirradiation, to provide respectively a longer survival and a significantly improved symptom control.

BACKGROUND: CNS embryonal tumors are a clinically and biologically heterogeneous group of tumors, more frequently arising in very young children. In the last few years, tumor classification through DNA methylation profiling has been demonstrated to be a powerful diagnostic tool which could be especially informative in this setting. METHODS: We reviewed original diagnosis and molecular profile of childhood CNS embryonal tumors other than medulloblastoma or AT/RT from a retrospective single-center cohort. Sixteen FFPE tissue samples from 14 unique patients (diagnosed from 1996 to 2017) were analyzed using DNA methylation arrays and matched with the Heidelberg classifier. Then, cohort characteristics and outcome were re-evaluated according to the results of the array. RESULTS: Median age at diagnosis was 2.7 years; there was no statistically significant difference between ETMRs and CNS embryonal tumors, NOS. Male to female ratio was 4:3. Median OS was 17,5 months (IQR 10.2-103.3 months) and ETMRs presented the worst outcome. Methylation profiling matched with an adequate score in 50% of samples (8/16). DNA methylation profile was consistent with ETMR in two samples but only one showed amplification of C19MC. Seven CNS embryonal tumors, NOS were properly reclassified as supratentorial ependymoma and diffuse pediatric-type HGG (4 and 1) or better defined as CNS neuroblastoma, FOXR2-altered (2). Methylation profiling added a unique diagnostic contribution in 64.3% of all cases (9/14). After the integration of methylation array results, survival markedly differed according to the novel integrated diagnoses; supratentorial ependymomas presented the longest median OS while no patients refined as CNS neuroblastoma or HGG survived. CONCLUSIONS: Our study confirmed that DNA methylation profiling provides relevant information for the classification of rare neoplasms like CNS embryonal tumors. Especially for selected cases with ambiguous histology, implementation of this tool should be considered to improve diagnostic precision and tailor patients’ management.

Aims of patient follow-up are: discovering relapse to apply second-line therapy for possible cure, accruing patients in phase 1/2 protocols if second-line therapy is not standardized/curative, evaluating/treating iatrogenic effects. To lessen the patient/family emotional and social economic burdens, we should ideally understand if scheduled radiological follow-up has a better rationale/outcome than the symptomatic relapse. We analyzed the Italian series of 2016 (doi:10.1093/neuonc/now108) comprehending 160 newly diagnosed pediatric/adolescent patients with intracranial ependymoma (EPD) according to relapse status (recurrence at scheduled exam [RECPT]/sign-symptomatic recurring [SYMPPT]). RECPT and SYMPPT were assessed in Cox model as time-dependent variables for overall survival (OS). Differences in characteristics between RECPT and SYMPPT subgroups were assessed by Wilcoxon-Mann-Whitney or Fisher Exact tests. Kaplan-Meier curves depicted event-free survival (EFS) and OS after recurrence according to signs/symptoms. There were 16 SYMPPT /34 RECPT, at a median follow-up of 55 months. No significant differences were found between SYMPPT/RECPT for gender, age, tumor grade/site, shunt, residual disease, radiation boost, type of relapse (local/distant/combined). Time-to-relapse (median:19 months, range 5–104) and treatment adoption did not differ between SYMPPT/RECPT while signs/symptoms depicted an unfavorable factor for OS after relapse (5-year OS: 8% vs 37%). Adjusted model in multivariate analysis confirmed that presence of signs/symptoms was prognostically unfavorable. In order to improve the OS in symptomatic patients, their early identification-in the first two/three years after diagnosis- would be desirable. Perhaps, this could be obtained paying attention to “heuristically detected” subgroup of patients, not just describing general prognostic variables but discovering possible biology differences according to signs/symptoms.