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Choroid plexus tumors (CPT) constitute 2%–5% of all pediatric brain tumors and include high grade choroid plexus carcinoma (CPC). About 40% of CPC patients harbor germline TP53 mutations, associated with diminished survival rates. However, the number of TP53 carriers might be underestimated due to suboptimal ability of Sanger sequencing to identify mosaicism. We describe an 18-month-old boy with ultra-rare, bilateral disseminated CPC and negative family history of cancer. Next generation sequencing (NGS) revealed constitutional mosaicism of de novo TP53 mutation, which was barely detectable by Sanger sequencing. This is the first description of a de novo TP53 mutation mosaicism in a patient with CPC. Up to now four cases of de novo TP53 mutations in CPC patients have been described but none of them were mosaic. Since TP53 mutation mosaicism may have an impact on management of patients and predisposition to other cancers, a reliable method of identification is important. Our results highlight the utility of high-throughput technologies in detection of potentially important genetic markers.

BACKGROUND The optimal management for children with recurrent choroid plexus carcinoma (CPC), is not established. We report two children with germline TP53 mutations, whose CPC relapses were managed with marrow-ablative chemotherapy and oral biologically-targeted therapies. PATIENTS: Patient A: A 17 months old male presented with non-metastatic bilateral CPC. A de novo mosaic germline TP53 mutation was identified. After near-total resections, 16 months of standard chemotherapy were administered; 18 months later, localized tumor growth developed, again near-totally resected. Two cycles of re-induction chemotherapy were administered followed by three cycles of thiotepa/carboplatin with autologous hematopoietic cell rescue (AuHCR) and subsequently 21 months of sirolimus and thalidomide, continuing without residual or recurrent disease. Patient B: A 30 months old male presented with left lateral ventricular non-metastatic CPC. A de novo TP53 germline mutation was identified. Following sub-total resection, craniospinal irradiation with boost was administered followed by eight cycles of standard chemotherapy; 18 months later, localized recurrence developed; gross total resection was followed by 15 months of standard dose chemotherapies; four months thereafter, a second local recurrence developed, again gross totally resected. He then received one cycle of high-dose cyclophosphamide followed by three cycles of thiotepa/carboplatin with AuHCR. Subsequently he received sirolimus and thalidomide for 12 months, complicated by progressive pancytopenia. A small localized CPC recurrence was noted, gross totally resected, concomitant with myelodysplastic syndrome; he underwent an allogeneic matched unrelated donor marrow transplantation. CONCLUSIONS Marrow-ablative chemotherapy with post-transplant targeted biological therapy may afford durable survival for select children with recurrent CPC.

OBJECTIVES: The detection of the clinically important genetic markers, including mosaic mutations, is challenging but essential for precise clinical decision making. Next-generation sequencing (NGS) analysis with deep sequence coverage is a reliable approach for detection of genetic variants, including low-level mutations. Here we present usefulness of such approach in the detection of constitutional mosaicism in bilateral choroid plexus carcinoma and glioblastoma. METHODS: Whole exome sequencing of DNA extracted from probands leukocytes was performed on an Illumina HiSeq 1500 using the Nextera Rapid Capture Enrichment Kit (Illumina). The detected variants were validated by NGS deep amplicon sequencing on the Illumina MiSeq in the patient’s DNA extracted from buccal cells, urine sediment samples and tumor samples. RESULTS: NGS analysis revealed constitutional mutations c.742C>T in TP53 in patient with bilateral choroid plexus carcinoma and c.2392T>C in PSM2 in patient with glioblastoma. They were observed in only 12 of 91 (13.2%) and 37 of 116 (32%) sequencing reads, respectively. Identified TP53 substitution was not found in patient’s parents, indicating an apparent de novo mutation. The presence of allelic imbalance in samples from buccal cells and urine sediment supports the occurrence of constitutional mosaicism. Importantly, TP53 variant was undetectable when Sanger sequencing was applied. CONCLUSION: Our results highlight the utility of the NGS technology in the detection of mosaic mutations which may not be detectable by Sanger sequencing. This may be important for management of patients and genetic counseling, including a predisposition to other cancers. Funded by National Science Centre, Poland (2016/23/B/NZ2/03064 and 2016/21/B/NZ2/01785)

INTRODUCTION: Pineoblastoma is a rare, highly aggressive supratentorial tumour, more frequently diagnosed in young children. The prognosis remains poor. AIM: To present own experience with children with pineoblastoma. PATIENTS AND METHODS: 14 pts: 8 girls and 6 boys treated between 1998 and 2017 were analyzed. 5 pts (36%) were under 3 years of age. 7 pts underwent complete tumour resection, 2-partial resection and 5- biopsy. At the onset of treatment six patients had disseminated disease. 9 pts were treated according to protocol for MB HR group (with radiotherapy), 5 pts according to own baby protocol. RESULTS: 9 pts (64%) achieved good response to treatment (CCR-4 pts, CR-4 or PR-1). Four patients experienced tumour progression. 7 out of 14 patients are alive 3 ms to 17years from diagnosis (median 3years 4ms). Seven patients died (10ms to 8years from diagnosis). 1 pt died of long term post- radiotherapy sequelae. 5 yr EFS was 23 %, OS- 57%. 10 yr EFS and OS were 23 and 30,1% consecutively. 10 out of 14 pts relapsed 7ms to 4 years 3ms from diagnosis. 9 pts received second line treatment- 4 are alive. Children younger than 3 years of age treated without radiotherapy had worse outcome with 5 yrs OS estimated at 0% vs 74,1% in older children treated with chemotherapy and radiotherapy (p=0,014). CONCLUSION: Pineoblastoma is highly malignant CNS neoplasm of childhood with dismal prognosis. In our series children below 3 years of age treated without radiotherapy had poorer responses and worse outcome.

The aim of the study was to asses QoL in Medulloblastoma (MB) survivors according to risk groups. MATERIAL AND METHOD: Between 2005-2015 132 patients (40 girls, 92 boys aged 2 9/12 – 17 6/12) were treated of MB. 44 patients were standard risk and 88 high risk. Patients in SR group received radiotherapy to CNS 25Gy whereas HR - 36Gy. Age at analysis 6 1/12 to 29. Analysis included 5 year EFS/OS and assessment of: weight/height in percentiles according to risk groups and age at diagnosis, hearing loss, hearing aids, hair loss and occurrence of posterior fossa syndrome(PFS). Psychosocial assessment, including IQ, education, work, physical and social activities, interpersonal relationships was performed and compared in risk groups. RESULTS: 5 years EFS was 83% in SR and 76,6% HR (p=0,112), OS 89,7% and 82,3%. There was no significant difference in hearing loss between risk groups, but there was greater use of hearing aids in the latter (p=0,003), hair loss was markedly worse in HR (p=0,022). SR patients and those older than 10 years at diagnosis were higher as compared to other survivors. PFS occurred more often in HR group (p=0,005). IQ, educational achievements, physical and social activity and interpersonal relationships were significantly better in SR group (p

Choroid plexus tumors (CPT) comprise choroid plexus papilloma (CPP, WHO grade I), atypical choroid plexus papilloma (aCPP, WHO grade II), and choroid plexus carcinoma (CPC, WHO grade III). CPT from 20 nations were prospectively recruited into the CPT-SIOP-2000 study (01/2000–03/2010, n=129, median follow-up 7.4 years) and the CPT-SIOP registry (04/2010-01/2018, n=119). Non-surgical risk-stratified treatment consisted of i) chemotherapy for all CPC, all metastatic CPT and incompletely resected aCPP regardless of metastases ii) focal radiotherapy in non-metastatic CPC >3y, iii) craniospinal radiotherapy in non-metastatic CPC >3y during the registry phase. Non-metastatic CPP and aCPP R0 were followed by surveillance. CPT-SIOP-2000 randomized six cycles of carboplatin/VP16/VCR vs. cyclophosphamide/VP16/VCR. Alternating combination of these cycles were given to registry patients with CPC (n=16). WHO grading was the most significant prognostic variable for OS and EFS in CPT patients, five-year OS/EFS accounting for 100/96% in CPP (n=84), 97/79% in aCPP (n=88) and 58/35% in CPC (n=76). Of note, 5y OS/EFS was 100/92% for aCPP patients 2y (n=22). CPCs opting for postop surveillance only progressed with dissemination. Carboplatin based chemotherapy trended superiorly. Clinical staging had minor impact on survival in the primary treatment groups. Radiotherapy for CPC without Li-Fraumeni syndrome had a survival advantage in the first five years of follow-up, craniospinal field did not improve survival for non-metastatic CPC. Delayed radiotherapy for young patients with CPC that progressed on chemotherapy achieved meaningful responses (n=8). In conclusion: adjuvant therapy improves outcome for high risk CPT.

Astroblastoma is a rare CNS tumor of glial origin distinguished from other gliomas in the recent International Classification of Tumors of the Central Nervous System proposed by the World Health Organization. We present our experience with 3 astroblastoma patients. Between 2003–2017 among 978 patients with tumors of glial origin treated at our Institution 3 patients (0,3 %) were diagnosed with astroblastoma. There were 2 girls and 1 boy aged 2.5, 3, 5.5 years. Two patients had supratentorial tumors, one tumor was located infratentorially. All patients underwent subtotal tumor resection received pre-irradiation chemotherapy, local irradiation (54Gy) and maintenance chemotherapy. All patients are alive 1, 5 yrs 8 m, 13 yrs2m from diagnosis. Our results as of other authors confirm favorable prognosis and rarity of astroblastoma in pediatric population.

Background Ependymal tumors are the third most common group of brain tumors in children, accounting for about 10% of all primary brain neoplasms. According to the current WHO classification, they comprise four entities with the most frequent ependymoma and anaplastic ependymoma. The most of pediatric tumors are located within the posterior fossa, with a tendency to infiltrate the vital brain structures. This limits surgical resection and poses a considerable clinical problem. Moreover, there are no appropriate outcome prognostic factors besides the extent of surgical resection. Despite definition of molecular subgroups, the majority of childhood ependymomas present a balanced genome, which makes it difficult to establish molecular prognostic factors. Methods The purpose of our study was to explore whether miRNA expression could be used as prognostic markers in pediatric infratentorial ependymomas. We also performed a mRNA expression pattern analysis of NELL2 and LAMA2 genes, with immunohistochemical illustrations of representative cases. The miRNA and mRNA expression was measured in 53 pediatric infratentorial ependymomas using a real-time quantitative PCR. Results Three miRNAs were shown to efficiently differentiate between grade II and III ependymomas: miR-17-5p, miR-19a-3p, and miR-106b-5p. Survival analysis showed that the probabilities of overall (p = 0.036) and event-free survival (p = 0.002) were reduced with higher than median miRNA expression levels of miR-17-5p. Using multivariate analysis adjusted for patient's age, sex, tumor grade and localization, we showed statistically significant associations with event-free survival (p = 0004) and borderline statistical significance with overall survival (p = 0.057) for miR-17-5p. Correlation analysis of miR-19a, miR-17-5p, miR-106b revealed that their expression levels were significantly correlated with EZH2 expression, suggested marker of PFA ependymomas. Furthermore, lower expression level of LAMA2 mRNA was shown to be associated with an increased risk of death in covariate-adjusted analyses. Conclusions Our data provide a better understanding of pediatric ependymoma and suggests the presence of plausible molecular biomarkers connected with the outcome.

Ganglioglioma (GG) is a low-grade neoplasm, often associated with intractable epilepsy in pediatric patients. Available data suggest a relationship between GG and other glioneuronal lesions. So far, little is known about activation of kinases belonging to the mTor (mammalian target of rapamycin) pathway, although its upregulation is often found in brain tumors. Involvement of mTor kinase is responsible for excessive proliferation. In the current study we focused on the possible role of the Erk/Mapk (extracellular-signal-regulated kinase/mitogen-activated protein kinase) pathway in GG development. Eight GG tumors were resected from pediatric patients. Collected data reveal activation of proteins from the Erk pathway: Mek (extracellular regulated protein kinase kinase/mitogen-activated protein kinase kinase), Erk, Rsk1 (ribosomal S6 kinase 1), Rheb (Ras homolog enriched in brain) and Msk1 (mitogen- and stress-activated protein kinase 1), as detected by the western blot method. Moreover, activation of other proteins upstream of mTor - IGF-1R β (insulin-like growth factor 1β receptor), INR β (insulin receptor β), Akt/PKB (protein kinase B) - or downstream - 4E-BP1 (eukaryotic translation initiation factor 4E-binding protein 1) and rpS6 (ribosomal protein S6) - was also confirmed.

LG-49. LOW GRADE GLIOMA (LGG) OF THE SPINAL CORD. SPECIFIC LOCATION NEEDS SPECIFIC TREATMENT Marta Perek-Polnik, Iwona Filipek, Monika Drogosiewicz, Ewa Swieszkowska, Wieslawa Grajkowska, Elzbieta Jurkiewicz, Marcin Roszkowski, and Bozenna Dembowska-Baginska; The Children’s Memorial Health Institute, Warsaw, Poland INTRODUCTION: Spinal cord LGG constitute approximately 3,5% of all LGG locations. No specific therapeutic guidelines are available for this specific LGG site. AIM: Analysis of childhood spinal cord LGG. METHODOLOGY: 28 patients treated between2004-2015wereanalyzed for: sex, age, symptoms, pathology, treatment and outcome. RESULTS: There were 20 boys and 8 girls, aged 10 months-17 years, median 4.5 years. Paresis,scoliosis and pain were the most common symptoms. Pathology revealed Pilocytic astrocytoma in 21, Pilomyxoid astrocytoma in 4, LGG NOS in 3 patients. In 5 patients total or subtotal resections was performed, in 17 partial resection, in 6 biopsy were performed. In 13 pts neurological improvement was observed, in 7 – deterioration, the rest remained stable. 13 patients had no further treatment. 15 received chemotherapy: 7 following surgical treatment, 8 at tumor progression. 12 patients started with LGG protocol, 3 with VLB. In 10 patients stabilization, in 5 minimal tumor regression were observed. All patients are alive with median follow-up 3 years 8 months. 5 yr and 10 yr EFS are 52,1%, 27,7, respectively. 10 patients are walking without paresis, 9 with paresis, 2 have scoliosis, 6 pts use wheelchair, 1 is paralized. CONCLUSIONS: Spinal cord LGG have a good prognosis. Surgery improves neurological outcome, but radical resections are not mandated to achieve that. Some patients with tumor residual may not require further treatment, but at tumor progression chemotherapy is the treatment of choice. Quality of life should be the priority in choosing surgical strategy. Neuro-Oncology 18:iii78–iii96, 2016. doi:10.1093/neuonc/now075.49 #The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Neurofibromatosis type I (NF1) is a relatively frequent autosomal dominant disorder with different manifestations from mild cosmetic problems to severe disease requiring multidisciplinary treatment. THE AIM of our study was lo analyze types of disorders in paediatric population of NF1 patients treated in the Children's Memorial Health Institute and to present the schedule of care adopted in our institution.Medical records of 130 children, 70 girls and 60 boys aged from 1 year to 20 years 3 ms treated in the Children's Memorial Health Institute were analyzed. Type of mutation (familial or sporadic), age at diagnosis, type and frequency of disorders in the whole group of patients and in the familial and sporadic types were assessed.The familial type of NF1 was found in 58 patients, among whom there were, 23 patients from 10 families. It was sporadic in 40 pts and in 32 the type of mutation is unknown. The age at diagnosis ranged from 3 months to 17 years, median 6 years. The most frequent disorders were: T2-weighted hyperintensities of the white matter in 77 pts (59%), schooling problems in 60 pts (46%), skeletal deformations in 49 pts (37%), dysmorphia in 39 pts (30%), hyperactivity in 34 pts (26%), epilepsy in 29 pts (22%). There was a correlation between white matter hyperintensities and the presence of optic nerves gliomas (71%), schooling problems (58%), hyperactivity (77%) and dysarthria (85%). In 65 pts (53%) optic nerve gliomas were found, 45 patients required treatment. Plexiform neurofibroma requiring treatment was found in 25 pts (19%,), 6 had intraspinal penetration and in 4 spine compression was observed. Two patients were diagnosed with ganglioneuroma. Malignant tumours were found in 7 pts (5%), with a prevalence of soft tissues sarcomas. Skeletal disorders occurred more frequently in tNFl sporadic type than in familial cases (p=0.05). Based on our experience a management protocol was formulated. At the time of diagnosis this includes examination by the oncologist, neurologist, ophthalmologist, geneticist and additional investigations: abdominal ultrasound, chest X-rays, MR of the brain; found disorders indicate further consultations and studies. The check-up should be repeated annually and include all previous studies that revealed any abnormalities.1. Diagnosis of NF1 is delayed until complications of the disease occur. 2. In the studied group skeletal disorders were more frequent in the sporadic than in the familial type. 3. The paediatric population with NF1 varies from the adult NF1 patients in type of disorders, diagnostic and treatment requirements. Therefore there is a need for different care standards in the two groups. 4. The knowledge about NF1 and the standards of care should be transferred to general practitioners in order to diagnose these patients early and to refer them to specialized centres.

Despite progress in neuro-oncology, treatment results of children and adolescents with brain stem tumours remain poor. There are also controversies concerning the role of chemotherapy in the treatment of these tumours. THE AIM of our study was to analyze treatment results of patients with brain stem tumours treated with radiotherapy alone and with the addition of chemotherapy and to assess which chemotherapy protocol is the most efficient.Between 1981-2004, 126 patients were treated in our department. The patients were divided into 2 groups according to treatment methods applied. The first group consisted of 49 patients treated with radiotherapy alone. In the second group 77 patients were irradiated and received chemotherapy. Overall survival (OS) at 1 and 5 years was analyzed in both groups. The efficacy of treatment of patients from the second group was assessed by evaluating reaction to radiotherapy, to different chemotherapy protocols and duration of tumour regression. Additionally OS was assessed separately for patients with low grade gliomas treated in the second group.Seven out of 49 patients from the first group are alive with a follow up from 8 years 9 months to 24 years, median 6 years 7 months. In the second group, 25 out of 77 patients are alive with the follow up from 7 months to 8 years 2 months, median--l year 7 months. OS at l and 5 years for patients treated with radiotherapy alone is 48 and 14% and for those receiving additionally irradiation 59 and 18% respectively (statistically insignificant). Best tumour response was achieved in 42% of patients with radiotherapy but in 75% of cases regression lasted from 2 weeks to l year 3 months, median 4 months. Addition of chemotherapy consisting of cisplatinum and temozolamide resulted in tumour regression in 27% of patients lasting from 4 weeks to 4 years 5 months, median 4 months. OS for patients with LGG was 34.6% at 5 years.1. Radiotherapy in brain stem tumours allows to achieve tumour regression but short duration of remission and poor final outcome forces to search for other, effective treatment. 2. Patients with brain stem tumours may benefit from chemotherapy in terms of prolonging survival. 3. Chemotherapy consisting of temozolamide and cisplatinum seems to be promising and might add to improvement of treatment results, but further clinical studies are needed. 4. Patients with low grade gliomas of the brain stem constitute a separate group with a better prognosis.