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Pineoblastomas have been thought to portend a poor prognosis, especially in younger children or those with metastases. Long term survivors after relapse, especially for those with metastatic disease are rare. We report a young girl with a DICER1 mutation who survived recurrent metastatic pineoblastoma. She was initially diagnosed at the age of 3 with a localized pineoblastoma, underwent gross total surgical resection, and received high dose chemotherapy with autologous stem cell transplant per COG ACNS0334 without radiation therapy. 16 months after completion of treatment, she relapsed at primary site with widespread spinal metastasis. She then received cranial spinal radiation of 3600Gy with proton beam, with boost to primary to 5580Gy, followed by chemotherapy with Temozolomide, Irinotecan and Avastin per COG ACNS0821. She is now 3 years and 3 months from completion of treatment, is doing well clinically with stable imaging findings. No particular alteration was identified from the tumor molecular testing of her initial pineoblastoma. Of note, she was diagnosed with pleuropulmonary blastoma soon after her initial diagnosis of pineoblastoma, and was found to have a DICER1 mutation (c.2062C>T; pR688*) thought to be a nonsense mutation. While radiation therapy following recurrence is known to improve the outcome, more recent studies suggest that tumors lacking the molecular features of high grade glioma also has a positive impact on prognosis. In addition, we speculate that DICER1 mutations might increase sensitivity of cancer cells to some chemotherapy through modulating gene expression and /or interfering with DNA repair mechanisms, therefore, affecting treatment outcome.

METHODS Through the Advancing Treatment for Pediatric Craniopharyngioma (ATPC) consortium we accumulated preoperative MRIs and tumor RNA for 50 unique ACP patients. MRIs were assessed quantitatively for 28 different features and analyzed using Multiple Factor Analysis (MFA) and optimal clustering was determined via maximization of Bayesian Information Criterion (BIC). Following bulk RNAseq, differential expression and pathway enrichment were performed using standard methodologies (i.e., DESeq2 and GSEA). RESULTS MRI features were well represented in the first 3 dimensions of MFA (variance explained=67.32%); specifically tumor/cyst size, ventricular size, and cyst fluid diffusivity. Using this three-way axis, we identified 3 patient subgroups. Transcriptional differences between these subgroups indicated one group was enriched for DNA damage response and MYC related pathways, one group enriched for SHH, and one group enriched for WNT/β-catenin and EMT-related pathways. CONCLUSION This preliminary work suggests that there may be unique gene expression variants within ACP, which may be identified preoperatively using easily quantifiable MRI parameters. These radiogenomic signatures could provide prognostic information and/or guidance in the selection of antitumor therapies for children with ACP.

BACKGROUND Craniopharyngiomas are rare embryonic malformations of the sellar region with high survival rates but high morbidity due to long-term sequelae caused by the location of the tumour. We summarise our institution’s experience on the management and outcomes of paediatric craniopharyngiomas in Singapore. METHODS This was a retrospective review of all paediatric patients (18 years and below) with histologically diagnosed craniopharyngioma managed by the National University Hospital, Singapore from January 2002 to June 2017. Data on clinical presentation, imaging, treatments, and outcomes were extracted from the electronic medical records using a standardized data collection form. Data analysis was conducted using RStudio (Version 1.2.5033). Institutional ethics approval was obtained for the study. RESULTS We identified 12 cases of paediatric craniopharyngiomas. The majority of cases were male (8, 66.7%) and the median age at presentation was 6.0 (IQR 3.8 – 9.5). Initial surgical management was tumour excision (11, 91.7%) or insertion of a reservoir into the cyst cavity (1, 8.3%). All cases had diabetes insipidus, 10 (83.3%) had endocrine dysfunction, and 8 (66.7%) had visual impairment on long term follow up. 7 (58.3%) cases had recurrence, and 3 (25.0%) had demised. Cox-regression showed that females (HR=33.9, p=0.049), and Chinese race (HR=13.3, p=0.034) were at higher risk for recurrence, but age at diagnosis and residual tumor on post-operative MRI was not significant. CONCLUSION The management of craniopharyngioma is complex as it is complicated by high recurrence rates and significant long-term morbidity. Further research on treatment strategies focusing on maintaining quality of life is important.

Chordomas are rare midline axial skeletal neoplasms that typically present in adults. They are infrequent in childhood with typical localization in the spheno-occipital skull base. They are derived from remnants of the embryonic notochord. We present the case of 4 months old girl, who was born with „blueberry muffin” syndrome and was first negatively diagnosed for neuroblastoma and leukemia (two negative skin biopsies were performed) was admitted with axial laxity. In imaging testes there was a tumor of the scull base, metastases in the lungs and kidneys (that were not seen at previous assessments) and a small lesion in the heart. The third biopsy of skin lesion was performed and pathological examination revealed a neoplasm composed of cords, clusters, and chains of multivacuolated cells embedded within a myxoid matrix and separated by fibrous septa. No atypical and dedifferentiated features were present. Mitotic activity was not observed. Neoplastic cells showed the typical cytoplasmic immunostaining for EMA, S100 and cytokeratin AE1/AE3, strong nuclear brachyury expression, and retention of nuclear INI-1 expression. The diagnosis of chordoma was established. Neoplastic tissue and blood samples were obtained for molecular analysis using next generation sequencing, including germline mutations assessment (are ongoing). Chemotherapy as for soft tissue sarcomas was undertaken. Currently a patient is on treatment with improvement of neurological status.

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.

BACKGROUND DICER1 syndrome is a rare inherited tumor predisposition syndrome linked to an increased risk of several malignancies. Affected individuals most commonly develop pleuropulmonary blastoma (PPB) and ovarian sex cord-stromal tumors. Brain tumors in these patients are rare, however; the increased frequency of pineoblastoma in this population has been established. Traditionally, pineal parenchymal tumors of intermediate differentiation (PPTIDs) have not been associated with DICER1 syndrome, with research suggesting alternative mutations driving tumorigenesis. These tumors are pathologically and clinically diverse, with long-term surveillance based on therapeutic interventions. Here we describe a case of a germline DICER1 mutation in a patient with a PPTID, suggesting that this mutation is not limited to pineoblastoma as previously reported. CASE: We describe a 19 year-old female with a WHO grade III PPTID treated with multimodal therapy including surgery, craniospinal irradiation (CSI) and chemotherapy. She was noted to have a thyroid mass at diagnosis and was subsequently diagnosed with a benign thyroid nodule, followed most recently by a cataract with pathology concerning for medulloepithelioma of the ciliary body. Due to the known association between medulloepithelioma and DICER1 syndrome, targeted germline sequencing was obtained and confirmed a pathogenic heterozygous mutation. CONCLUSION To our knowledge this is the first report of a PPTID in a patient with DICER1 syndrome. This association highlights the clinical implications of molecular evaluation in pediatric brain tumors, for both immediate therapeutic decisions and long-term surveillance.

BACKGROUND Constitutional Mismatch Repair Deficiency (CMMRD) is a cancer predisposition syndrome caused by biallelic mutations in the mismatch repair pathway, and high-grade glioma (HGG) constitute the most prevalent brain tumours. Pseudoprogression alludes to radiological changes that mimic tumour progression, but are in fact due to other causes such as therapy related inflammation. It can occur as early as three months post treatment. To our knowledge, its characteristics in CMMRD patients has not been reported. METHODS We retrospectively identified seven patients with CMMRD and history of HGG at The Royal Children’s Hospital, Melbourne from 2005 to 2019. Our objective was to review the characteristics of pseudoprogression in this cohort. RESULTS Out of the seven patients, two with constitutional loss of PMS2 demonstrated evidence of pseudoprogression. Patient 1 presented at 16 years old with a cerebellar anaplastic astrocytoma. She developed clinical and radiological progression within two weeks of starting radiotherapy, persisting up to four months after completion. However, six months post radiation she improved without intervention and the tumour remains stable five years post therapy. Patient 2 presented at 17 years old with a midbrain anaplastic astrocytoma, and showed signs of progression four weeks after completion of radiotherapy. She was then treated with Bevacizumab, an anti-VEGFA antibody with remarkable response. She subsequently received Nivolumab, a checkpoint inhibitor with ongoing stable disease for four months. CONCLUSION Our findings showed that pseudoprogression can occur early in the treatment course in CMMRD patients. Identification of this entity is important for appropriate clinical management.

Craniopharyngiomas are benign intracranial tumors located in the sellar and suprasellar region. Their size and extent of invasion into surrounding structures vary considerably. While the majority of craniopharyngiomas on presentation are between 1–3 cm without hypothalamic invasion, a significant proportion of patients present with ‘giant’ craniopharyngiomas of >4cm in dimension with large cystic extension through the 3rd ventricle. These tumors pose a challenge both for surgical resection as well as for radiation therapy. Proton beam therapy (PBT) has become the preferred standard of care after subtotal resection of pediatric craniopharyngiomas. In the setting of giant craniopharyngioma, the use of proton therapy allows a reduction of dose to surrounding normal brain, but changes in cyst volume can result in either under-coverage of tumor or excess dose to surrounding brain, an effect further magnified by the sharp gradients associated with proton dose distributions. In this case report we describe the proton treatment planning and intra-treatment monitoring of two patients with giant craniopharyngiomas with largest pre-operative of dimension 6cm, and 9cm, respectively, and 6cm and 5.5cm, respectively, pre-radiation. Both patients had drains inserted to Ommaya reservoirs. We performed surveillance imaging during RT utilizing spiral computer tomography (CT) on a weekly basis and reconstructed the treatment dose on the surveillance CTs to ensure target coverage and normal tissue sparing. We compared the dosimetry in these cases for PBT versus intensity-modulated radiation therapy, characterized the cyst evolution during treatment in 3 dimensions, and define an optimized protocol for treatment planning and intra-treatment monitoring.

Childhood craniopharyngioma is a rare and slow growing brain tumour, often located in the sellar and suprasellar region. It commonly manifests with visual impairment, increased intracranial pressure and hypothalamic and/or pituitary deficiencies. Visual impairment in childhood adversely affects a child’s daily functioning and quality of life. We systematically reviewed the literature to provide an extensive overview of the visual function in children with craniopharyngioma at diagnosis in order to estimate the diversity, magnitude and relevance of the problem of visual impairment. Of the 543 potentially relevant articles, 84 studies met our inclusion criteria. Visual impairment at diagnosis was reported in 1041 of 2071 children (50.3%), decreased visual acuity was reported in 546 of 1321 children (41.3%) and visual field defects were reported in 426 of 1111 children (38.3%). Other ophthalmological findings described were fundoscopic (32.5%) and orthoptic abnormalities (12.5%). Variations in ophthalmological testing methods and ophthalmological definitions precluded a meta-analysis. The results of this review confirm the importance of ophthalmological examination in children with craniopharyngioma at diagnosis in order to detect visual impairment and provide adequate support. Future studies should focus on long-term visual follow-up of childhood craniopharyngioma in response to different treatment strategies to provide insight in risks and ways to prevent further loss of vision.

INTRODUCTION Among choroid plexus tumors (CPTs), metastasis occurs more frequently as pathological grading increases. There could be an underestimation of pathological diagnosis if disseminated CPTs are diagnosed with lower grade tumors such as choroid plexus papilloma (CPP) or atypical choroid plexus papilloma (aCPP). Thus, molecular diagnosis using genome-wide DNA methylation profiling may be useful to clarify malignant potential among thetumor entity. Here, we report about a case of aCPP with intracranial dissemination that was molecularly diagnosed by methylation profiling. CASE DESCRIPTION: A 2-year-old girl presented with a history of vomiting. Brain magnetic resonance imaging showed a large tumor mass in the right lateral ventricle and diffuse enhancement surrounding her brainstem, which suggested dissemination. Gross total resection of the mass was performed. Intraoperative findings revealed multiple spot metastatic lesions on the inner wall of lateral ventricle. The pathological diagnosis was aCPP owing to the presence of a glandular structure with a papillary pattern suggesting a neoplasm of epithelial origin, increased cellularity, several necrotic areas, and an intermediate number of mitoses. The CPT-SIOP-2000 treatment protocol was followed without radiation therapy, and the disseminated lesion was disappeared during the chemotherapy. Methylation data of the current case was entered into a recently published classifier, and the tumor was classified as methylation class “plexus tumor, subclass pediatric A” with high confidence (calibrated score 0.96), which includes cases diagnosed as CPP and aCPPs. CONCLUSION Our case indicates the clinical significance of molecular confirmation of diagnosis among CPTs, particularly lower grade tumors with dissemination.

BACKGROUND Choroid plexus tumors (CPT) include choroid plexus papilloma (CPP), atypical choroid plexus papilloma (aCPP), and choroid plexus carcinoma (CPC). Because of their rarity, limited data are available on the current status of treatment and outcomes for pediatric CPTs. METHOD We retrospectively reviewed clinical information on patients with CPT patients aged between 0 and 30 years at diagnosis and were treated in 8 institutions in Japan. RESULTS Of forty-two cases initially diagnosed as CPT, 18 cases were reviewed by central pathologists. As a result, the diagnosis of CPC or aCPP in five cases were changed to other tumors including AT/RT and astroblastoma. The remaining 37 cases were subjected to analysis. Median age at diagnosis was two years (0 to 25) and the mean follow-up period was seven years. All 26 patients with CPP (n=20) or aCPP (n=6) underwent gross-total resection without adjuvant therapy. Of them 24 patients are alive without recurrence. Four patients of patients with CPC (n=11) died of cancer. Five patients including three patients experienced local relapse, achieved complete remission after resection of tumor plus chemoradiotherapy. All three patients with dissemination of CPC at diagnosis or relapse died of the disease. At least three patients were diagnosed with Li-Fraumeni syndrome: one died of medulloblastoma and one patient developed osteosarcoma. CONCLUSION Compared with the excellent prognosis of CPP, the survival rates for CPC, especially disseminated CPC are unsatisfactory. Our results also underline the importance of considering genetic testing of TP53 for patients with CPC.

BACKGROUND We report the outcomes of patients with pineoblastoma enrolled on the Head Start I-III trials. METHODS Twenty-three children were enrolled between 1991–2009. Treatment included maximal surgical resection followed by five cycles of intensive-chemotherapy and consolidation with marrow-ablative chemotherapy and autologous hematopoietic cell rescue (HDCx/AuHCR). Irradiation following consolidation was reserved for children over six years of age or those with residual tumor at the end of induction. RESULTS The median age was 3.12 years (range:0.44–5.72). Three patients withdrew from the protocols and two patients experienced chemotherapy-related mortality. Eight patients experienced progressive disease (PD) during induction chemotherapy. Ten patients received HDCx/AuHCR; eight experienced PD post-consolidation. Seven patients received craniospinal irradiation (CSI) with a median dose of 20.7 Gy (range:18–36 Gy) with boost(s) (median dose 27 Gy, range:18–36 Gy); three received CSI as adjuvant therapy (2 post-HDCx/AuHCR) and four upon progression/recurrence. The 5-year progression-free survival (PFS) and overall survival (OS) were 9.7% (95%,CI:2.6–36.0%) and 13% (95%,CI:4.5–37.5%), respectively. Three patients survived beyond five years. Nineteen patients relapsed in the following sites: local site (n=4), distal site (n=6), local and distal sites (n=9). Favorable OS prognostic factors were CSI (hazard ratio (HR)=0.30 (0.11–0.86), p=0.025), and HDCx/AuHCR (HR=0.40 (0.16–0.99), p=0.047). CONCLUSION CSI and HDCx/AuHCR were statistically associated with improved survival. The overall poor outcomes and high PD rate during later induction cycles and following consolidation chemotherapy warrants consideration of fewer induction cycles before consolidation and the intensification of consolidation with multiple cycles of marrow-ablative chemotherapy.

BACKGROUND Constitutional mismatch repair deficiency syndrome (CMMRD) is a severe cancer predisposition syndrome resulting in early onset central nervous system (CNS) and other cancers. International guidelines for surveillance exist but no study has systematically evaluated the efficacy of this protocol. METHODS We surveyed all confirmed CMMRD patients in the International Replication Repair Deficiency Consortium. A surveillance protocol consisting of frequent biochemical, endoscopic and imaging (CNS and total body MRI) studies were employed. Survival analyses and efficacy of each method were assessed. RESULTS Surveillance data were collected from 105 CMMRD individuals from 41 countries. Of the 193 malignant tumors, CNS malignancies were the most common (44%). The surveillance protocol uncovered 49 asymptomatic tumors including 16 glioblastomas and medulloblastomas. Five-year overall survival was 89% for tumors discovered by surveillance, and 61% for symptomatic tumors (p6 months as per protocol. Finally, of the low grade tumors identified asymptomatically, 5 were low grade gliomas. All of the low grade gliomas, which were not resected transformed to high grade tumors at a median of 1.6 ± 0.9 years. CONCLUSION These data support a survival benefit in CMMRD patients undergoing a surveillance protocol. Adherence to protocol and resection of lower grade lesions may improve survival for patients with CNS tumors.

BACKGROUND Little is known about cancer risk associated with pathogenic germline SUFU variants. METHODS Data of all previously published and 25 still unpublished patients with a pathogenic germline SUFU mutation were compiled. RESULTS 124 patients in 67 families were identified, most of them ascertained after the occurrence of a medulloblastoma (MB) or as part of Gorlin syndrome cohorts. Overall, 30 patients were healthy carriers and 94 patients developed a total of 129 tumors (up to 4 tumors/patient): 68 MBs, always as first tumor (median age at diagnosis: 1.5yr [0.1–5]), 22 patients with at least 1 basal cell carcinoma (BCC) (median 10/patient) (median age at first BCC: 43yr, [17–52]), 15 meningiomas (median age 43yr, [13–72]), 7 ovarian stromal/fibrous tumors (median age 12yr [5–34]), and 17 other tumors including 5 sarcomas (median age: 50yr [7–79]). Median age at last follow-up was 30yr. Nineteen patients died, including 11 from MB. Second malignancies were diagnosed in 21 patients including 13 in MB survivors. Mutations were inherited in 58/66 (88%) of cases in which inheritance could be tested and de novo in 8. In 6/67 families (9%), >2 children were diagnosed with a MB. CONCLUSION In this large cohort of germline SUFU mutation carriers, MB in infants is the most frequent tumor but the spectrum also includes typical Gorlin syndrome tumors (BCC, meningiomas, and ovarian stromal/fibrous tumors) either as first tumors or as second malignancies. This broad tumor spectrum and the high risk of second malignancies justify the implementation of specific cancer surveillance programs.

Neurocutaneous melanocytosis (NCM) is a rare disease characterized by excessive proliferation and deposition of melanocytes in the leptomeninges and brain parenchyma, occurring in children with large congenital melanocytic nevi (LCMN). Manifestations of NCM range from asymptomatic CNS melanin deposition to cranial neuropathies, seizures, and hydrocephalus. Patients with NCM are at risk for malignant melanoma. We conducted a retrospective, single-institution study of patients with LCMN evaluated at Memorial Sloan Kettering Cancer Center from June 2000 to January 2020. Of 55 patients studied, 15 had no radiographic NCM, and 40 had radiographic NCM at initial evaluation. MRI findings included: focal melanocytosis (33), diffuse leptomeningeal disease (4), solid melanoma (3). Malformations were identified in 13, including arachnoid cyst (4), congenital hydrocephalus (4), Dandy-Walker malformation (3), and tethered cord (1). Twenty-one patients completed imaging once and were followed clinically. Seventeen with serial imaging (10 with focal melanocytosis, 7 with normal MRI) remained stable over a median 24-month follow up (range: 1–124). Six had suspected radiographic progression of NCM without melanoma. Malignant melanoma developed in 11 patients, 5 with focal melanocytosis on initial imaging. Median time from focal melanocytosis identification to melanoma diagnosis was 80 months (range: 18–200). Median age at melanoma diagnosis was 9.9 years (range: 1.1–25.3). Median survival from melanoma diagnosis was 9.1 months (range: 1–60.4). Focal NCM on neuroaxis imaging does not predict time to transformation to malignant melanoma. Serial imaging is not indicated in absence of disease-modifying treatment. Clinical follow up of at-risk individuals is essential in early identification of complications.

INTRODUCTION Everolimus is an inhibitor of mTORC1 (mammalian target of rapamycin complex 1), it is Health Canada and FDA approved for SEGA and renal angiomyolipoma in the setting of tuberous sclerosis complex (TSC). There is little data available in regards to this treatment of TSC associated retinal astrocytoma (RA). Although the behaviour of RA is often indolent or slowly progressive, aggressive behaviour with retinal detachment and neovascular glaucoma requiring enucleation has been reported in several patients. Definite TSC diagnosis is established when either two major features or one major and two minor features are present. Probable TSC diagnosis is established when one major plus one minor feature is present. METHODS We report a child with probable TSC mosaicism, with negative serum NGS for TSC but RA and retinal achromic patch on the left. A left retinal peripapillary astrocytoma around optic nerve and very close to fovea was noted. There was concern that if it grew or there were to be any leakage it would cause visual impairment. This lead to therapy with everolimus 4.5 mg/m2/d aiming for level between 5 and 10 mcg/L. RESULTS This boy has had a gradual reduction of the RA over the last 29 months, with healthy retina in the region no longer occupied by the lesion and preserved vision. He has tolerated therapy well with occasional mouth ulcers. CONCLUSION mTORC1 inhibition is effective therapy to preserve vision in the setting of retinal astrocytoma and tuberous sclerosis mosaicism.

BACKGROUND Giant cell tumor of bone(GCTB) is a rare neoplasm with unpredictable behavior, possible malignant transformations, and/or lung metastases. Surgery is usually the treatment of choice. In unresectable or metastatic cases, treatment with denosumab is a new treatment option. CASE PRESENTATION: A 14-years-old female presented with cachexia, dysphagia, diplopia, discoordination, strabismus, and multiple cranial nerve palsies in 10.2015. MRI revealed intra-extracranial mass arising from C2 vertebrae, compressing the medulla oblongata and the left cerebellar hemisphere, invading to the sphenoid bone and nasopharynges. Biopsy showed a GCTB. Surgical resection was done, which was incomplete because of tumor location (cranial nerve and vertebral artery involvement). Then local radiation therapy was performed 50.4Gy. During RT patient’s condition declined and MRI showed disease progression. Treatment with denosumab 120mg q4w was initiated in 03.2016, which yielded successful results. Disease was under control for three years until 03.2019. Then she returned with clinical symptoms of diplopia and severe headache. MRI showed local tumor progression. Repeated biopsy revealed undifferentiated pleomorphic sarcoma, which could be either a malignant transformation of GCTB or a new tumor. The patient later underwent two cycles of chemotherapy with Ifosfamide/Doxorubicin. MRI after 2nd cycle showed marked tumor progression. The patient didn’t receive any further treatment because of cachexia and died due to disease progression in 12.2019. CONCLUSION To our knowledge, this is the youngest patient ever reported with a skull base tumor with such a clinical development, successful and long-time remission with denosumab and with such a chemotherapy-resistant malignant transformation or second cancer.

Diffuse leptomeningeal glioneuronal tumors (DLGNT) are rare with an unknown etiology and unestablished incidence. Most frequently reported genetic alteration is KIAA1549-BRAF fusion. We present four DLGNT cases diagnosed between 2005–2018. Patient 1 is a female who presented with a 2-year history of back pain subsequently diagnosed with pilocytic astrocytoma. Re-imaging 3 months post-resection revealed a low grade glioneuronal tumor with BRAF duplication. Patient 2 is a female who presented with recurrent vomiting, dizziness, and hydrocephalus. The patient underwent biopsy which was consistent with oligodendrogliomatosis; no genetic analysis was done. Patient 3 is a male who presented with worsening headaches and intermittent vomiting. Approximately 5 months after resection, imaging showed leptomeningeal disease and further testing revealed KIAA1549-BRAF fusion and 1p deletion. Patient 4 is a male who presented with hydrocephalus. Imaging showed disseminated leptomeningeal enhancement without a dominant mass lesion; biopsy and clinical history confirmed the diagnosis. All four patients received chemotherapy, Patients 1 and 3 underwent radiation therapy, and Patient 3 received a MEK-inhibitor to which he had a great response. However, the patient was non-compliant and had PD which continued despite re-starting therapy. Patients 1, 2, and 3 have died of progressive disease; survival was Patient 1, 276 days, Patient 2, approximately 7 years and 8 months, and Patient 3, 2 years and 11 months. Patient 4 remains alive with disease 4.5 years from diagnosis. There is much to be learned about this rare, poorly understood disease but hope for improvement through therapeutic targeting of the MAPK pathway.

Primary tumours of the meninges are rare accounting for only 0.4–4.6% of all paediatric tumours of the central nervous system. Due to the rarity of these tumours in children, and the consequent absence of collaborative prospective trials, there is no clear consensus on how the unique characteristics of paediatric meningiomas impact clinical status, management approach, and survival. Much of the evidence and treatment recommendations for paediatric meningiomas are extrapolated from adult data. Translating and adapting adult treatment recommendations into paediatric practice can be challenging and might inadvertently lead to inappropriate management. In 2009 Traunecker et al. published guidelines for the management of intracranial meningioma in children and young people on behalf of UK Children’s Cancer and Leukaemia Group (CCLG). Ten years later we have developed the updated guidelines following a comprehensive appraisal of the literature. Complete surgical resection is the treatment of choice for symptomatic meningiomas, while radiotherapy remains the only available adjuvant therapy and may be necessary for those tumours that cannot be completely removed. However, significant advances have been made in the identification of the genetic and molecular alterations of meningioma, which has not only a potential value in development of therapeutic agents but in surveillance of childhood meningioma survivors. This guideline builds upon the CCLG 2009 guideline. We summarise recommendations for the diagnosis, treatment, surveillance and long-term follow up of children and adolescents with meningioma.

OBJECTIVE In recent years, the endoscopic endonasal approach (EEA) has been increasingly used for pediatric craniopharyngiomas. We here present our experience and the outcomes of the EEA resection of pediatric craniopharyngiomas. MATERIALS AND METHODS Between April 2014 and December 2019, 16 cases of pediatric craniopharyngiomas were operated at the Osaka city university (OCU) hospital. Eight patients were diagnosed with primary craniopharyngiomas while 8 had a recurrent tumor. There were 5 males and 11 females, with a mean age of 10.7 years (3–17 years). EEA was selected in all patients and a case of large muti-lobulated tumor was resected by combination of microscopic transcranial approach. RESULTS Gross total resection was achieved in 14 patients and near total resection in other 2. Post-op CSF leak occurred in 3 patients, which was treated with re-exploration. Pituitary stalk was preserved intraoperatively in 4 cases, and 15 patients developed diabetes insipidus and anterior hormonal replacement therapy was required in 15 patients at last follow-up. Visual improvement was noted in 4 patients while vision remained unchanged in the rest. Neuropsychological function status was preserved in all patients, and there was no new-onset obesity postoperatively. The mean follow-up duration was 35.1 months (2 – 69 months) and 4 of 8 recurrent cases had re-recurrence during this period, however there was no recurrent in 8 primary cases. CONCLUSIONS EEA should be the surgical modality of choice for treating pediatric craniopharyngiomas. It results in better visual and cognitive outcomes with a significantly increased extent of resection.

Treatment strategy for trilateral retinoblastoma (TRb: very rare RB with brain tumor) or retinoblastoma with central nervous system (CNS) involvement is not established yet. We retrospectively reviewed our seven cases of these rare almost fatal tumors. Their ages at diagnosis are 0y3m-1y10m (median 1y3m) (Male 4, Female 3). Only one had RB family history. Their affected eyes were bilateral 3, unilateral 3 and no 1. Their CNS involvements were suprasellar tumor 4, pineal tumor 1 and cerebrospinal fluid (CSF) cytology positive 2. Three of the suprasellar tumor patients had spinal metastasis. Four of the seven patients were TRb and one were genetically classified suprasellar retinoblastoma. All of them were treated with chemotherapy and four received high-dose chemotherapy. Three brain tumors of four TRb almost disappeared with chemotherapy. Two of them also received radiotherapy but relapsed. Although one radiation-free long-term TRb survivor developed secondary osteosarcoma, he got remission again and live 5 more years. One CSF positive Rb patient with chiasm invasion died of disease 11 months later. The other patient had no chiasm invasion nor CSF involvement at diagnosis, but his CSF cytology turned to positive after his second cycle of chemotherapy. He got remission with radiotherapy and high-dose chemotherapy, and alive without disease for 4 years. 2-year RFS and 2-year OS of all patients were 40% and 60%. Although our TRb patients responded to chemotherapy, it was difficult to avoid radiotherapy except one. Data accumulation is necessary for better treatment of these cancer-predisposed patients.

Chordoma is an uncommon bone tumor arising from notochordal remnant, which accounts for 1–4% of all bone malignancies. It commonly occurs along the cranial-spinal axis, and skull base is one of most frequent sites, representing 35–49% of all chordoma cases. Surgical resection is widely accepted as the first choice of treatment. There are only limited number of reports about pediatric chordoma cases, and its biological behavior including genetic backgrounds were largely unknown. Here, we present a 5 year-old girl with a large aggressive skull base chordoma of 6 cm in maximum diameter, which eventually had multiple systemic metastasis. We initially tried chemotherapy based on the protocol for the osteosarcoma, but in vain. Because the tumor was highly vascularized on angiography, after embolization of the feeding arteries and bilateral internal maxillary arteries, endoscopic endonasal surgery was performed. The tumor was sufficiently removed, achieving effective mass reduction, and the residual tumors involving the lower cranial nerves and craniocervial junction were additionally treated with Gamma Knife radiosurgery. However, one month later, it showed systemic metastasis to bilateral cervical lymph nodes and lung. We tried chemotherapy with nivolmab and imatinib for this patient, whereas they showed the partial effect. The genetic analysis revealed somatic TP53 c.569C>T, (p.P190L) mutation in chordoma specimen. In the past literature, we found only one study of the adult chordoma cases, in which majority of the patients had somatic TP53 mutation (p.P72R). Further investigation with large number of the cases is essential to clarify the molecular biology of pediatric chordomas.

BACKGROUND As genetic testing for both germline and tumor mutations has increased in completeness, complexity, and availability, more mutations and their impact on patient outcomes have been identified. METHODS A retrospective review of pediatric patients who have identified germline mutations and a different tumor mutation was conducted. Data collected included demographics, tumor type, germline mutation status, tumor mutation status, relapse status, and patient outcome. RESULTS Six patients aged 8–13 years old (median age 10 years) were identified for analysis. Four patients had pilocytic astrocytoma and two had pilomyxoid astrocytoma. One of the patients with pilocytic astrocytoma also had MPNST diagnosed very early at age 9. The combination of germline/tumor mutations is as follows: Neurofibromatosis Type I (NF1)/BRAF v600e, NF1, CHEK2/MYB-QKI, NF1, Klinefelter, ATM, MUTYH, GPC3/BRAF-KIAA fusion, NF1/BRAF-KIAA (2 patients), and Marfan’s/BRAF-KIAA. The number of relapses per patient following initial diagnosis range from 3–7 with an average of 3.3. Four of the patients are alive and on therapy, which two are deceased. The two deceased patients both had NF1/BRAF-KIAA fusions and pilocytic astrocytomas. CONCLUSIONS Patients with differing and compounded germline and tumor molecular genetic mutations have worse outcomes. These patients have more relapses and death when compared to those patients with one mutation, either germline or tumor. Broad molecular testing and germline testing for mutations is crucial in determining patient risk for poor outcomes.

Ewing sarcoma family of tumors predominantly affect the pediatric population in the long bones of the extremities or the pelvis, and only 8% of cases arise within the spine. Primary Ewing’s sarcoma of the cervical spine is extremely rare and less than 30 cases have been reported in the literature thus far. Here we present a case of primary Ewing’s sarcoma of the cervical spine in a 28-year-old female who presented with a three-month history of neck pain and right arm radiculopathy. MRI revealed a homogeneously contrast enhancing, eccentric mass with dural tail at C2-C7. After undergoing a hemilaminectomy, histopathology confirmed extraosseous Ewing’s sarcoma with CD99 positivity. A comprehensive systemic and neuraxis work-up ruled out overt metastasis. We extrapolated data from children’s cooperative group studies and IESS-II clinical trial to formulate a three phase treatment protocol as described below. To date, patient is in remission with no evidence of any residual disease in the cervical spine. In conclusion, although Primary Ewing’s sarcoma of the cervical spine is extremely rare it should be considered a differential diagnosis in patients with neck pain and a spinal mass under the age of thirty. Less than 25% of EFT’s present with overt metastasis and almost all have subclinical metastatic disease at the time of diagnosis, therefore, a comprehensive evaluation and systemic chemotherapy is recommended. We recommend a multidisciplinary approach of surgical decompression to preserve neurological functions, followed by compressed chemotherapy regimens, reevaluation for local treatment, and adjuvant chemotherapy.

OBJECTIVE An unexpectedly high incidence of sarcomas of the Central Nervous System (SCNS) was recently observed in Peru. We describe clinical and biological characteristics of the disease. METHODS Seventy pediatric patients with primary SCNS diagnosed between January 2005 and June 2018 were analyzed. DNA methylation profiling and gene panel sequencing was available from 28 and 27 tumors, respectively. RESULTS Median age was 6 years (range 2–17.5), 66/70 patients had supratentorial tumors, 56 patients intratumoral hemorrhage at diagnosis. Three patients fulfilled clinical criteria of NF1; 35 had café-au-lait spots and/or freckling. DNA-methylation profiling classified 28/28 as “intracranial spindle cell sarcoma with rhabdomyosarcoma-like features and DICER1 mutations”. DICER1 mutations were found in 26/27, TP53 mutations in 22/27, and RAS-pathway gene mutations (NF1, KRAS, NRAS) in 19/27 tumors, all of which were somatic (germline control available in n=19 cases). Survival was analyzed in 57 patients with non-metastatic disease who received adjuvant therapy. Two patients had metastatic disease, eleven did not receive or abandoned treatment. Two-year OS was 66.3% (95%-CI: 54–81%), 2-year PFS 51% (38–67%). PFS was highest in patients treated with postoperative ICE chemotherapy followed by radiotherapy and ICE (2y-EFS 79% [59–100%], n=18) and worse after upfront radiotherapy followed by ICE (40% [19–85%]; n=10) or VAC (50% [28–88%], n=12) and radiotherapy only (21% [6–71%], n=11; p=0.008). CONCLUSION Primary SCNS with DICER1 mutation have an aggressive clinical course. A combination of chemotherapy and radiotherapy seems beneficial. A link to a cancer predisposition syndrome could not be established so far.

Inflammatory myofibroblastic tumor (IMT) is a mesenchymal neoplasm composed of fascicles of myofibroblastic spindle cells in a background of prominent inflammatory infiltrate. It is categorized as ‘intermediate, rarely metastasizing’ in the World Health Organization classification of tumors of soft tissue and bone. We present a novel case of concurrent brain and lung tumor with diagnosis of TFG-ROS1-rearranged IMT in a 14 year old female patient, in which targeted next-generation sequencing became a powerful tool for detection of genomic alterations in both lung and brain tumors. At age 9, the patient’s lung mass was incidentally found and investigated for various infectious diseases with negative result. At age 14, she presented with seizure and was noted to have a stable size lung mass and a left temporal lobe tumor. The left temporal lobe tumor showed a desmoplastic spindle cell neoplasm involving the meninges and cerebral cortex and Desmoplastic Infantile Ganglioglioma (DIG) was considered one of differentials. Subsequently, her right lung mass was resected and showed a similar spindle cell neoplasm with a background of dense fibrosis and chronic inflammation, consistent with Inflammatory Myofibroblastic Tumor. Molecular microdissection revealed that both tumors shares TFG-ROS1 fusion which is associated with (t(3;6) (q12;q22)), thus it is strongly suggestive that two tumors arose from the same origin. No predisposition syndrome was identified.

BACKGROUND Obesity, cardiovascular disease (CVD), and relapse/progression have major impact on prognosis in pediatric brain tumor (BT) patients. Cranial MRI is part of routine follow-up. METHODS In a cross-sectional study, we analyzed nuchal skinfold thickness (NST) on MRI performed for BT follow-up monitoring as a novel parameter for body composition (BC) and CVD in 177 BT patients (40 WHO grade 1–2 BT; 31 grade 3–4 BT; 106 craniopharyngioma (CP)), and 53 healthy controls (HC). Associations of NST with body mass index (BMI), waist-to-height ratio (WHtR), caliper-measured skinfold thickness (cSFT), and blood pressure (BP) were analysed in BT and HC. RESULTS CP patients showed higher BMI, WHtR, NST and cSFT when compared with BT and HC, whereas these differences were not detectable between BT and HC. However, WHO grade 1–2 BT patients were observed with higher BMI, waist circumference and triceps cSFT when compared to WHO grade 3–4 BT patients. NST showed high correlations with BMI, WHtR, and cSFT. NST, BMI and WHtR had predictive value for CVD in terms of increased BP, and in multivariate analysis, only BMI was selected for the final model resulting in an odds ratio of 1.25 (1.14–1.379). In CP patients with hypothalamic involvement/lesion or gross-total resection, rate and degree of obesity were increased. CONCLUSIONS As monitoring of MRI and BC play an important role in follow-up after BT, NST could serve as a novel useful parameter for assessment of BC and CVD risk in BT patients.

Second malignant neoplasms following treatment for primary central nervous system (CNS) tumors in children are rare occurrences but may often have dire consequences, particularly, if thought to be induced by prior therapies. The authors retrospectively reviewed pediatric patients with primary CNS malignancies from the University of Wisconsin over the last 25 years (1994 – 2019) with any secondary malignant neoplasm and determined seven patients met criteria. Treatment modalities were reviewed with all patients receiving surgery, chemotherapy, and radiotherapy for treatment of their first malignancy. The second neoplasms found included 4 high-grade gliomas, 1 meningioma, 1 thyroid carcinoma, and 1 myelodysplastic syndrome. The median latency time between diagnoses was 9 years (range 4 -17 years). The outcomes varied according to histopathology of the second neoplasm with the high-grade glioma patients all deceased from progressive disease. The high-grade gliomas were thought to have been induced by prior radiation in most cases. The remaining patients are still alive, at the time of this writing, and in follow up after treatment for their second neoplasm. Thus, long-term follow up is essential for children treated for a primary CNS tumor given the variety of second neoplasms that could arise with differential consequences. In addition to our single institutional outcomes, we will also present an updated review of the literature of pediatric patients with primary CNS tumors and second malignancies.

INTRODUCTION Choroid plexus tumors (CPT) are rare intraventricular neoplasms of epithelial origin. They usually occur in the 2nd year of life, corresponding to 0.4–0.6% of intracranial tumors in this age group. They are sub classified, according to WHO 2016, in choroid plexus carcinoma (CPC), atypical choroid plexus papilloma (ACPP) and choroid plexus papilloma (CPP). Li-Fraumeni syndrome (LFS) is present in 50% of patients with CPC. In Brazil, the TP53 p.R337H mutation affects 0.3% of the population in the South/Southeast. OBJECTIVE Evaluate the incidence of genetic mutations in patients with choroid plexus tumors and therefore the importance of genetic evaluation. PATIENTS AND METHODS Between 1992–2019, 38 patients were diagnosed with CPT in our institution, 23 with CPC. From 2012, 21 patients were referred for genetic evaluation, 16 of which had CPC (2 had previously CPP). Positive family history for neoplasms was present in 87.5%; 37.5% compatible with LFS, 50% of them with mutations. All the patients with positive, but unspecific, family history of neoplasms, had pathogenic mutation. The molecular investigation of the TP53 gene in patients with CPC was performed and positive in 56.2%: R337H (5 patients), R110C, R158H, H179R, R196* (1 patient each). Of those with R337H, p53 protein immunohistochemistry resulted in 90–100% positivity. One of the patients with CPP that evolved to CCP had the H179R mutation. Clinical course was similar among them, and with those without mutations. CONCLUSION These results confirm the need for genetic evaluation in patients with choroid plexus tumors for adequate therapeutic management and long-term follow-up.

BACKGROUND Despite poor clinical outcomes, no targeted therapies have been established for the treatment of Adamantinomatous Craniopharyngioma (ACP). The only known genetic aberration is a mutation in CTNNB1 that results in the nuclear accumulation of beta-catenin. Nuclear beta-catenin is an established inducer of Epithelial-to-Mesenchymal Transition (EMT). ACP cyst fluid is enriched with pro-inflammatory and SASP cytokines, many of which are also directly implicated in EMT. We sought to investigate the role of EMT in ACP pathology. METHODS Normal human epithelial cells were cultured and treated with ACP cyst fluid (10%) for 1, 2, 4 and 8 days. Cell morphology was monitored by live cell brightfield microscopy. The expression of EMT associated genes, ZEB1, ZEB2, SNAI-1, SLUG, TWIST, E-Cadherin, Beta-Catenin and Vimentin was determined by RT-qPCR. RESULTS ACP cyst fluid treated epithelial cells were markedly transformed into long, spindle-shaped cells. ACP cyst fluid treatment resulted in the progressive up-regulation of ZEB2 over 8 days (RQ=12.0; P CONCLUSION ACP cyst fluid can induce EMT-like changes in normal human epithelial cells. In conjunction with the frequency of beta-catenin mutation in ACP, it is possible that EMT plays a crucial role in the pathology of ACP. Understanding ACP pathology in the context of the EMT paradigm may aid the development of new targeted therapeutics.

PURPOSE As much as 40% of pediatric brain tumor patients will experience varied levels of Vasculopathy (VS), however few predictive factors have been described. Here we describe the type and timing of VS and explore the relationship between treatment modality and the timing, location, and distribution of VS. METHODS 94 pediatric Craniopharyngioma patients underwent surgery and proton radiotherapy. Pre- and post-treatment imaging, cumulative physical and biological proton dose maps, clinical characteristics, and measures of dyslipidemia were evaluated. MR and MRAs were evaluated for pre- and post-radiotherapy VS (type, workup, location, and severity). VS events were segmented and described according to their normal brain region, and vascular territory. RESULTS 47 patients were found to have 154 confirmed VS of varying severity with a median time to event of 3.41 years 95% CI 3.08–3.88. 22% (N=21) of patients had ≥1 pre-existing instances of VS and 26.6% (N=25) had a dyslipidemia at diagnosis. Forty-six (48.9%) patients had evidence of VS post-RT with 9.5% (N=9) being clinically significant. Aspirin was recommended in 10.6% (N=10) patients. Only 4 (4.2%) patients required revascularization. Clinical characteristics were not predictive of VS. An increased frequency of VS were observed along the operative corridor and high-dose radiotherapy field. CONCLUSIONS VS often precedes radiotherapy necessitating appropriate baseline imaging. Surgery type and extent are interrelated to the risk for radiotherapy-induced VS. While the spatial radiotherapy dose distribution approximated most vascular injury events, it was not all-inclusive. Spatial modeling of biological and physical dose may offer insights into therapy related vascular injury.

Malignant transformation of CPP is rare and the mechanisms remain elusive. We report a case of progression of papilloma into carcinoma where we performed molecular sequencing of both samples. A boy was found to have a brain mass soon after birth. The gross total resection (GTR) was diagnostic of CPP. Six years later he developed a recurrent mass that demonstrated progression to a choroid plexus carcinoma (CPC). The patient received chemotherapy according to a “HeadStartII” protocol. He is 2.5 years off therapy and disease-free. A sequencing study consisting of 1700 genes and tumor transcriptome was done. The analysis of both samples revealed a germline variant of TP53(R248W) with LOH and an allele frequency of 39% in the germline sample, suggesting a mosaicism. Analysis of both samples identified extensive aneuploidy and similar pattern of gains in chromosomes 7/8/12/20/21/X. Copy number aberrations newly acquired in the carcinoma included copy gain of chromosomes 5q/12/15q/20, and copy loss of chromosomes 5q/13/22. The papilloma was found to harbor 3 somatic mutations with 4% to 21% allelic fractions, all lost in the carcinoma. These mutations were of unknown significance and with too low allelic fractions to be responsible for the transformation. More pertinently, chromosomal aneuploidy was significant with additional losses in the carcinoma. This resulted in the losses of two critical tumor suppressor genes, RB and BRCA2, playing a possible role in the observed transformation. The “HeadStart” experience suggested that the prognosis of TP53 mutant CPC may be improved in the absence of radiation therapy.

In 2006 we reported the youngest case of a large clival chordoma, a 15-week old baby, the second case to present without skull base involvement and the fourth case of chordoma in a patient with tuberous sclerosis. This unusually rare case (surgically un-resect able) underwent endoscopic skull-base diagnostic biopsy and a novel chemotherapy regime that aimed to control his disease[i]. Initial tumour control was achieved with chemotherapy (Ifosfamide, doxorubicin with dexrazonane, intrathecal hydrocortisone, methotrexate, cytarabine). Carboplatin and etoposide were later given for a further year. Following this, Sirolimus and imatinib were used for another twelve months due to primary tumour regrowth and three new skull-vault lesions. Sirolimus alone was continued for an additional year, but stopped due to optic neuritis. Imatinib was given until further progression two years later, leading to a change to everolimus. Surgery for the ventral foramen magnum was performed a year later. The patient received further surgery and radiotherapy for tumour recurrence. Sadly the tumour metastasised and he succumbed at age 13. Chordomas are aggressive and recur frequently. Complete primary resection followed by radiotherapy/proton beam therapy offers the best chance of cure but is not an option in infants with giant lesions, as in our case. We inform on alternative targeted treatment strategies and review the literature on these rare lesions. [i] Kambogiorgas D, St George EJ, Chapman S, English M, Solanki G: Infantile Clivus chordoma without clivus involvement: Case report and review of the literature, Childs Nerv System (2006) 22:1369–1374

BACKGROUND Adamantinomatous craniopharyngioma (ACP) is a devastating skull-base tumor believed to derive from epithelial remnants of the primordial craniopharyngeal duct (Rathke’s pouch), which gives rise to the anterior pituitary gland. Genetically engineered mouse models of ACP demonstrate that perturbation of the fetal anterior pituitary can generate tumors analogous to ACP. Clinical and preclinical data indicate that IL-6 blockade may contribute to ACP tumor control, with the most common agent being the humanized monoclonal antibody, tocilizumab. This agent demonstrated poor blood-brain barrier (BBB) penetration in primates. We present findings from two children enrolled on a phase 0 clinical trial (NCT03970226) of a single dose of preoperative intravenous tocilizumab prior to resection of newly diagnosed ACP. METHODS Blood samples were obtained at multiple timepoints. Serum was isolated via ficoll separation. Tumor tissue and cyst fluid were obtained 4–6 hours following the single IV dose of tocilizumab. Tissue was snap-frozen. Tumor was homogenized in RIPA buffer. Free tocilizumab in serum, cyst fluid, and tumor tissue was measured using enzyme-linked immunosorbent assay (ELISA) against a standard curve. RESULTS Both patients in this trial demonstrated clinically relevant levels of tocilizumab (≥ 4µg/mL) in serum, cyst fluid, and tumor tissue, compared to undetectable levels in control samples. CONCLUSION ACP resides outside BBB protection. In addition to demonstrating the feasibility of systemic delivery of tocilizumab, these findings indicate that other large molecules, including those known to have poor BBB penetration, may be systemically delivered as part of an antitumor regimen in the treatment of ACP.

Germline biallelic mutations in one of the mismatch repair genes (MSH2/MSH6/MLH1/PMS2 results in constitutional mismatch repair deficiency (CMMRD), a condition associated with multiple tumors arising from multiple organs during childhood, and these individuals rarely reach adulthood. The paucity of information with respect to these conditions leads to mismanagement and may be a factor in the high mortality of patients with CMMRD. Two international consortia, the European CARE4CMMRD, and the international replication repair deficiency (RRD) consortium, are addressing the many challenges associated with this condition. To address specific issues surrounding the management of CMMRD in low and middle income countries (LMIC), a multidisciplinary taskforce of 11 specialists from nine countries was formed. Preliminary conclusions are: 1) Immunohistochemistry for CMMRD should be considered for all patients with suggestive clinical features. In countries where CMMRD is common, malignant gliomas, colon cancers and T cell lymphomas should be stained routinely as the prevalence of CMMRD in these tumors can exceed 40%. 2) Temozolomide should not be used in the management of malignant glioma. By contrast, preclinical studies have suggested increased sensitivity to nitrosoureas. For the management of CMMRD related lymphoma and leukemia, mercaptopurines should not be avoided or discontinued as a part of the standard of care before more data are collected. 3) Management with checkpoint inhibitors should be limited to centers with intensive care units and expertise in complex supportive care to manage side effects of immune therapy. 4) Surveillance protocols have demonstrated long term survival benefits and should be implemented in LMIC.

BACKGROUND CPTs are known to be rare TP53-dependent neoplasms, while major molecular alterations underlying tumor progression, especially in TP53-wild type cases, are still unclear. METHODS 18 primary CPT, including 16 choroid plexus carcinomas (CPC) and two atypical choroid plexus papillomas (CPP), were evaluated for copy number status of 87 major oncogenes and tumor suppressor genes by nCounter Cancer CNV assay by Nanostring and TP53 and RB1 by MLPA. Germline TP53 nucleotide substitutions were analyzed by Sanger sequencing. RESULTS Pathogenic germline TP53 variants were present in 4 cases confirming Li-Fraumeni syndrome (LFS). Two patients have somatic TP53 substitutions. Only one patient with LFS harbored somatic TP53 deletion. In 7 patients, heterozygous deletions of RB1 involving from 3 exons to the whole coding sequence detected by MLPA were discovered. All these findings were validated by nCounter CNV assay. Additionally, four patients have WT1 deletions, two patients – BRCA2, and in 1 case - NF1, concomitant with RB1 deletions in 3 cases. Interestingly, in one patient who faced a progression of CPP to CPC germline, RB1 deletion was detected, and in both subsequent tumors, the length of the deleted region progressively increased. Notably, that RB1 deletions are mostly mutually exclusive to TP53 substitutions. 3 of 4 patients with RB1 deletions having follow-up period >1 year faced with tumor-related adverse events. CONCLUSIONS Somatic or uncommon germline RB1 heterozygous deletions have been unraveled as a novel mechanism of aggressive CPT and could be implemented in prognosis definition schemes.

BACKGROUND Noonan syndrome (NS) is associated with germline Ras signaling pathway mutations, RAS overactivation and increased tumorigenesis risk. Rosette-forming glioneuronal tumors (RFGT) are rare indolent tumors. We report the molecular profiling of two patients with NS and RFGT. PATIENT 1: A 22-year-old male with NS was diagnosed with RFGT after partial tumor resection followed by focal irradiation. He was enrolled on a comprehensive genomic profiling study involving paired tumor-normal whole exome sequencing and RNA sequencing of the disease-involved tissue, revealing a germline PTPN11 alteration (p.Gly60Ala) consistent with NS, and a somatic deletion (p.Ile442_Thr454del) in PIK3R1 and a somatic variant (p.Lys656Glu) in FGFR1 with concomitant increased expression of PIK3R1 and FGFR1 by RNA-sequencing. The patient remains without tumor progression now nine months since irradiation. PATIENT 2: A 19-year-old male with persistent headaches, underwent a brain MRI demonstrated multiple abnormal signals in the pineal region and midbrain. He had a stereotactic biopsy revealing RFGT. He was enrolled on the genomic study revealing a germline PTPN11 alteration (p.Asn308Asp) resulting in a new diagnosis of NS. Several family members were subsequently identified with clinical features of NS, including his mother and two siblings, enabling appropriate counseling. Two somatic variants were found in trans in PIK3R1 (p.Thr454_Phe456del and p.Glu451_Asn453delinsAsp), and a somatic variant (p.Val695Met) in FGFR1, with resultant overexpression of PIK3R1. The patient is monitored with surveillance imaging. CONCLUSION We report the molecular profiling of two patients with NS and RFGT; strongly suggesting their connection to RASopathies through the overactivation of the MAPK and PI3K/AKT/mTOR signaling pathways.

BACKGROUND Data on female fertility, pregnancy, and outcome of offspring after childhood-onset craniopharyngioma (CP) are rare. STUDY DESIGN Observational study on pregnancy rate and offspring outcome in female CP patients recruited in KRANIOPHARYNGEOM 2000/2007. RESULTS A total of 451 CP patients (223 female) have been recruited, and 269 (133 female) were postpubertal at study. Six of 133 female CP patients (4.5%) with median age of 14.9 years at CP diagnosis had 9 pregnancies, giving birth to 10 newborns. Three patients achieved complete surgical resections. No patient underwent postoperative irradiation. Five natural pregnancies occurred in 3 CP patients without pituitary deficiencies. Four pregnancies in 3 CP patients with hypopituitarism were achieved under assisted reproductive techniques (ART) (median 4.5 cycles, range: 3–6 cycles). Median maternal age at pregnancy was 30 years (range: 22–41 years). Six babies (60%) were delivered by caesarean section. Median gestational age at delivery was 38 weeks (range: 34–43 weeks); median birth weight was 2,920 g (range: 2,270– 3,520 g), the rate of preterm delivery was 33%. Enlargements of CP cysts occurred in 2 women during pregnancy. Other complications during pregnancy, delivery, and postnatal period were not observed. CONCLUSIONS Pregnancies after CP are rare and were only achieved after ART in patients with hypopituitarism. Close monitoring by an experienced reproductive physician is necessary. Due to a potentially increased risk for cystic enlargement, clinical, ophthalmological, and MRI monitoring are recommended in patients at risk. Perinatal complications, birth defects, and morbidity of mothers and offspring were not observed.

Sarcomas of bone, soft tissue, or neural origin may occasionally invade the central nervous system (CNS), causing diagnostic and therapeutic challenges. We aim to investigate the clinical features of sarcomas involving the CNS at initial presentation. During 2015/01–2019/12, nine consecutive patients (4 Males and 5 Females) younger than 30 years of age treated at a University Healthcare System in Northern Taiwan were included. The median age was 8.7 years (range, 2–24 years); diagnoses were Ewing Sarcoma with EWSR1 rearrangements (n=4), CIC-NUTM1 Sarcoma (n=1), Osteosarcoma (n=2), Malignant Peripheral Nerve Sheath Tumor (MPNST; n=1), and extramedullary myeloid sarcoma (n=1). The tumors originated from the skull (n=1), dura (n=1), vertebra (n=4), spinal canal (n=1), or extra-CNS sites (n=2). Four patients had metastases (1 Ewing sarcoma, 2 osteosarcoma, and 1 extramedullary myeloid sarcoma). The main symptom at diagnosis was facial/eye pain (n=2), back pain (n=3), arm weakness (n=1), or gait disturbance (n=3). Upfront neurosurgical decompression (n=7) or urgent radiotherapy (n=1) was performed in most patients. At a median follow-up duration of 20.1 months, the overall survival rate was 70%. All patients with Ewing sarcoma (n=4) and CIC-NUTM1 sarcoma (n=1) achieved Complete Response after surgery, interval-compressed chemotherapy, radiotherapy, and adjuvant chemotherapy. Patients with stage IV osteosarcoma (n=2) had Partial Response; the patients with MPNST and extraskeletal myeloid sarcoma died of Progressive Disease at 18 and 3 months after diagnosis, respectively. We conclude that timely decompression, early diagnosis, and histology-driven multimodality treatment are effective strategies in managing sarcomas involving the CNS.

BACKGROUND CNS high-grade neuroepithelial tumor with MN1 alteration (CNS HGNET-MN1) are a rare entity recently described as a high-grade tumor containing a mixture of solid and pseudopapillary patterns with MN1 rearrangement. METHODS CNS HGNET-MN1 patients were identified using genome wide methylation arrays across 5 institutions (the Hospital JP Garrahan, Hospital for Sick Children, the University Hospital Motol, Royal Children`s Hospital and Christchurch Hospital) and was correlated with treatment and outcome. Central imaging review with radiological features analysis was performed. RESULTS We identified 9 patients harboring CNS HGNET-MN1 tumors through application of the Heidelberg brain tumor classifier. Seven tumors were T supratentorial and two in the spinal cord. Median age was 5 (range 3.6–14.6). All patients had surgery (6 GTR and 3 STR) as initial management followed by radiotherapy (focal 5/CSI 1) and systemic chemotherapy in 2 patients. Four of the 9 patients relapsed by 3 years post diagnosis, with 2 local and 2 metastatic failures despite complete surgical resections and radiotherapy. Three patients died due to tumor relapse after 24 months despite upfront radiotherapy. Seven of 9 patients had an initial diagnosis of ependymoma. CONCLUSION Treatment of CNS HGNET-MN1 remains a major challenge with multiple failures, despite aggressive surgical resections and upfront involved field radiotherapy. Further multicenter, international prospective studies are required to determine the optimal treatment strategy for this group of tumors.

DNA mismatch repair machinery is an integral part of the human genome and its defect has been involved in tumorigenesis and treatment resistance. Heterozygous monoallelic germline loss of function in MLH-1, MSH-2, MSH-6 or PMS-2 is involved in Lynch syndrome, whereas biallelic mutations cause constitutional mismatch repair deficiency (CMMRD) which is associated with hematologic malignancies and glioblastoma. We report here the clinical characterization and molecular analyses of 7 patients who presented with gliomas and MMR machinery aberrations. Two patients had a clinical diagnosis of NF-1 with dermatologic stigmata, of whom one patient has CMMRD and the other has Lynch syndrome. Two patients had a known family history of Lynch syndrome upon their diagnosis of glioma. Three patients with high-grade glioma and negative family history, 2 had germline mutations in MMR genes, and one had numerous mutations including MMR genes with microsatellite instability. Patients were initially treated with chemotherapy and radiation for high-grade gliomas (HGG); 5/7 had progression. Median time to progression was 12 months (range: 5–52), and median time from progression to death was 7 months (range: 2–25). One patient had low-grade glioma initially but progressed to HGG and is currently on therapy. Another patient treated with temozolomide and radiation is currently receiving maintenance therapy without any disease recurrence. Although the literature data on brain tumors with MMR deficiency is limited, these consistently show that MMRD-associated gliomas are treatment-resistant and have a dismal outcome. Collaborative efforts are needed to better understand this subgroup of pediatric HGG and to define optimal treatment strategy.

BACKGROUND Primary central nervous system lymphoma (PCNSL) are very rare in children. CLINICAL CASE: An 11-year-old male presented with a 2 months history with myoclonic movements in the upper right limb, and a sudden frontal headache, gait disturbance due to right hemiparesis and an ipsilateral convulsive episode. Upon admission he had critical condition, with hypertensive skull syndrome, Glasgow of 12, Karnofsky 40%, right hemiparesis, swallowing disorder, facial paralysis, and loss of photo motor reflex and unilateral amaurosis. A CT and MRI showed a huge tumor mass in the left tempo-parietal region, infiltrating the white matter and shifting the midline. A Tumor biopsy was done, and reported diffuse small cell non-Hodgkin lymphoma of high-grade, Burkitt type. Systemic lymphoma workup was negative. He received six cycles of chemotherapy based on high dose methotrexate, rituximab and triple intrathecal.After the second cycle an ophthalmologic evaluation was done, and found infiltration to the right retina, for which 6 cycles of intra vitreous chemotherapy with methotrexate were applied, he showed an excellent response, and recovered all his neurological functions except that right hemianopia persist. Control MRI showed partial response at 2nd cycle and complete response after the 4th cycle. No Radiation was performed. CONCLUSION This report highlights the fact that pediatric PCNSL may be effectively treated by a combination of HDMTX and rituximab-based chemoimmunotherapy without irradiation. Lack of awareness of this rare entity may lead to extense resections of brain, and potential permanent secuelae that were avoided in this illustrative case.

INTRODUCTION Intellectual assessment in children with craniopharyngioma after tumor removal is still unknown. We assessed intellectual development in children who underwent microsurgical resection in our institute over the last twelve years. MATERIALS AND METHODS Ten children among 41 patients with craniopharyngioma treated and followed at Kagoshima University Hospital between 2007 and 2019 were reviewed. We also assessed intellectual development in 10 years or younger children with craniopharyngioma one year after tumor removal. Intelligence was assessed using the Wechsler Intelligence Scale for Children-Fourth Edition (WISC-Ⅳ). RESULTS Ten children underwent microsurgical tumor removal. The mean age at surgery was 5.8 (range 1–10) years. Transcranial approach was performed in 8 children, transsphenoidal approach in two children. The mean follow up period was 110 months. Gamma knife surgery (GKS) was performed in 6 children less than 6 months after first surgery. Regional recurrences occurred in 5 children, and additional GKS was performed in four children, second microsurgical removal in one child. Severe obesity with a transient electrolyte imbalance occurred in one child. Eight children with GH deficiency underwent GH replacement therapy. Eight children were assessed working memory index (WMI), processing speed index (PSI), Perceptual reasoning index (PRI), and verbal comprehension index (VCI) using WISC 4. Each mean value of WMI, PSI, and PRI was lower than VCI, except for 2 children with normal full scale intelligence quotient. CONCLUSION WMI, PSI and PRI in children with intellectual disabilities were lower tendency than VCI after surgical removal of craniopharyngiomas in the present study.

Chordoma is a rare tumor and while SMARCB1 alterations have been observed in poorly differentiated chordomas, conventional chordomas are not well understood. We interrogated nuclear and mitochondrial genomes of 11 chordoma samples from 7 children. Frozen tumor tissue DNA was extracted and whole exome libraries generated using Agilent SureSelect Human All Exon V6 kit plus mtDNA genome capture kit. Libraries were sequenced using Illumina Nextseq 500. MuTect2, VarDict and LUBA variant callers were used with allele frequency cutoff 2%. Potential germline variants were filtered bioinformatically. In total, 656±74 high-confidence somatic variants, including 368±43 nonsynonymous variants per sample were detected. Of 2,607 combined unique nonsynonymous variants, 95% were missense. Remaining high impact variants were frameshift (37%), stop gain (39%), splice acceptor/donor (22%), start and stop loss (2%). Of the unique nonsynonymous variants, 137 fall within Cosmic Cancer Census Genes, including high impact variants in SETD2, MLLT4. No previously reported TBXT, CDKN2A, PI3K, LYST mutations identified. Tumor Mutation Burden/Megabase was 10±1. The mitochondrial analysis revealed heteroplasmic m.11727C>T MT-ND4 missense variants in three tumors resected at different time points from the same patient, and another heteroplasmic m.1023C>T rRNA mutation from the primary and recurrent tumors of another patient. Intriguingly, two Children’s Brain Tumor Tissue Consortium patients with chordoma had identical heteroplasmic m.10971G>A MT-ND4 nonsense mutations. Pediatric chordomas appear to lack somatic nuclear mutations. Observing recurrent mitochondrial mutations across multiple tumors from the same and/or different patients is striking, suggesting they may be implicated in tumorigenesis and be potential diagnostic markers.

Congenital mismatch repair deficiency (CMMRD) is a pediatric cancer predisposition syndrome secondary to biallelic mutations in mismatch repair genes including MLH1, MSH2, MSH6, and PMS2. Due to the resulting lack of repair mechanisms, these patients develop a high intracellular mutational burden and have a high risk of development of multiple malignancies at a young age. Similar to patients with Lynch Syndrome (monoallelic mutations in MMR genes), these patients are at risk for development of central nervous system (CNS) tumors including high grade gliomas. Forty-eight percent of patients with CMMRD are diagnosed with a CNS malignancy. In this interesting case, a patient developed three metachronous malignancies prior to the age of 13, including Burkitt lymphoma, T-Cell lymphoma and anaplastic astrocytoma. Genomic analysis revealed a high mutational burden in his initial tumors, with multiple oncogenic mutations, as well as a previously unreported germline compound heterozygous MSH6 E744fs*12 and R248fs*8 alteration. He received a gross total resection of the tumor which in previous studies has been shown to have the highest impact on survival. Surgery was followed by radiation and ongoing treatment with an immune checkpoint inhibitor with stable disease at 6 months. The purpose of this case report is to describe the interesting presentation of CMMRD and discuss the previously unreported biallelic MSH6 mutations.

BACKGROUND Neuronal and mixed neuro-glial tumors of the central nervous system (CNS) are relatively rare. Dysembryoplastic neuroepithelial tumor (DNET) is a benign, rare, slow-growing tumor, but in many cases is associated with intractable epilepsy. OBJECTIVE To report the experience with DNET at a single free-standing children’s institution. METHODS A retrospective chart review of 24 patients with confirmed DNET between 2001 and 2019 was performed. Data was collected on clinical characteristics, tumor location, surgical management, histopathological and molecular findings, and outcomes. RESULTS Mean age at diagnosis was 10 years (range 2 to 19 years), with female predominance (54.2%). Most common presenting symptoms were seizures (79.2%) and headaches (12.5%). Location of the tumor was temporal (29.2%), frontal (25.0%), parietal (16.7%), cerebellar (12.5%) and occipital (4.2%). A gross total resection was achieved in half the cases. Recurrence occurred in 4 patients (16.7%), all of whom had subtotal resections. The average follow up since diagnosis was 4.6 years (range 0.3 to 14 years). Nineteen patients presented with seizures, of which 63.2% were seizure free after surgery. The samples with molecular genetic testing (microarrays or FISH), were all normal except one patient positive for BRAF V600E mutation. CONCLUSIONS This is the first and largest review of pediatric DNETs in the last 10 years. Despite majority of patients having a favorable outcome after surgery, a subset of patients remains symptomatic. As molecular mechanisms in DNET remain unknown, future aim is to describe the molecular characteristics of our DNET population, and correlate with outcomes.

At one month of age, a female presented with a giant congenital nevus along lower back and thighs and hydrocephalus. A ventriculoperitoneal shunt was placed. An MRI was done at six months, initially reported as normal. At eleven months of age, five months after original MRI, patient presented with dysconjugate gaze and lethargy. MRI showed new 3.8 x 3.7 x 3.4 cm right cerebellopontine angle mass extending into Meckel’s cave and foramen ovale along with leptomeningeal disease extending from the mass along the entire length of the spinal cord. Retrospective review of prior MRI revealed subtle leptomeningeal enhancement concerning for neurocutaneous melanosis (NCM). Given the leptomeningeal disease, family elected for open biopsy and debulking of lesion instead of aggressive resection. Histologically, the mass showed hypercellular spindle cell neoplasm with mitotic activity and necrosis mixed with remnants of normal cranial nerve. GFAP was negative, excluding a glioma. HMB-45, MITF, panmelanoma, and Melan-A were negative, excluding melanoma. A negative myogenin stain ruled out ectomesenchymoma. S-100 protein and SOX-10 positivity with variable loss of staining for trimethylation of histone H3 K27 were indicative of malignant peripheral nerve sheath tumor (MPNST). Given the course of the mass, trigeminal nerve MPNST was presumed. Given the poor prognosis of intracranial MPNST and NCM, family elected to forgo treatment and was discharged with hospice. She died 25 days after surgery. Cranial nerve MPNST is rare. MPNST in patients with NCM has not previously been reported to our knowledge.

PURPOSE Patients with recurrent craniopharyngioma after radiotherapy (RT) have few treatment options. At our institution, re-irradiation has been offered to selected individuals with recurrent craniopharyngioma not suitable for further surgery, intracystic therapy or targeted agents. METHODS A retrospective study was performed of patients with craniopharyngioma treated with two courses of fractionated RT. First RT (RT1) prescriptions ranged from 50–54 Gy in 25–30 fractions; re-irradiation (RT2) prescriptions were 54 Gy in 30 fractions with full, in-field overlap of dose. The maximum dose to organs-at-risk (brainstem, optic structures) were maintained at or below the prescription dose. There was no cumulative dose limit to any structure. RESULTS We identified four patients. Median RT1-to-RT2 interval was 5.8 years (range, 4.7–20.4). Cumulative maximum doses to optic chiasma and nerves were >100 Gy in all four patients. With a median follow-up of 33 months after RT2, three patients had disease control and are alive at 9, 23 and 42 months from RT2; one patient developed progressive disease and died 33 months after RT2. In three evaluable patients, vision remained stable or improved after RT2; the remaining one patient had no light perception prior to re-irradiation. Two patients had neuropsychological testing before and after RT2; neurocognitive domains were generally stable in one patient but working memory declined in the second patient. CONCLUSIONS Despite exceeding usual tolerances for optic chiasm and nerves, visual outcomes were stable in all living patients. Re-irradiation should be discussed as a treatment option for patients with recurrent craniopharyngioma but without other therapeutic options.

INTRODUCTION Adamantinomatous craniopharyngiomas (ACPs) are characterized by activating mutations in the CTNNB1 gene. Here we perform a comprehensive genomic analysis of 23 ACPs to define the landscape of genomic alterations in this disease. METHODS We performed whole-genome sequencing of 24 ACPs and their matched normal tissues. We used Mutect 2.0 to detect mutations and indels in these samples and MutSig2CV to identify significant mutations. Copy numbers were called using the GATK4 pipeline and GISTIC 2.0 was applied to identify significant alterations. Finally, SvABA was applied to identify genome-wide structural variants and rearrangements. RESULTS 18/24 (75%) of the sequenced ACPs harbored activating mutations in exon 3 of CTNNB1 gene with an average variant allele fraction (VAF) of 0.4±0.1. These mutations have previously been shown to activate the WNT signaling pathway in these tumors. No other significantly recurrent mutations were detected in our samples. The ACPs were quiet with regard to copy number alterations and no recurrent amplifications or deletions were detected. 528 structural variations and rearrangements were detected in total in all 24 samples with an average of 22 variants per sample. Gene-Set Enrichment Analysis (GSEA) of the RNAseq data revealed upregulation of WNT/B-catenin (FDR q-value CONCLUSION Our study identified previously described activating CTNNB1 mutations in the majority of ACPs. In addition, we identified several rearrangements and structural variations in these tumors that could play an important role in the pathogenesis of the disease.

Diffuse leptomeningeal disseminated glioneuronal tumor (DL-GNT) is a rare brain tumor that presents as a plaque-like subarachnoid tumor, commonly involving the basal cisterns and interhemispheric fissure of children but lacking intraparenchymal tumor. Here we report two cases focusing on clinicopathologic features. In all patients, radiography revealed characteristic leptomeningeal thickening and enhancement with minor superficial parenchymal lesions. The broadcast of the knowledge about this type of disease is important to increase awareness on this subject.