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Atypical teratoid rhabdoid tumor (ATRT) is a rare, highly malignant central nervous system cancer arising in infants and younger children, historically considered to be homogeneous, monogenic, and incurable. Recent use of intensified therapies has modestly improved survival for ATRT; however, a majority of patients will still succumb to their disease. While ATRTs almost universally exhibit loss of SMARCB1 (BAF47/INI1/SNF5), recent whole genome, transcriptome, and epigenomic analyses of large cohorts reveal previously underappreciated molecular heterogeneity. These discoveries provide novel insights into how SMARCB1 loss drives oncogenesis and confer specific therapeutic vulnerabilities, raising exciting prospects for molecularly stratified treatment for patients with ATRT.

BACKGROUND: Central nervous system (CNS) germinomas are treatment-sensitive tumors with excellent survival outcomes. Current treatment strategies combine chemotherapy with radiotherapy (RT) in order to reduce the field and dose of RT. Germinomas originating in the basal ganglia/thalamus (BGTGs) have proven challenging to treat given their rarity and poorly defined imaging characteristics. Craniospinal (CSI), whole brain (WBI), whole ventricle (WVI), and focal RT have all been utilized; however, the best treatment strategy remains unclear. METHODS: Retrospective multi-institutional analysis has been conducted across 18 institutions in four countries. RESULTS: For 43 cases of non-metastatic BGTGs, the 5- and 10-year event-free survival (EFS) were 85.8% and 81.0%, respectively, while the 5- and 10-year overall survival (OS) were 100%, and 95.5%, respectively (one patient fatality from unrelated cause). Median RT doses were as follows: CSI: 2250 cGy/cGy(RBE) (1980 to 2400 cGy/cGy[RBE]), WBI: 2340 (1800 to 3000 cGy/cGy[RBE]), WVI: 2340 cGy/cGy(RBE) (1800 to 2550 cGy/cGy[RBE]), focal: 3600 cGy (3060 to 5400 cGy). Thirty-eight patients (90.5%) received chemotherapy. There was no statistically significant difference in the EFS based on initial field extent (p=0.84). Nevertheless, no relapses were reported in patients who received CSI or WBI. Chemotherapy alone had significantly inferior EFS compared to combined therapy (p=0.0092), but patients were salvageable with RT. CONCLUSION: Patients with BGTGs have excellent outcomes and RT proved to be an integral component of the treatment plan. This group of patients should be included in future prospective clinical trials and the best RT field should be investigated further.

Objective To better characterize the ways that migraine affects multiple domains of life. Background Further understanding of migraine burden is needed. Methods Adults with migraine randomized to mindfulness-based stress reduction or headache education arms (n = 81) in two separate randomized clinical trials participated in semistructured in-person qualitative interviews conducted after the interventions. Interviews queried participants on migraine impact on life and were audio-recorded, transcribed, and summarized into a framework matrix. A master codebook was created until meaning saturation was reached and magnitude coding established code frequency. Themes and subthemes were identified using a constructivist grounded theory approach. Results Despite most participants being treated with acute and/or prophylactic medications, 90% (73/81) reported migraine had a negative impact on overall life, with 68% (55/81) endorsing specific domains of life impacted and 52% (42/81) describing impact on emotional health. Six main themes of migraine impact emerged: (1) global negative impact on overall life; (2) impact on emotional health; (3) impact on cognitive function; (4) impact on specific domains of life (work/career, family, social); (5) fear and avoidance (pain catastrophizing and anticipatory anxiety); and (6) internalized and externalized stigma. Participants reported how migraine (a) controls life, (b) makes life difficult, and (c) causes disability during attacks, with participants (d) experiencing a lack of control and/or (e) attempting to push through despite migraine. Emotional health was affected through (a) isolation, (b) anxiety, (c) frustration/anger, (d) guilt, (e) mood changes/irritability, and (f) depression/hopelessness. Cognitive function was affected through concentration and communication difficulties. Conclusions Migraine has a global negative impact on overall life, cognitive and emotional health, work, family, and social life. Migraine contributes to isolation, frustration, guilt, fear, avoidance behavior, and stigma. A greater understanding of the deep burden of this chronic neurological disease is needed to effectively target and treat what is most important to those living with migraine.

Outcomes for children with high-grade gliomas (HGG) remain dismal despite aggressive treatment strategies. The use of targeted therapy for BRAFV600E mutated malignancies including HGG is being explored as a potentially well tolerated and effective therapeutic option. The results of adult melanoma studies demonstrating that combination therapy with BRAF inhibitors and MEK inhibitors results in prolonged survival led us to employ this treatment strategy in children with BRAFV600E mutated HGG. In this case series, we describe three pediatric patients with HGG with confirmed BRAFV600E mutation who demonstrated responses to combination therapy with dabrafenib and trametinib.

Isocitrate dehydrogenase (IDH) mutations are rare in pediatric and adolescent gliomas. We recently identified three adolescent/young adult (AYA) patients with IDH‐mutant low grade gliomas of the brainstem with several key clinicopathologic and molecular features in common. We discuss these three cases and review the current literature.

Background Recent large-scale genomic studies have revealed a spectrum of genetic variants associated with specific subtypes of central nervous system (CNS) tumors. The aim of this study was to determine the clinical utility of comprehensive genomic profiling of pediatric, adolescent and young adult (AYA) CNS tumors in a prospective setting, including detection of DNA sequence variants, gene fusions, copy number alterations (CNAs), and loss of heterozygosity. Methods OncoKids, a comprehensive DNA- and RNA-based next-generation sequencing (NGS) panel, in conjunction with chromosomal microarray analysis (CMA) was employed to detect diagnostic, prognostic, and therapeutic markers. NGS was performed on 222 specimens from 212 patients. Clinical CMA data were analyzed in parallel for 66% (146/222) of cases. Results NGS demonstrated clinically significant alterations in 66% (147/222) of cases. Diagnostic markers were identified in 62% (138/222) of cases. Prognostic information and targetable genomic alterations were identified in 22% (49/222) and 18% (41/222) of cases, respectively. Diagnostic or prognostic CNAs were revealed by CMA in 69% (101/146) of cases. Importantly, clinically significant CNAs were detected in 57% (34/60) of cases with noncontributory NGS results. Germline cancer predisposition testing was indicated for 27% (57/212) of patients. Follow-up germline testing was performed for 20 patients which confirmed a germline pathogenic/likely pathogenic variant in 9 cases: TP53 (2), NF1 (2), SMARCB1 (1), NF2 (1), MSH6 (1), PMS2 (1), and a patient with 47,XXY Klinefelter syndrome. Conclusions Our results demonstrate the significant clinical utility of integrating genomic profiling into routine clinical testing for pediatric and AYA patients with CNS tumors.

Intradural extramedullary peripheral primitive neuroectodermal tumor (pPNET) with t(11;22) is a rare clinical finding in the pediatric population with few published cases in the literature. The authors report 3 cases of intradural primary pPNET and discuss the clinical presentation, treatment, and survival of the patients. Clinicians should be vigilant in considering pPNET in the differential diagnosis of extradural masses. The authors also compare the clinical course and outcome of therapy with primary PNET of the central nervous system and Ewing sarcoma family of tumors. In addition, this report highlights the risk for leptomeningeal dissemination at recurrence and discusses the importance of central nervous system-targeted therapy for durable disease control.

Introduction Medulloblastoma is a malignant embryonal tumor of the cerebellum that occurs predominantly in children. To find germline genetic variants associated with medulloblastoma risk, we conducted a genome-wide association study (GWAS) including 244 medulloblastoma cases and 247 control subjects from Sweden and Denmark. Methods Genotyping was performed using Illumina BeadChips, and untyped variants were imputed using IMPUTE2. Results Fifty-nine variants in 11 loci were associated with increased medulloblastoma risk (p –5), but none were statistically significant after adjusting for multiple testing (p –8). Thirteen of these variants were genotyped, whereas 46 were imputed. Genotyped variants were further investigated in a validation study comprising 249 medulloblastoma cases and 629 control subjects. In the validation study, rs78021424 (18p11.23, PTPRM) was associated with medulloblastoma risk with OR in the same direction as in the discovery cohort (ORT = 1.59, pvalidation = 0.02). We also selected seven medulloblastoma predisposition genes for investigation using a candidate gene approach: APC, BRCA2, PALB2, PTCH1, SUFU, TP53, and GPR161. The strongest evidence for association was found for rs201458864 (PALB2, ORT = 3.76, p = 3.2 × 10–4) and rs79036813 (PTCH1, ORA = 0.42, p = 2.6 × 10–3). Conclusion The results of this study, including a novel potential medulloblastoma risk loci at 18p11.23, are suggestive but need further validation in independent cohorts.

BACKGROUND: For several types of cancer, biological differences and outcome disparities have been documented in adolescents/young adults (AYAs, 15–39 years old) versus children. This study compared clinicopathological features and survival between younger AYAs and children with low-grade glioma (LGG), a common brain tumor among AYAs. METHODS: This was a secondary analysis of Children’s Oncology Group legacy study CCG-9891/POG-9130, which enrolled participants 0–21 years of age with newly-diagnosed LGG treated with surgery alone. For analysis, participants were categorized as children (0–14 years old) or early AYAs (eAYAs, 15–21 years old) and compared on demographics, clinical presentation, tumor characteristics, surgical outcomes, progression-free survival (PFS) and overall survival (OS). RESULTS: Among 468 children and 50 eAYAs, more eAYAs presented with seizures (34.0% vs 19.2%; p=0.015), without other significant differences in clinicopathological features. Five-year PFS rates for children and eAYA were 80.2% (95% Confidence Interval [95%CI], 76.1–83.7) and 83.0% (95%CI, 68.8–91.1), respectively; 5-year OS rates were 97.3% (95%CI, 95.2–98.5) and 95.4% (95%CI, 82.7–98.8), respectively. Multivariable analysis including all participants showed presence of residual tumor to be an independent predictor of PFS (

Atypical teratoid rhabdoid tumor (ATRT) is a central nervous system tumor with poor outcome. ACNS0333, a Children’s Oncology Group phase 3 trial, enrolled 65 evaluable patients who received two cycles of induction chemotherapy, three cycles of consolidative high-dose chemotherapy (HDCT), and focal radiation therapy (RT) pre- or post-consolidation. Craniospinal irradiation (CSI) was left to clinician discretion. We retrospectively analyzed medical records of 27 children treated at our institutions according to ACNS0333. Median age at diagnosis was 14 months (range 4–165); 13 (48%) were male. M-stage was M0, M2, and M3 for 18 (66%), 5 (19%), and 4 (15%), respectively. Tumor location was supratentorial (n=14, 52%), infratentorial (n=12, 44%), or both (n=1, 4%). Complete resection was achieved for 17 (63%). All but one completed induction. Of 13 (51%) with residual disease at diagnosis, 5 (36%) and 7 (50%), respectively, exhibited complete and partial response to induction. Three patients progressed on therapy, and six progressed after completion of therapy at a median of 9.7 months. In all, 18 patients completed RT (16 focal/4 CSI and 6 pre-/12 post-consolidation). Three died of therapy-related toxicity (two in primary therapy and one in relapse therapy), and 8 died of disease. Sixteen patients (59%) are alive at a median follow up of 53 months (range 9–114). Of 17 with germline testing, eight (47%) had rhabdoid predisposition syndrome of whom three are alive. At the time of presentation, data for approximately 50 patients is expected, and we will compare outcomes to soon-to-be published data from ACNS0333.

INTRODUCTION Irradiation-sparing approaches are used in young children with medulloblastoma (MB) given the vulnerability of the developing brain to neurocognitive impairment. Limited data are available following relapse for these patients. We aimed to describe the management and outcomes of young children with MB who relapsed after initial treatment without craniospinal irradiation (CSI). METHODS International retrospective study including patients with MB diagnosed between 1995-2017, ≤ 72 months old, initially treated without CSI, who subsequently relapsed. RESULTS Data are available for 66 patients. The median age at initial diagnosis was 27 months (range, 6-72). At diagnosis, 27 patients had metastatic disease. Initial therapy included conventional chemotherapy or with high-dose chemotherapy (HDC) in 30 and 36 patients, respectively. Eight (12.1%) received upfront focal irradiation. Molecular subgrouping was available for 27 (41%) patients. Ten were SHH, five group 3, six group 4 and six others were non-WNT/non-SHH. The median time from initial diagnosis to relapse was 13 months (range, 3-63). Relapse was local, disseminated, or combined in 39%, 32%, and 29%, respectively. The median time to death from relapse was 18 months. Curative intent therapy was given in 53 patients with irradiation (81%), conventional chemotherapy without HDC (40%), and HDC (25%). For patients who received irradiation, 85% received CSI (median dose 33 Gy, 18-41.4) and 15% focal irradiation. Ten patients received chemotherapy without salvage irradiation. The median follow-up time was 44 months (range, 4-255), 33 (62%) patients who underwent curative-intent therapy were alive, including 8/10 SHH, 2/3 group 3, 2/6 group 4, and 4/5 non-WNT/non-SHH. Three of four patients with SHH and treated without salvage radiotherapy are survivors. The 5-year OS for curative intent was 70%. CONCLUSION A substantial proportion of young children who relapse following irradiation-sparing strategies can be salvaged. A proportion of children with SHH MB can be salvaged without salvage radiotherapy.

PURPOSE: Irradiation-avoiding strategies have been used with relative success in the treatment of infants and young children with medulloblastoma. While advances in cancer genomics have significantly improved our understanding of the tumor biology of medulloblastoma allowing for improved prognostication and risk-stratification, the molecular subgroup-specific outcomes of infants and young children with medulloblastoma treated with irradiation-avoiding strategies remains unknown. METHODS: Molecular and clinical features of children with medulloblastoma treated with irradiation-avoiding strategies at Children’s Hospital Los Angeles were analyzed. Molecular subgrouping of these patients was determined using a 31-gene TaqMan Low Density Array signature. Survival analyses were conducted based on 3 molecular subgroups (SHH, Group 3, and Group 4). RESULTS: Twenty-eight patients with medulloblastoma received irradiation-sparing regimens and were included in this analysis. Patients were divided into SHH (n = 16), Group 3 (n = 3) and Group 4 subgroups (n = 9). Subgroup specific 5-year progression-free and overall survival was 81.2% (95% CI 52.5–93.5) and 93.7% (95% CI 63.2–99.1) for SHH, 0% and 0% for Group 3 and 0% and 44.4% (95% CI 13.6–71.9) for Group 4. CONCLUSION: The majority of young children with SHH-subgroup medulloblastoma can be treated effectively with irradiation-sparing regimens. Our results support the use of chemotherapy-only strategies for upfront treatment of young children with SHH medulloblastoma, while demonstrating the urgent need for intensification/augmentation of treatment for patients with group 3/4 medulloblastoma.

BACKGROUND Germ cell tumors (GCT) arising from non-midline structures (basal ganglia, thalamus, and posterior fossa) are rare. Although patients with midline (pineal and suprasellar) germinoma have excellent survival with chemotherapy and whole ventricular irradiation (WVI), germinoma in non-midline locations have traditionally been treated with craniospinal irradiation (CSI) or whole brain irradiation (WBI) to achieve similar outcomes. However, CSI and WBI are associated with significant long-term neuropsychological sequelae. METHODS We describe the clinical and neuropsychological outcomes of patients with non-midline germinoma treated at the Children's Hospital Los Angeles between 1990 and 2015. RESULTS Nine patients had basal ganglia/thalamic germinoma and one patient had a cerebellar primary. Eight patients received chemotherapy followed by reduced dose/volume irradiation, whereas two patients received chemotherapy alone as upfront therapy. One patient in the chemotherapy alone group relapsed after 4.3 years and was salvaged with CSI plus boost. The overall survival for the entire cohort was 100% at a median follow-up of 8.5 years. Neuropsychological data were available for six patients at a median of five months (baseline) and 4.2 years (follow-up) post-diagnosis. At four-year follow-up, data available revealed intact overall cognitive ability, verbal memory, and executive functioning, but persistent deficits in fine motor function. Comparison of baseline to follow-up suggests a downward trend in working memory, planning/problem-solving, verbal memory, and visuospatial integration. CONCLUSION Chemotherapy followed by reduced dose/volume of irradiation is an effective strategy resulting in long-term survival in patients with non-midline germinoma. Neuropsychological data suggest relatively minimal morbidity over time.

Medulloblastoma (MB) is the most common malignant brain tumor in children. Currently, "one-size-fits-all" radiation and chemotherapy treatment regimen is employed for treating MB patient, causing at least some children to undergo highly aggressive and in some cases, inadequate radiation therapy. Consequently, there is a need for prognostic and predictive tools for identifying disease aggressiveness and ultimately which patients with MB may be able to benefit from de-escalation of therapy. Genomic characterization of MB has recently identified 4 distinct molecular subgroups: Sonic Hedgehog (SHH) , Wingless (WNT) , Group 3, Group 4 each exhibiting different clinical behavior. The molecular sub-types have unique risk-profiles and outcomes, and patients could potentially benefit from sub-group specific treatments. However, the transition of these molecular MB subtypes into clinical practice has been limited due to challenges in availability of molecular profiling in most hospitals, as well as variability in clinical assessment. In this work, we present a radiomic feature that captures subtle tissue deformations caused due to the impact of tumor growth on the normal-appearing brain around tumor (BAT), to distinguish molecular sub-types of MB. First, we obtain voxel-wise deformation magnitude from the deformation orientations, after registering Gadolinium (Gd)-enhanced T1-w MRI scan for every study to a normal age-specific T1w MRI template. Deformation statistics are then computed within every 5mm annular BAT region, 0 < d < 60mm, where d is the distance from the tumor infiltrating edge, to capture subtle localized deformation changes around the tumor. Our results using multi-class comparison via one-way ANOVA and post-hoc comparison showed significant differences across deformation magnitudes obtained for Group 3, Group 4, and SHH molecular sub-types, observed up to 15-mm outside the infiltrating edge. Our feasibility results suggest that the subtle deformation features in BAT observed on routine Gd-T1w MRI may potentially serve as surrogate markers to non-invasively characterize molecular sub-types of pediatric MB.

BACKGROUND Central nervous system (CNS) germinomas are radiotherapy (RT)-sensitive tumors with excellent survival. Current treatment strategies combine chemotherapy with RT to reduce the field and dose of RT. There is no standard treatment for germinomas originating in the basal ganglia/thalami (BGTG) given their rarity and poorly-defined imaging characteristics. Craniospinal (CSI), whole brain (WBI), whole ventricle (WVI), and focal RT have been previously utilized; however, the optimal strategy remains unclear. METHODS Retrospective multi-institutional analysis was conducted across 18 institutions in four countries. RESULTS For 46 cases with non-metastatic BGTG, the event-free survival (EFS) was 86.9% at both 5 and 10 years, while overall survival (OS) was 100%, and 95.7% respectively at 5 and 10 years. Median RT dose and range for the various treatment volumes were as follows: CSI (n=10): 2340 cGy (1980–3060 cGy), WBI (n=8): 2340 (1800–3000 cGy), WVI (n=14): 2340 cGy (1800–2550 cGy), focal (n=9): 3600 cGy (3060–5400 cGy). There was no statistically significant difference in the EFS based on RT modality (p=0.57), but EFS for subjects with CSI and WBI were both 100%. The three subjects who received chemotherapy alone had significantly lower EFS than those who received chemotherapy and RT (p=0.001), but were salvageable with RT. CONCLUSION In the largest study to date for BGTG, there were no significant differences in outcomes between patients who received CSI, WBI, WVI or focal RT. This group of patients should be included in future prospective clinical trials, and a more limited RT field may be considered.

Objectives: The aims of this study were: to evaluate the prevalence of abdominal wall defects in the Polish population, to analyze temporal trends in the prevalence, to identify areas (clusters) of high risk of abdominal wall defects, and to characterize, with respect to epidemiology, children with abdominal wall defects and their mothers in the area defined as a cluster. Material and Methods: We used isolated congenital malformations (gastroschisis Q79.3 and omphalocele Q79.2 according to the International Statistical Classification of Diseases and Related Health Problems, 10th revision (ICD-10, the extended version)) data reported to the Polish Registry of Congenital Malformations (PRCM) over the years 1998– 2008 based on the population of 2 362 502 live births. We analyzed 11 administrative regions of Poland with complete epidemiologic data. Results: Of 11 regions, 2 had a significantly higher standardized prevalence of isolated gastroschisis: Dolnośląskie (1.7/10 000 live births, p = 0.0052) and Śląskie (1.9/10 000 live births, p < 0.0001). Furthermore, within the region of Dolnośląskie, we defined a clear prevalence of the isolated gastroschisis cluster (p = 0.023). We comprehensively examined demographic and socio-economic risk factors for abdominal wall defects in this area, and we found that these factors failed to account for the cluster. Conclusions: We identified a distinct prevalence cluster for isolated gastroschisis, although a precise reason for the disease clustering in this region remains unknown. Cluster identification enables more focused research aimed at identification of specific factors with teratogenic effects.

Background High-dose chemotherapy (HDC) strategies were developed to avoid unacceptable neurotoxicity associated with craniospinal irradiation in infants with embryonal brain tumors. However, the impact of molecular and pathological characterizations in such approaches and long-term outcome have not been widely described in young children. Methods We retrospectively collected information from seven North American institutions, on young children with medulloblastoma (MB) treated with sequential HDC, as per the CCG 99703 protocol. Data collection included clinical presentation, histology, molecular subgroup, irradiation, ototoxicity, and neurocognitive evaluations. Results The cohort included 53 patients diagnosed at a median age of 24 months (2.9–63.2). Seventeen patients (32.1%) had nodular desmoplatic MB, all belonging to the sonic Hedgehog (SHH) subgroup, as did 30% of classic MB. The 5-year progression-free survival (PFS) and overall survival (OS) was 69.6% (±6·9%) and 76.1% (±6.5%), respectively. Seventeen (32.1%) patients received irradiation (nine adjuvant radiotherapy [RT]). Patients with SHH and group 3 MB had a 5-year PFS of 86·2% (±7.4%) and 49·1% (±14%), respectively (P = 0.03). The 5-year PFS radiation free for group 3 MB was 46.4%. Patients with macroscopic metastasis (M2 and M3) had a worst survival. Fifteen (45.5%) patients had significant ototoxicity. Mean Full Scale Intellectual Quotient (FSIQ) for 24 survivors was 91.6 (range 52–119). Conclusions This HDC strategy led to an encouraging OS while only 20% of the patients received adjuvant RT. SHH MB, irrespective of histological subgroup, had an excellent outcome. Such intensive therapy may not be needed for this subgroup. Patients with classic histology or group 3 had an encouraging PFS of 58% and 46.4%, respectively, in the absence of adjuvant RT. The neurocognitive profile of the survivors appears to be within the normal range.

10525 Background: Absence of integrase interactor 1 (INI1) expression is a defining molecular feature of rhabdoid tumors (RT), epithelioid sarcoma (ES), and chordomas, inducing dependence on enhancer of zeste homolog-2 (EZH2). Tazemetostat (TAZ) is a selective EZH2 inhibitor approved by the FDA for treatment of patients (pts) ≥16 yrs with metastatic or locally advanced ES ineligible for complete resection. Data from a Phase 1 (Ph1) pediatric dose-escalation study (Ph1a) of TAZ were previously reported; herein we report interim efficacy and safety from the Ph1 pediatric dose-expansion study (Ph1b). Methods: NCT02601937 is a Ph1, multicenter study in pts 6 months – 18 yrs evaluating TAZ administered BID at 1200 mg/m2 in Ph1b, per Ph1a recommendation. Ph1b cohorts enrolled pts based on tumor type: Atypical teratoid RT (ATRT), RT, and other INI1-negative tumors (including ES and chordoma). The Ph1b primary endpoint was overall response rate (ORR). Secondary endpoints included safety/tolerability, duration of response (DOR), and survival. Results: Ph1b has enrolled 47 pts who received TAZ oral suspension. Across all tumor types, ORR was 17% (Table). Responses were observed in ATRT (4/21), chordoma (2/4), and ES (2/7); 1 pt dosed at 520mg/m2 and 7pts at 1200mg/m2. In the ATRT cohort, 19% of pts responded to TAZ with a median DOR of 6.5 months. The median DOR has not yet been reached in the other cohorts, with ongoing responses in 3 pts. TAZ was generally well tolerated with no drug-related deaths. Most common adverse events (AE) include vomiting, nausea, and cough. During Ph1b enrollment, 1 pt with chordoma (dosed at TAZ 900 mg/m2 for 15 months in Ph1a) developed a secondary malignancy (T-cell lymphoblastic lymphoma). In response, the pediatric recommended Ph2 dose was revised to limit exposure in pts without CNS involvement to 520 mg/m2 TAZ (maximum dosing of 1 yr after response, pts to go off-treatment until disease progression). Conclusions: Interim results indicate TAZ is generally well tolerated in children with an AE profile similar to adults. Pt enrollment in the non-ATRT, INI1-negative cohorts is ongoing. TAZ shows promising anti-tumor activity in a subset of pediatric tumors, including ATRT, chordoma, and ES. Clinical trial information: NCT02601937. [Table: see text]

Avoiding irradiation in infants/young children with malignant brain tumors has been associated with inferior survival. We reviewed medical records of infants/young children with malignant brain tumors diagnosed at our institution between 1991–2015 that completed intensive induction followed by myeloablative chemotherapy/AuHCR and either did or did not receive XRT post-AuHCR. Ninety-nine patients were identified (55 medulloblastoma, 21 PNET, 15 AT/RT, and 8 choroid plexus carcinoma). Twenty-seven of 99 patients received irradiation post-AuHCR and 72 did not. XRT group had 41% of patients with residual tumor post-induction and 44% with disseminated disease versus 18% and 26%, respectively, in no-XRT group. 5-year event-free survival (EFS) and overall survival (OS) for all patients was 63 + 5% and 73 + 5%. 5-year EFS and OS rates for patients receiving XRT post-AUHCR were 69 + 9% and 78 + 8% versus 60 + 6% and 71 + 6%for no-XRT group (p=0.26 and 0.64). For patients with residual tumor post-induction, 5-year EFS was 65 + 14% for XRT group versus 34 + 14% for no-XRT group (p=0.12). For patients with localized disease at diagnosis, 5-year EFS was 86 + 9% in XRT group versus 65 + 7% in no-XRT group (p=0.12). 5-year EFS for patients with disseminated disease in XRT and no-XRT groups was 47%. For medulloblastoma patients, 5-year EFS and OS rates were 65 + 7% and 89 + 10% in XRT group and 67 + 16% and 82 + 6% in no-XRT group. 5-year EFS was 80 + 13% for AT/RT patients in XRT group versus zero in no-XRT group. For infants/young children with malignant brain tumors completing AuHCR, administration of XRT did not provide significant survival advantage, with the exception of AT/RT.

INTRODUCTION: Children with diffuse intrinsic pontine glioma (DIPG) have a dismal prognosis. Checkpoint blockade has revolutionized treatment of some resistant cancers. METHODS: Pembrolizumab, a PD-1 inhibitor, was administered to children with progressive DIPG (Stratum A) and results are reported here. Children aged 1-18yrs with progressive DIPG were eligible with functional scores >60 and physiologic or less steroid usage, among standard eligibility criteria. Pembrolizumab was administered at 2mg/kg IV every three weeks. Tumor tissue (if available), serum and MRI studies were collected for correlative analysis. RESULTS: Five patients with progressive DIPG were enrolled from June-July 2015. The median age at diagnosis was 3.5yrs (range,2.8-6.9), and median time from diagnosis to study entry was 14.6 months (range,8.7-20.7). Progression-free survival (PFS) was 1.02 months (range,0.5-1.7); overall survival from initial treatment was 1.7 months (range,0.5-6.2). All patients clinically and/or radiographically worsened after one (n=1) or two (n=4) doses of pembrolizumab. Grade 3 or greater treatment-related adverse events included fatigue (n=2) and new or increased grade neurologic symptoms. Correlative analysis is ongoing. CONCLUSIONS: Checkpoint inhibition holds potential for CNS cancer treatment; however, special consideration is required in the CNS with limited space and large disease burdens. In our study, patients rapidly deteriorated neurologically after initiation of checkpoint blockade, with a shorter median PFS than expected by analogous historical trials; pembrolizumab protocols were amended to exclude recurrent DIPG patients after these events. Our findings suggest caution when utilizing immunotherapy in actively progressing tumor in the brain stem.

PURPOSE: Prognosis for central nervous system (CNS) non-germinomatous germ cell tumor (NGGCT) patients that relapse during induction is poor. We present our experience for these patients. METHODS: Medical records of CNS NGGCT patients at Children’s Hospital Los Angeles between 2008 and 2014 were reviewed for clinical characteristics, treatment, and outcome. RESULTS: Eight (27.6%) of 29 patients relapsed or were refractory during induction chemotherapy, an average of 6.3 months from diagnosis. Five patients had pineal primaries and three patients had synchronous pineal and suprasellar tumors. All patients had tumor marker (TM) elevation in serum and/or CSF; four patients underwent biopsy. Three patients had local relapse, two local and ventricular, and three had TM-only relapse. All received re-induction chemotherapy with gemcitabine 800mg/m2, paclitaxel 170mg/m2, and oxaliplatin 100mg/m2 (GemPOx). After re-induction, the three TM-only relapses continued to have no evidence of disease (NED) radiographically, three patients showed a partial response (PR), and two patients had stable disease (SD). Seven patients received high-dose chemotherapy with a thiotepa-based regimen followed by autologous stem cell rescue (ASCR). After ASCR, radiographically, three TM positive cases continued to be NED, three had a PR, and one patient had SD. Six received additional irradiation post-transplant, of which five are alive. Six of eight relapsed/refractory patients are alive at 41, 42, 66, 71, 78, 79 months from initial diagnosis. CONCLUSIONS: Relapsed/refractory CNS NGGCT patients can be successfully salvaged by re-induction chemotherapy followed by consolidation with a thiotepa-based myeloablative regimen and re- irradiation.

BACKGROUND: Radiation therapy, while a mainstay of medulloblastoma treatment, is associated with significant age-dependent neurocognitive morbidity in children. Relatively little is known about the subgroup-specific outcome of infants and young children with medulloblastoma treated with irradiation-sparing regimens. METHODS: Infants and young children

Pediatric brain tumors as a group, including medulloblastomas, gliomas, and atypical teratoid rhabdoid tumors (ATRT) are the most common solid tumors in children and the leading cause of death from childhood cancer. Brain tumor-derived cell lines are critical for studying the biology of pediatric brain tumors and can be useful for initial screening of new therapies. Use of appropriate brain tumor cell lines for experiments is important, as results may differ depending on tumor properties, and can thus affect the conclusions and applicability of the model. Despite reports in the literature of over 60 pediatric brain tumor cell lines, the majority of published papers utilize only a small number of these cell lines. Here we list the approximately 60 currently-published pediatric brain tumor cell lines and summarize some of their central features as a resource for scientists seeking pediatric brain tumor cell lines for their research.

Posterior fossa ependymomas (EPN_PF) in children comprise two morphologically identical, but biologically distinct tumor entities. Group-A (EPN_PFA) tumors have a poor prognosis and require intensive therapy. In contrast, group-B tumors (EPN_PFB) exhibit excellent prognosis and the current consensus opinion recommends future clinical trials to test the possibility of treatment de-escalation in these patients. Therefore, distinguishing these two tumor subtypes is critical. EPN_PFA and EPN_PFB can be distinguished based on DNA methylation signatures, but these assays are not routinely available. We have previously shown that a subset of poorly prognostic childhood EPN_PF exhibits global reduction in H3K27me3. Therefore, we set out to determine whether a simple immunohistochemical assay for H3K27me3 could be used to segregate EPN_PFA from EPN_PFB tumors. We assembled a cohort of 230 childhood ependymomas and H3K27me3 immunohistochemistry was assessed as positive or negative in a blinded manner. H3K27me3 staining results were compared with DNA methylation-based subgroup information available in 112 samples [EPN_PFA (n=72) and EPN_PFB tumors (n=40)]. H3K27me3 staining was globally reduced in EPN_PFA tumors and immunohistochemistry showed 99% sensitivity and 100% specificity in segregating EPN_PFA from EPN_PFB tumors. Moreover, H3K27me3 immunostaining was sufficient to delineate patients with worse prognosis in two independent, non-overlapping cohorts (n=133 and n=97). In conclusion, immunohistochemical evaluation of H3K27me3 global reduction is an economic, easily available and readily adaptable method for defining high-risk EPN_PFA from low-risk posterior fossa EPN_PFB tumors to inform prognosis and to enable the design of future clinical trials.

Genetic analysis of familial forms of Alzheimer's disease (AD) causally links the proteolytic processing of the amyloid precursor protein (APP) and AD. However, the specific type of amyloid and mechanisms of amyloid pathogenesis remain unclear. We conducted a detailed analysis of intracellular amyloid with an aggregation specific conformation dependent monoclonal antibody, M78, raised against fibrillar Aß42. M78 immunoreactivity colocalizes with Aß and the carboxyl terminus of APP (APP-CTF) immunoreactivities in perinuclear compartments at intermediate times in 10. month 3XTg-AD mice, indicating that this represents misfolded and aggregated protein rather than normally folded APP. At 12. months, M78 immunoreactivity also accumulates in the nucleus. Neuritic plaques at 12. months display the same spatial organization of centrally colocalized M78, diffuse chromatin and neuronal nuclear NeuN staining surrounded by peripheral M78 and APP-CTF immunoreactivity as observed in neurons, indicating that neuritic plaques arise from degenerating neurons with intracellular amyloid immunoreactivity. The same staining pattern was observed in neuritic plaques in human AD brains, showing elevated intracellular M78 immunoreactivity at intermediate stages of amyloid pathology (Braak A and B) compared to no amyloid pathology and late stage amyloid pathology (Braak 0 and C, respectively). These results indicate that intraneuronal protein aggregation and amyloid accumulation is an early event in AD and that neuritic plaques are initiated by the degeneration and death of neurons by a mechanism that may be related to the formation of extracellular traps by neutrophils. © 2014 Elsevier Inc.

BACKGROUND: Vemurafenib is an orally administered inhibitor of BRAF-V600E kinase approved for the treatment of BRAF-V600E mutated melanoma. We have previously presented favorable radiographic response and safety data for vemurafenib in children with BRAF-V600E mutated brain tumors and report here an update on outcomes of this cohort, as well as pharmacokinetic (PK) data of patients taking whole (n=18) or crushed (n=6) tablets. METHODS: Vemurafenib was given orally, either as crushed or whole tablets, beginning at the adult dose equivalent of 550 mg/m2, twice daily. Toxicity, PK, and response were assessed. Doses of 420 mg/m2 and 550 mg/m2 were assessed by a 3 + 3 design in a dose de-escalation study. PK plasma samples were analyzed using HPLC at Covance Inc and modeled by standard PK methods using Phoenix v8 (Certera, Princeton, New Jersey). RESULTS: PK analyses demonstrated a significant accumulation factor (approximately six-fold) over time with each vemurafenib dose. In the “crushed” tablet cohort, bioavailability was approximately 96% of that seen in patients receiving whole tablets. The steady-state area-under-the-curve (AUC(ss)) median (range) was 754mg*h/L (464–920) in the whole tablet cohort and 621mg*h/L (184–1043) in the crushed tablet cohort. Updated best radiographic objective responses are: one complete response (CR), eleven partial responses (PR), and seven with stable disease (SD). Sustained responses were observed for over 50 months. Patients with SD had 30% lower AUC(ss) compared PR+CR. However, a logistic regression model using AUCss as a predictor of PR+CR was not significant given the observed variability. CONCLUSIONS: Children with BRAF-V600E mutated brain tumors treated with vemurafenib have durable responses. PK modeling confirmed similar PK paramaters in children as compared to adults treated for melanoma. Using crushed tablets to administer a liquid suspension of drug resulted in similar drug exposure to whole tablets.

Medulloblastoma (MB) is the most common malignant brain tumor of childhood. Current therapies are toxic and not always curative that necessitates development of targeted immunotherapy. However, little is known about immunobiology of this tumor. In this study, we show that MB cells in 9 of 20 primary tumors express CD1d, an antigen-presenting molecule for Natural Killer T cells (NKTs). Quantitative RT-PCR analysis of 61 primary tumors revealed an elevated level of CD1d mRNA expression in a molecular subgroup characterized by an overactivation of Sonic Hedgehog (SHH) oncogene compared with Group 4. CD1d-positive MB cells cross-presented glycolipid antigens to activate NKT-cell cytotoxicity. Intracranial injection of NKTs resulted in regression of orthotopic MB xenografts in NOD/SCID mice. Importantly, the numbers and function of peripheral blood type-I NKTs were preserved in MB patients. Therefore, CD1d is expressed on tumor cells in a subset of MB patients and represents a novel target for immunotherapy.

High-dose chemotherapy (HDC) strategies were developed in brain tumor protocols for young children to prevent neuropsychological (NP) impairments associated with radiotherapy. However, comprehensive NP evaluations of these children treated with such strategies remain limited. We examined the long-term neurocognitive outcomes of young children (

Ependymomas in children occur most commonly in the posterior fossa of the brain and cause significant morbidity and mortality. The pathogenesis of these tumors remains obscure as recent whole genome and whole exome sequencing efforts have not yielded recurrent genetic mutations. These tumors exhibit abnormal CpG island methylation, suggesting that epigenetic alterations may be a significant driver. To gain insights into the epigenetics of childhood ependymomas, we performed mass spectroscopy for histone modifications to discover that H3K27 trimethylation was globally reduced in these tumors. Despite global reduction in H3K27me3, ChIP-sequencing for H3K27me3 revealed genomic enrichment at several loci important for neurodevelopment. In a cohort of 195 childhood posterior fossa ependymoma samples, reduction in H3K27me3 was associated with worse prognosis (p

Li–Fraumeni syndrome (LFS) is an autosomal dominant cancer predisposition syndrome caused by germline alterations in the tumor suppressor gene TP53. LFS is associated with numerous malignancies including astrocytoma. Sanger sequencing and chromosomal microarray studies of blood and tumor tissue from a 4-yr-old boy with glioblastoma demonstrated a germline TP53 mutation with loss of heterozygosity for the short arm of Chromosome 17 as the second inactivating event in the tumor. There was no family history of LFS, but the child's mother had recently died from metastatic choriocarcinoma after antecedent normal term delivery of a then 6-mo-old daughter. The choriocarcinoma contained the same TP53 mutation detected in the proband and the 6-mo-old daughter was confirmed to be a carrier. Unexpectedly, the germline TP53 mutation was found to be inherited from the unaffected father. We report here the second genetically confirmed case of TP53-mutated choriocarcinoma in the partner of an LFS patient. Based on this case and recent literature, female partners of LFS patients may have increased risk of choriocarcinoma due to transmission of germline TP53 mutation from male carriers. Although the Toronto protocol has established an effective approach to detect tumors and improve survival in children and adults with LFS, there is a need to expand the current criteria to include surveillance of female partners of LFS patients for choriocarcinoma and other gestational trophoblastic disease. Recognition of this unique mode of transmission of TP53 mutations should be considered in genetic counseling for cancer risk assessment and family planning.

Background: The defining molecular feature of rhabdoid tumors, epithelioid sarcoma (ES), and poorly differentiated chordomas is the absence of tumor expression of INI1 (SMARCB1), a subunit of the SWI/SNF chromatin remodeling complex. INI1 loss impairs SWI/SNF activity and induces a dependence on the activity of EZH2, the catalytic subunit of PRC2, a separate complex responsible for chromatin remodeling and transcriptional repression through trimethylation of lysine 27 on histone H3 (H3K27me3). Tazemetostat, a potent and selective EZH2 inhibitor, has demonstrated tumor regressions in INI1-negative preclinical malignant rhabdoid tumor (MRT) models and durable objective responses in adults with certain INI1-negative ES or chordoma. Interim results from dose escalation (DEsc) cohorts of a Phase (Ph) 1 pediatric study are reported. Methods: EZH-102 (NCT02601937) is a Ph 1, multicenter study of tazemetostat dosed continuously as an oral suspension administered twice daily (BID) in patients (pts) aged 6 months to 21 years with synovial sarcoma, or INI1-negative tumors including atypical teratoid rhabdoid tumors (ATRT), MRT, ES, chordoma, and others. A “Rolling 6” design was used for DEsc. Objective response was assessed every 8 weeks using disease-appropriate response criteria, i.e., RANO or RECIST 1.1. Primary endpoints included identification of dose-limiting toxicities (DLT) and recommended Ph 2 dose (RP2D). Secondary endpoints included characterization of safety/tolerability, pharmacokinetics (PK), and duration of response. Exploratory endpoints included assessing the relationship between tazemetostat exposure and the pharmacodynamic (PD) marker H3K27me3 in peripheral blood. Results: Forty-six pts have been treated in 7 dose cohorts: 240 (n=8), 300 (n=6), 400 (n=6), 520 (n=7), 700 (n=6), 900 (n=6), and 1200 mg/m2 BID (n=7). One pt at 300 mg/m2 had DLTs of dyspnea (grade 4)/hypoxia (grade 3), but no DLTs were observed in any other cohort. Adverse events were generally mild to moderate, consistent with the safety profile observed in adults. Plasma concentrations were generally dose-proportional across the dose range studied and were lower at steady-state on Day 15 vs. those measured on Day 1. Mean systemic exposure in the 1200 mg/m2 cohort was ~ 4-fold greater than that at the adult RP2D of 800 mg BID. A PK:PD relationship between C1D15 tazemetostat exposure and H3K27me3 levels in peripheral blood monocytes and granulocytes was observed with consistent and significant post-dose reductions in H3K27me3 at the 900 and 1200 mg/m2 doses. Confirmed complete or partial responses (CR/PR) per RECIST/RANO were observed in pts with ES (n=1), chordoma (n=2), and ATRT (n=1) at dose levels ranging from 520 to 900 mg/m2. Conclusion: Tazemetostat was generally well tolerated in children and showed promising antitumor activity including CRs in pts with INI1-negative tumors. The RP2D of 1200 mg/m2 BID was defined on the basis of PK, PD, and clinical safety, and resulted in higher systemic exposure than in adults. Dose expansion cohorts are currently enrolling. Citation Format: Susan Chi, Maryam Fouladi, Neerav Shukla, Franck Bourdeaut, Ashley Margol, Guy Makin, Geoff McCowage, Cynthia Wetmore, Margaret Macy, Ted Laetsch, Darren Hargrave, Navin Pinto, Joanna Yi, Dave Ebb, Giles Robinson, Maria Roche, Benjamin Suttle, Alicia Clawson, Peter Ho, Jill Rodstrom, Scott Daigle, Karsten Nysom. Phase 1 study of the EZH2 inhibitor, tazemetostat, in children with relapsed or refractory INI1-negative tumors including rhabdoid tumors, epithelioid sarcoma, chordoma, and synovial sarcoma [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A175.

PURPOSE: Bifocal presentation of central nervous system (CNS) germinomas, with synchronous pineal and suprasellar involvement, is common, and associated with favorable outcome. However, the incidence and outcome of bifocal presentation of non-germinomatous germ cell tumors (NGGCT) is less well described. METHODS: Medical records of patients with CNS NGGCT treated at Children's Hospital Los Angeles between 1993 and 2014 were reviewed for clinical characteristics, treatment and outcome. RESULTS: Seven (24.1%) of 29 patients diagnosed with CNS NGGCT between 1993 and 2014 had bifocal involvement. The mean age at diagnosis was 13.1 years (range: 8-22 years). Diagnosis was made on tumor marker elevation in seven patients, and confirmed on histopathology on one patient. Seven patients had elevated AFP and one patient had elevated βHCG in serum and/or CSF. Two patients are still undergoing therapy and have not been included in the survival analyses. Four of remaining five patients are long term survivors at 41, 56, 57, and 97 months. Patient #1 received initial chemotherapy without irradiation, relapsed in the 3rd ventricle at 10 months, and was successfully salvaged with high-dose chemotherapy (HDCx) with autologous hematopoietic stem cell rescue (AuHCR) and 3600cGy craniospinal irradiation (CSI) with local boost. Patient #2 had partial response to chemotherapy, underwent HDCx and AuHCR, followed by 3600cGy CSI with boost. Patients #3 and #4 received chemotherapy with a complete response, followed by whole ventricular irradiation with a local boost. Patient #5 received chemotherapy only, developed ventricular relapse at 75 months, was treated with cyclophosphamide and vinblastine followed by CSI with boost, but died at 87 months. CONCLUSIONS: Our experience suggests that bifocal NGGCT may be more common than previously thought, and may be more likely to have yolk-sac component given elevated AFP, and therefore have a better prognosis than other NGGCT.

Medulloblastoma, the most common malignant brain tumor in children, occurs with increased frequency in individuals with Fanconi anemia who have biallelic germline mutations in BRCA2. We describe an 8 year old child who had disseminated anaplastic medulloblastoma and a deleterious heterozygous BRCA2 6174delT germline mutation. Molecular profiling was consistent with Group 4 medulloblastoma. The posterior fossa mass was resected and the patient received intensive chemotherapy and craniospinal irradiation. Despite this, the patient succumbed to a second recurrence of his medulloblastoma, which presented eight months after diagnosis as malignant pleural and peritoneal effusions. Continuous medulloblastoma cell lines were isolated from the original tumor (CHLA-01-MED) and the malignant pleural effusion (CHLA-01R-MED). Here we provide their analyses, including in vitro and in vivo growth, drug sensitivity, comparative genomic hybridization and next generation sequencing analysis. In addition to the BRCA2 6174delT, the medulloblastoma cells had amplification of MYC, deletion at Xp11.2 and isochromosome 17, but no structural variations or overexpression of GFI1 or GFI1B. To our knowledge, this is the first pair of diagnosis/recurrence medulloblastoma cell lines, the only medulloblastoma cell lines with BRCA2 6174delT described to date, and the first reported case of a child with medulloblastoma associated with a germline BRCA2 6174delT who did not also have Fanconi anemia.

BACKGROUND: Medulloblastomas in children can be categorized into four molecular subgroups with differing clinical characteristics such that subgroup determination aids in prognostication and risk-adaptive treatment strategies. Magnetic resonance spectroscopy (MRS) is a widely available, non-invasive tool used to determine metabolic characteristics of tumors providing diagnostic information without the need for tumor tissue. In this study we investigated the hypothesis that metabolite concentrations measured by MRS would differ between molecular subgroups of medulloblastoma allowing for accurate subgroup determination. METHODS: Magnetic resonance spectroscopy was used to measure metabolites in medulloblastomas across molecular subgroups (SHH = 12, Groups 3/4 = 17, WNT = 1). Levels of fourteen metabolites were analyzed to determine those which were most discriminant for medulloblastoma subgroups in order to construct a multivariable classifier to distinguish between combined Group 3/4 and SHH tumors. RESULTS: Medulloblastomas across molecular subgroups revealed distinct spectral features. A five metabolite subgroup classifier inclusive of creatine, myo-inositol, taurine, aspartate and lipid 13a was developed that could discriminate between Group 3/4 and SHH medulloblastomas with excellent accuracy (cross-validated Area Under the Curve AUC = 0.88). Group 3 and Group 4 tumors demonstrated metabolic profiles with readily detectable taurine, lower levels of lipids and high levels of creatine. SHH tumors showed prominent choline and lipid with low levels of creatine and little or no evidence of taurine. CONCLUSIONS: The data show that medulloblastomas of different molecular subgroups differ metabolically as measured using MRS. MRS is a potentially useful and accurate tool to determine medulloblastoma molecular subgroups.

Introduction: For many forms of cancers, survival improvement in the AYA population has lagged behind that of younger patients. One contributing factor could be differences in drug metabolism and tolerance of cancer treatment. Although previous studies have documented greater vincristine-related neurotoxicity (VRNT) in AYA vs. younger patients, comparative vincristine PK studies have yielded mixed results with no clear difference in PK related to age. One limitation of these studies is that age, rather than a more physiological assessment of developmental maturity, was used for the comparison. The primary aim of this study was to determine whether developmental differences in vincristine PK related to Tanner Stage could be detected in a sample of children and AYAs undergoing treatment for ALL. Our hypothesis was that vincristine PK would be related to Tanner Stage. Methods: From September 2014-March 2015, a purposeful sample of 30 patients with a diagnosis of ALL treated at Children9s Hospital of Los Angeles were recruited to this IRB-approved study either prior to starting Induction phase or during Maintenance phase. Tanner Stage was classified as ≤2 or ≥4, excluding Tanner Stage 3. Vincristine blood levels were obtained around the first dose during Induction or any single monthly dose during Maintenance at pre-specified time points: 0 min, 10 min, 30 min, 1 hour, 12 hour (Induction only), and 24 hours. For all patients, the vincristine dose was 1.5 mg/m 2 (max 2 mg). Vincristine levels were determined by high performance liquid chromatography. Mean vincristine clearance was compared using the independent T-test. Univariate and multivariate linear regression analysis via backward selection was performed using Tanner Stage, age, sex, BMI, fluconazole exposure, and treatment phase as predictors. P-values were two-sided with significance set at Results: The age range was 1-24 yrs ( 2 , respectively (p=0.71). As summarized in Tables 1 and 2, in both univariate and multivariate analyses no predictors, including Tanner Stage, were associated with vincristine clearance. Conclusions: In this pilot study, we were unable to detect an association between vincristine clearance and Tanner Stage. These data suggest that even when using a measure more reflective of physiological maturity than age, substantial developmental differences in vincristine clearance appear to be lacking. This calls into question the potential explanation of altered clearance for the increased VRNT observed in AYAs, and suggests that future investigations should be directed toward potential developmental differences in vincristine pharmacodynamics. Our data may have implications for understanding other differences in chemotherapy toxicity observed in AYAs. Disclosures No relevant conflicts of interest to declare.

Pediatric posterior fossa ependymomas are poorly understood childhood brain tumors and have no effective treatments. The biology of these tumors is obscure as recent sequencing efforts suggest that they lack recurrent genetic alterations. A subset of these tumors termed PF-A ependymomas exhibits CpG-island hypermethylation implicating epigenetic alterations in their pathogenesis. Through comprehensive analyses of histone modification, we discovered global H3K27me3 reduction in a subset of these tumors. Tumors with lowered H3K27me3 showed many clinical and biologic similarities with PFA-ependymomas. Global reduction in H3K27me3 is likewise observed in pediatric gliomas that bear histone H3K27M mutations termed diffuse intrinsic pontine gliomas (DIPG) that also arise in the posterior fossa of young children. Analyses of ependymomas with reduced H3K27me3 and H3K27M mutant DIPGs showed many similarities in DNA methylation and enrichment of H3K27me3 in many genomic loci important for neuroglial specification. Combined integrative analysis of both tumor types uncovered common epigenetic deregulation of select factors that control radial glial biology and radial glia in the developing posterior fossa showed reduced H3K27me3. Finally, PF ependymomas with lowered H3K27me3 were more invasive radiologically and exhibited poor prognosis in three independent cohorts (P300). These data have clinical implications for biomarker development and to inform epigenetic approaches to treat PF ependymomas. Citation Format: Sriram Venneti, Jill Bayliss, Piali Mukherjee, Chao Lu, Siddhant Jain, Chan Chung, Daniel Martinez, Benjamin Sabari, Ashley Margol, Pooja Panwalkar, Abhijit Paroloia, Melike Pekmezci, Richard Mc Eachin, Marcin Cieslik, Benita Tamrazi, Benjamin Garcia, Gaspare La Rocca, Mariarita Santi, Peter Lewis, Cynthia Hawkins, Ari Melnick, C David Allis, Craig B. Thompson, Arul Chinnaiyan, Alexander R. Judkins. A subset of poorly prognostic pediatric posterior fossa ependymomas exhibit lowered H3K27me3 and DNA hypomethylation and show epigenetic similarities with H3K27M mutant diffuse intrinsic pontine gliomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3863. doi:10.1158/1538-7445.AM2017-3863

Purpose: Medulloblastoma in children can be categorized into at least four molecular subgroups, offering the potential for targeted therapeutic approaches to reduce treatment-related morbidities. Little is known about the role of tumor microenvironment in medulloblastoma or its contribution to these molecular subgroups. Tumor microenvironment has been shown to be an important source for therapeutic targets in both adult and pediatric neoplasms. In this study, we investigated the hypothesis that expression of genes related to tumor-associated macrophages (TAM) correlates with the medulloblastoma molecular subgroups and contributes to a diagnostic signature. Methods: Gene-expression profiling using human exon array (n = 168) was analyzed to identify medulloblastoma molecular subgroups and expression of inflammation-related genes. Expression of 45 tumor-related and inflammation-related genes was analyzed in 83 medulloblastoma samples to build a gene signature predictive of molecular subgroups. TAMs in medulloblastomas (n = 54) comprising the four molecular subgroups were assessed by immunohistochemistry (IHC). Results: A 31-gene medulloblastoma subgroup classification score inclusive of TAM-related genes (CD163 and CSF1R) was developed with a misclassification rate of 2%. Tumors in the Sonic Hedgehog (SHH) subgroup had increased expression of inflammation-related genes and significantly higher infiltration of TAMs than tumors in the Group 3 or Group 4 subgroups (P < 0.0001 and P < 0.0001, respectively). IHC data revealed a strong association between location of TAMs and proliferating tumor cells. Conclusions: These data show that SHH tumors have a unique tumor microenvironment among medulloblastoma subgroups. The interactions of TAMs and SHH medulloblastoma cells may contribute to tumor growth revealing TAMs as a potential therapeutic target. Clin Cancer Res; 21(6); 1457–65. ©2014 AACR.

Purpose: We present here the first report of PID1 (Phosphotyrosine Interaction Domain containing 1; NYGGF4) in cancer. PID1 was identified in 2006 as a gene that modulates insulin signaling and mitochondrial function in adipocytes and muscle cells. Experimental Design and Results: Using four independent medulloblastoma datasets, we show that mean PID1 mRNA levels were lower in unfavorable medulloblastomas (groups 3 and 4, and anaplastic histology) compared with favorable medulloblastomas (SHH and WNT groups, and desmoplastic/nodular histology) and with fetal cerebellum. In two large independent glioma datasets, PID1 mRNA was lower in glioblastomas (GBM), the most malignant gliomas, compared with other astrocytomas, oligodendrogliomas and nontumor brains. Neural and proneural GBM subtypes had higher PID1 mRNA compared with classical and mesenchymal GBM. Importantly, overall survival and radiation-free progression-free survival were longer in medulloblastoma patients whose tumors had higher PID1 mRNA (univariate and multivariate analyses). Higher PID1 mRNA also correlated with longer overall survival in patients with glioma and GBM. In cell culture, overexpression of PID1 inhibited colony formation in medulloblastoma, atypical teratoid rhabdoid tumor (ATRT), and GBM cell lines. Increasing PID1 also increased cell death and apoptosis, inhibited proliferation, induced mitochondrial depolaization, and decreased serum-mediated phosphorylation of AKT and ERK in medulloblastoma, ATRT, and/or GBM cell lines, whereas siRNA to PID1 diminished mitochondrial depolarization. Conclusions: These data are the first to link PID1 to cancer and suggest that PID1 may have a tumor inhibitory function in these pediatric and adult brain tumors. Clin Cancer Res; 20(4); 827–36. ©2013 AACR.

Recent studies showing that microglia internalize the amyloid beta-peptide (Abeta) suggest that these cells have the potential for clearing Abeta deposits in Alzheimer's disease, and mechanisms that regulate the removal of Abeta may therefore be of clinical interest. Previous studies from this laboratory showing that C1q enhances phagocytosis of cellular targets by rat microglia prompted the current investigations characterizing the effects of C1q on microglial phagocytosis of Abeta. Microglia were shown to phagocytose Abeta1-42, in agreement with observations of other investigators. Uptake of Abeta1-42 was observed for concentrations of 5-50 microM, and phagocytosis of peptides containing (14)C or fluorescein (FM) labels was not affected by the interaction of microglia with C1q-coated surfaces. However, inclusion of C1q (125 nM-1.4 microM) in solutions of 50 microM Abeta1-42 inhibited the uptake of (14)C-Abeta1-42 and FM-Abeta1-42, suggesting that C1q blocks the interaction of Abeta with microglia. Uptake of Abeta was partially blocked by the scavenger receptor ligands polyinosinic acid and maleylated BSA. Inhibition of Abeta uptake by C1q may contribute to the accumulation of fibrillar, C1q-containing plaques that occurs in parallel with disease progression. These data suggest that mechanisms which interfere with the binding of C1q to Abeta may be of therapeutic value both through inhibition of the inflammatory events resulting from complement activation and via altered access of Abeta sites necessary for ingestion by microglia.

LG-16. RADIOGRAPHIC AND OPHTHALMOLOGIC CHARACTERISTICS OF OPTIC PATHWAY GLIOMA IN CHILDREN WITH NEUROFIBROMATOSIS 1 Elizabeth Unterbrink1, Benita Tamrazi1,2, Mark Borchert1,2, Ashley Margol1,2, Linda Randolph1,2, Tena Rosser1,2, Girish Dhall1,2, and Nathan Robison1,2; Children’s Hospital Los Angeles, Los Angeles, CA, USA; University of Southern California Keck School of Medicine, Los Angeles, CA, USA OBJECTIVE: To describe the natural history of optic pathway glioma (OPG) in children with neurofibromatosis 1 (NF1). METHODS: The Children’s Hospital Los Angeles (CHLA) institutional review board approved this retrospective study. Using a clinical database, we identified children with NF1 and OPG followed at CHLAwith at least 1 MRI obtained at ,12 years of age from 6/1/1997-5/31/2014. Demographic, treatment, and visual field/ acuity data were extracted. MRIs were reviewed by a neuroradiologist. RESULTS: Of 63 children with NF1 and OPG, 50 had available imaging and were included. Mean age at initial MRI was 4.8 years; mean follow-up was 6.8 years. OPG was apparent on brain MRI in 4/7 children at ,2 years (57%; 95% confidence interval[95%CI] 20-94); 19/23 by 4 years (83%; 95%CI 67-98); 29/31 by 6 years (94%; 95%CI 85-100); and 50/50 by 12 years. Among 13 children (26%) who subsequently received tumor-directed treatment, OPG was MRI-apparent in 5/6 children by 4 years (83%; 95%CI 54-100), 8/9 by 6 years (89%; 95%CI 68-100) and 13/13 by 8 years. Among children with detailed visual outcome data, visual impairment was seen in 6/20 at , 4 years (30%; 95%CI 10-50); and 26/45 by 12 years (58%; 95%CI 43-72). A subset had normalization of vision, with persistent visual abnormalities in only 14/41 children on follow-up (34%; 95%CI 20-49). DISCUSSION: A minority of children without MRI-apparent OPG at initial evaluation eventually developed symptomatic disease. The high incidence of early-onset visual abnormalities highlights the importance of early NF1 diagnosis and ophthalmologic screening. Neuro-Oncology 18:iii78–iii96, 2016. doi:10.1093/neuonc/now075.16 #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.

BACKGROUND: High dose chemotherapy strategies were developed to avoid craniospinal irradiation and prevent unacceptable neurotoxicity in young children. However, long-term outcome, including neurocognitive outcome, of this approach has not been widely described. METHODS: This retrospective study collected data from 7 institutions, on young children with medulloblastoma who received high-dose Carboplatin, Thiotepa according to the protocol {"type":"entrez-protein","attrs":{"text":"CCG99703","term_id":"384066493","term_text":"CCG99703"}}CCG99703 between 1998-2012. Data on pathology, molecular subgrouping, chemotherapeutic, radiation, ototoxicity, neurognitive evaluations and survival were collected. RESULTS: There were 53(30 males) patients diagnosed at a median age of 24 months(2.9-63.2). Twenty(37.7%) had metastatic disease and 35(66%) underwent gross total resection(GTR). Seventeen(32.1%) had nodular desmoplastic(ND) subtype. Twenty two(56.4%) out the 39 patients with molecular subtyping belong to the SHH group. Three patients received intrathecal chemotherapy, 6 received HD MTX during induction and 7 underwent maintenance chemotherapy. Seventeen patients received radiation, including only 9(16.9%) in an adjuvant setting. Complete continuous remission(CCR) after induction and consolidation were respectively 73.6% and 77.4 %. Two patients died of treatment related toxicity. Forty-two patients are alive at a median follow-up of 3.7 years from diagnosis with a projected 5-year PFS and OS of respectively 69.2%(±7) and 76.1%(±6.5). ND histology, SHH subgroup and CCR were significantly associated better PFS, but only CCR post induction remained significant for better OS. Non irradiated children had a better PFS compare to those who received radiation(5y PFS 84.6% versus 42.2%p = 0.007). Severe ototoxicity(≥ Brock grade 3) was present in 13.2% of 31 evaluable patients. Thirteen required hearing support. Neurocognitive assessements were available in 24 survivors(57%). Mean FSIQ for the cohort was 91(range 67-119). CONCLUSION: Young children with MB treated with this strategy have a very encouraging OS (76.4 %) while only 17% of the patients who received adjuvant radiation. Although the ototoxicity was significant, neurocognitive profile of the survivors appears to be within normal range.

The concept of tumor-promoting inflammation is a recognized enabling characteristic of cancer. Tumor associated macrophages (TAMs), one of the main contributors to the tumor microenvironment, have been identified in many adult malignancies and in the MYCN non-amplified high risk neuroblastomas. TAMs have been shown to promote cancer via multiple mechanisms including tumor cell growth and survival, invasion, metastasis, angiogenesis, inflammation, and immune regulation. Recent studies in adult gliomas have demonstrated increased expression of macrophage/microglia associated genes in subtypes of gliomas, however little is known about the role of inflammation in medulloblastomas, the most common malignant childhood brain tumor. In this study we examined the expression of inflammation-related genes and presence of TAMs in molecular subgroups of pediatric medulloblastoma. The molecular subgroups of medulloblastomas were initially identified using Human Exon Array (HuEx) microarray data from 168 samples (65 patients profiled at Children's Hospital Los Angeles and 103 from previously published cohort) using a modified algorithm based on non-negative matrix factorization. We then examined the inflammation and immunology related genes that were differentially expressed among the molecular subgroups and discovered greater expression of inflammation-related genes in tumors of the SHH molecular subgroup compared with those of the Group 3 and Group 4 subgroups. Gene expression analysis was then performed on 83 medulloblastoma samples using a custom-built TaqMan Low Density Array (TLDA) card containing 41 tumor-related and 4 inflammation-related genes that were significantly deregulated among medulloblastoma subgroups in the HuEx microarray analyses. Thirty-one of these genes were used to develop a signature predictive of molecular subgroup. The internal cross-validted error rate of the TLDA 31-gene signature was 8%, with predominant misclassifications occurring between Groups 3 and 4. The expression levels of CD163 and CSF1R, two markers associated with TAMs, were higher in tumors of the SHH subgroup compared to those in the WNT, Group 3, and Group 4 subgroups (CD163, t-test p=.02 for WNT and p Our study reports the first evidence of the presence of TAMs in medulloblastomas and provides a novel 31-gene TLDA signature that accurately determines molecular subgroups of medulloblastomas. The increase in expression of macrophage related genes and intratumoral macrophages was strongly associated with the SHH subgroup of patients. The identification of TAMs in medulloblastomas provides opportunity for testing new therapies directed against TAMs such as CSF1R inhibitors, and the recognition of the importance of tumor microenvironment in childhood brain tumors. Citation Format: Ashley Margol, Janahan Gnanachandran, Nathan Robison, Long Hung, Rebekah Kennedy, Marzieh Vali, Girish Dhall, Jonathan Finlay, Anat Epstein, Mark Krieger, Kathleen Dorris, Maryam Fouladi, Floyd Gilles, Alexander Judkins, Richard Sposto, Shahab Asgharzadeh. Presence of tumor-associated macrophages in SHH medulloblastoma. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr B18.

To evaluate whether baseline visual field data and asymmetries between eyes predict the onset of primary open-angle glaucoma (POAG) in Ocular Hypertension Treatment Study (OHTS) participants.A new index, mean prognosis (MP), was designed for optimal combination of visual field thresholds, to discriminate between eyes that developed POAG from eyes that did not. Baseline intraocular pressure (IOP) in fellow eyes was used to construct measures of IOP asymmetry. Age-adjusted baseline thresholds were used to develop indicators of visual field asymmetry and summary measures of visual field defects. Marginal multivariate failure time models were constructed that relate the new index MP, IOP asymmetry, and visual field asymmetry to POAG onset for OHTS participants.The marginal multivariate failure time analysis showed that the MP index is significantly related to POAG onset (P0.0001) and appears to be a more highly significant predictor of POAG onset than either mean deviation (MD; P = 0.17) or pattern standard deviation (PSD; P = 0.046). A 1-mm Hg increase in IOP asymmetry between fellow eyes is associated with a 17% increase in risk for development of POAG. When threshold asymmetry between eyes existed, the eye with lower thresholds was at a 37% greater risk of development of POAG, and this feature was more predictive of POAG onset than the visual field index MD, though not as strong a predictor as PSD.The MP index, IOP asymmetry, and binocular test point asymmetry can assist in clinical evaluation of eyes at risk of development of POAG.