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BACKGROUND The authors analyzed the incidence and types of second malignant neoplasms (SMNs) in patients treated for medulloblastoma. METHODS The authors compared the incidence of SMNs after radiotherapy (RT) for medulloblastoma in patients treated in 1973-2014 with the incidence in the general population with the multiple primary-standardized incidence ratio function of Surveillance, Epidemiology, and End Results 9. Observed-to-expected incidence (O/E) ratios and 95% confidence intervals (CIs) were reported for the entire cohort and by disease site according to age at diagnosis, treatment era, and receipt of chemotherapy. P values < .05 were considered statistically significant. RESULTS Of the 1294 patients with medulloblastoma who received RT, 68 developed 75 SMNs. The O/E ratio for SMNs among all patients was 4.49 (95% CI, 3.53-5.62; P < .05). The site at highest risk was the central nervous system (CNS; O/E, 40.62; 95% CI, 25.46-61.51), which was followed by the endocrine system (O/E, 15.95; 95% CI, 9.12-25.91), bone (O/E, 14.45; 95% CI, 1.75-52.21), soft tissues (O/E, 9.01; 95% CI, 1.09-32.56), the digestive system (O/E, 5.03; 95% CI, 2.51-9.00), and the lymphatic/hematopoietic system (O/E, 3.37; 95% CI, 1.35-6.94). The O/E ratio was higher for patients given chemotherapy and RT (O/E, 5.52; 95% CI, 3.75-7.83) than for those given RT only (O/E, 3.96; 95% CI, 2.88-5.32). CONCLUSIONS Patients with medulloblastoma are at elevated risk for SMNs in comparison with the general population. Variations in O/E for SMNs by organ systems were found for treatment modality, age at diagnosis, and time of diagnosis. The most common site, the CNS, was involved more often in younger patients and those given chemotherapy with RT.

BACKGROUND: H3 K27M-mutant diffuse midline glioma is a fatal malignancy with no proven medical therapies. The entity predominantly occurs in children and young adults. ONC201 is a small molecule selective antagonist of dopamine receptor D2/3 (DRD2/3) with an exceptional safety profile. Following up on a durable response in the first H3 K27M-mutant diffuse midline glioma patient who received ONC201 (NCT02525692), an expanded access program was initiated. METHODS: Patients with H3 K27M-mutant gliomas who received at least prior radiation were eligible. Patients with leptomeningeal spread were excluded. All patients received open-label ONC201 orally once every week. Safety, radiographic assessments, and overall survival were regularly assessed at least every 8 weeks by investigators. As of August 2018, a total of 18 patients with H3 K27M-mutant diffuse midline glioma or DIPG were enrolled to single patient expanded access ONC201 protocols. Among the 18 patients: seven adult (>20 years old) and seven pediatric (

Background Recurrent pediatric medulloblastoma and ependymoma have a grim prognosis. We report a first-in-human, phase I study of intraventricular infusions of ex vivo expanded autologous natural killer (NK) cells in these tumors, with correlative studies. Methods Twelve patients were enrolled, 9 received protocol therapy up to 3 infusions weekly, in escalating doses from 3 × 106 to 3 × 108 NK cells/m2/infusion, for up to 3 cycles. Cerebrospinal fluid (CSF) was obtained for cellular profile, persistence, and phenotypic analysis of NK cells. Radiomic characterization on pretreatment MRI scans was performed in 7 patients, to develop a non-invasive imaging-based signature. Results Primary objectives of NK cell harvest, expansion, release, and safety of 112 intraventricular infusions of NK cells were achieved in all 9 patients. There were no dose-limiting toxicities. All patients showed progressive disease (PD), except 1 patient showed stable disease for one month at end of study follow-up. Another patient had transient radiographic response of the intraventricular tumor after 5 infusions of NK cell before progressing to PD. At higher dose levels, NK cells increased in the CSF during treatment with repetitive infusions (mean 11.6-fold). Frequent infusions of NK cells resulted in CSF pleocytosis. Radiomic signatures were profiled in 7 patients, evaluating ability to predict upfront radiographic changes, although they did not attain statistical significance. Conclusions This study demonstrated feasibility of production and safety of intraventricular infusions of autologous NK cells. These findings support further investigation of locoregional NK cell infusions in children with brain malignancies.

Metachronous neoplasms have rarely been reported in patients with neuroblastoma. This report presents the clinical case of a 23-month-old child who was diagnosed with an anaplastic medulloblastoma 5 months after completing treatment for stage IV neuroblastoma. The patient was treated with complete surgical resection and adjuvant chemoradiation followed by maintenance chemotherapy at an outside institution and came to our institution for further management. A pathologic diagnosis and review of both the suprarenal and posterior fossa masses were performed, as well as a genetic analysis of both cerebellar tumor tissue and blood using next-generation gene sequencing. At our institution, the patient was submitted to induction chemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation and remains free of disease 2 years after completion of treatment. Genetic analysis revealed multiple somatic copy number variations with most deleted genes located in 2q37, a region which harbors genes involved in epigenetic regulation and tumor suppression. A homozygous deletion was found in the TSC2 gene, which is a clinically actionable gene, and patients with activating deletions in TSC2 can potentially be eligible for basket clinical trials with mTOR inhibitors. Germline single nucleotide variants were also identified in multiple genes involved in cancer (ALK, FGFR3, FLT3/4, HNF1A, NCOR1, and NOTCH2/3), cancer predisposition (TP53, TSC1, and BRCA1/2), and genes involved in DNA repair (MSH6, PMS2, POLE, and ATM). Metachronous neoplasms are rare and challenging to treat, hence genetic analysis and referral are needed to exclude hereditary cause. DNA sequencing of the tumor and germline can help identify alterations that increase predisposition or can be used to guide treatment decisions on recurrence and when standard options fail.

Neurocognitive late effects are unfortunately common following treatment for pediatric medulloblastoma. While radiation therapy is an essential component of treatment for most pediatric medulloblastoma patients, it is associated with neurocognitive compromise. Effects include deficits in cognitive speed and performance efficiency, aspects of attention, as well as working memory. Yet long after treatment it is difficult to tease apart relative contributions of other risk factors to neurocognitive functioning beyond radiation. We examined neurocognitive functioning in a sample of pediatric medulloblastoma patients prior to radiation therapy, including investigation of neurocognitive risk factors such as hydrocephalus, presence of posterior fossa syndrome, and duration of neurological symptoms prior to diagnosis. Results indicated that the sample functioned in the average range in terms of overall IQ (n=34, X̅=103). Patients also functioned in the normal range in terms of language-based ability (X̅=106), nonverbal ability (X̅=104), and working memory (X̅=103). However, the sample performed statistically significantly lower than the general population in terms of cognitive speed and efficiency (z=-2.026, p=.043). The sample was also rated by parents as exhibiting more attention problems relative to the general population (z=1.988, p=.047). There was no specific association with hydrocephalus, duration of symptoms, or history of posterior fossa syndrome. Results suggest weaknesses in attention and processing speed may exist in some pediatric medulloblastoma patients prior to radiation therapy secondary to tumor and related complications. Implications for future research are presented, along with difficulties inherent to “baseline” assessment with pediatric brain tumor survivors.

INTRODUCTION Spinal myxopapillary ependymoma (MPE) is a rare histological variant of ependymoma, classified as WHO grade I tumor. Further interrogation of the molecular and clinical profile is warranted, to better understand the biology and clinical phenotype. We summarize our institutional experience with spinal MPE including methylation-profiling. METHODS A retrospective analysis of charts during the period of 2001 to 2019 of histologically proven MPE was done. We performed methylation profiling for 12 patients by Infinium MethylationEPIC Kit. RESULTS 26 patients with spinal MPE were identified, median age of diagnosis was 34.2 years with a range of 11 to 59.9 years. Ten patients were below 30 years of age, lumbar spine location was commonest and 6 had leptomeningeal spread at diagnosis. All the patients underwent surgery and 11 received radiation following surgery. Eight patients below the age of 30 received radiation due to residual disease or metastases. Methylation profiling revealed 11,752 CpGs differentially methylated between the younger and older patients (p < 0.05), however only one CpG cg22496254 associated with gene NCAPG/DCAF16 (role in promoting mitosis) was detectable with FDR < 0.25 that overly methylated in the younger age group. This is a new finding in MPE. CONCLUSIONS Spinal MPE is a rare spinal tumor. Our study though limited by numbers, showed younger patients had aggressive phenotype, most requiring radiation. Methylation profiling reaffirmed this finding and trend in the younger patients. Prospective studies in a larger cohort of patients with methylation profiling are needed to identify prognostic variables and new targets for treatment.

INTRODUCTION Prospective studies for adult medulloblastoma (MB) are scarce and management guidelines are largely derived from pediatric experience and retrospective data. However, adult MB is a distinct disease for which limited data exist regarding clinical characteristic, prognostic factors, outcome based on upfront treatment, or patterns of recurrence. METHODS 200 patients (≥18 years at diagnosis) were identified from 1978 to 2017. Survival analysis was performed using the Kaplan-Meier method. RESULTS Median age at diagnosis 29 (18–63); 111 (55.5%) standard-risk (SR), 59 (29.5%) high-risk (HR), 30 (15%) unknown. 188 (94%) and 97 (48.5%) underwent radiotherapy and upfront chemotherapy, respectively. Median PFS: 6.28 years (4.9–11.2); median OS: 8.8 (7.8–12.4) years. Median time to first recurrence: 8.2 (5.1-not reached); 5-year recurrence-free rate: 71% in SR and 45% in HR patients. Survival after first recurrence: 2 years (1.64–2.4). Documented recurrence and risk group were associated with survival (HR 30.4, p< 0.0001 and 2.33, p< 0.001), but metastatic status and local vs. distant recurrence were not. The effect of upfront chemotherapy on survival did not reach statistical significance in SR patients. The use of chemotherapy regimens with or without vincristine or containing cisplatin vs. carboplatin, did not alter the survival outcome. In a subgroup of 57 SR patients who were seen at initial diagnosis and for whom complete staging and treatment information were available 3 and 5-year PFS were 94% (88%, 100%) and 76% (66%, 86%); OS at 5 years, 94% (87%, 100%). CONCLUSION No statistically significant difference was noted in outcome of patients treated without vincristine or with carboplatin instead of cisplatin, suggesting attenuated upfront regimens could be considered to reduce toxicity. Adult MB patients recur late and have a poor post-recurrence survival, therefore long-term follow-up, development of molecular risk-adjusted upfront treatment, and optimization of rescue treatments are needed.

BACKGROUND Despite its increasing use, circulating tumor cells (CTCs) have not been studied in pediatric brain tumors. METHODS Cell surface vimentin (CSV) is a marker for CTC detection. We developed an automated CSV-based CTC capture method for pediatric brain tumor using the Abnova Cytoquest platform. PBMCs isolated from blood samples from 52 brain tumor patients were processed to isolate CSV+ CTCs. Captured cells were then stained for CSV and CD45 and scanned to determine the number of CTCs. DIPG samples were additionally examined for H3K27M expression on CSV+ cells. Long term cancer survivors were used as a control cohort. RESULTS 86.4% of all the samples exhibited between 1–13 CSV+ CTCs, with a median of 2 CSV+ CTCs per sample. Using a value of ≥ 1 CTC as a positive result, the sensitivity and specificity of this test was 83.05% and 60.0% respectively. 19 DIPG samples were analyzed and 70% (13 samples) were positive for 1–5 CTCs. Five of these 7 positive CSV+ CTCs DIPG samples were also positive for H3K27M mutations by immunohistochemistry (71%). Mean survival in days for the CTC positive and negative DIPG samples were 114 and 211 days, respectively (p= 0.13). CONCLUSION This is the first study of CTCs in pediatric CNS tumors using an automated approach. Patients with brain tumors can exhibit CSV+ CTCs within peripheral blood. The use of specific molecular markers such as H3K27M can improve the diagnostic capability of liquid biopsies and may enable future disease assessment for personalized therapy.

BACKGROUND Embryonal Tumor with Multilayered Rosettes (ETMR) are rare tumors that are molecularly diagnosed by C19MC amplification. Rarity of this tumor has precluded profiling uniform therapeutic strategy. METHODS Retrospective review after institutional approval, identified 10 pediatric case of ETMR, treated at MD Anderson Cancer Center during the period of 2005 to 2019. RESULTS Median age of at diagnosis was 4.6 years. Tumor sites include frontal or parietal lobes (3), spine (3) and posterior fossa involving the brainstem (4). All patients received a combination of chemotherapy and radiation. 4 patients had metastasis at the presentation. 9 patients received focal radiation but only 6 of them received Craniospinal irradiation (CSI). Average dose of radiation was 50 Gy. Surgical resection was performed in all cases except the brainstem tumors. 7 children had recurrence including all the patients with metastasis at diagnosis (median time: 9.4 months), 1 passed away secondary to hemorrhage in brainstem and data was not available for 2 patients. 5/6 patients who received CSI had recurrence. CONCLUSIONS To-date no well-defined treatment regimens exists for these neoplasms, resulting in poor overall survival. Preclinical drug screen have shown the efficacy of topotecan, actinomycin D, and volasertib as potential new therapeutic candidates, though this has not translated successfully into the clinical arena. Given the limited success with current conventional therapeutic methods, molecular interrogation in addition to histopathological diagnosis are essential upfront, as it could provide clues to targeted therapy. Defining molecularly-based treatment with less toxicities and increased survival are warranted.

H3 K27M-mutant gliomas often manifest as midline gliomas, have a dismal prognosis, and have no effective treatments. ONC201 efficacy has been shown in high-grade glioma preclinical models and durable responses with single agent ONC201 have been reported in adults with recurrent H3 K27M-mutant gliomas. These observations led to a Phase I pediatric clinical trial of ONC201 dosed by body weight. This multi-center, open-label, 3 + 3 dose-escalation and dose-expansion clinical trial (NCT03416530) for H3 K27M-mutant glioma or non-biopsied DIPG has 6 arms: arms A and E determine the RP2D in pediatric post-radiation (recurrent or not-recurrent) H3 K27M-mutant glioma patients with ONC201 administered as an oral capsule as well as a liquid formulation, respectively. Both arms have completed accrual. The study is currently enrolling newly diagnosed DIPG patients to determine the RP2D for ONC201 in combination with radiation (arm B). Dedicated assessment of intratumoral ONC201 concentrations in midline gliomas patients (arm C) and the effects of ONC201 in H3K27M DNA levels in circulating CSF (arm D) are currently enrolling patients. ONC201 as a single agent in patients with progressive H3K27M mutant tumors following irradiation (excluding DIPG/spinal cord tumors) was recently opened (arm F). Once the RP2D is confirmed, there is a dose-expansion cohort to confirm the safety, radiographic efficacy and survival with ONC201. The primary endpoints of arms A, B, and E have been established with the RP2D of 625mg scaled by body weight as a capsule or liquid formulation administered alone or in combination with radiation without incidence of dose-limiting toxicity.

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.

ONC201, an anti-cancer DRD2 antagonist and ClpP agonist, is in Phase II trials for adult H3 K27M-mutant diffuse midline gliomas. In adults, the recommended phase 2 dose (RP2D) of 625mg ONC201 once a week has been established as a biologically active dose that is well tolerated. Radiographic regressions with single agent ONC201 have been reported in adult recurrent H3 K27M-mutant glioma patients. This multi-arm, dose-escalation and dose-expansion trial determined the pediatric RP2D of ONC201 administered as an oral capsule (Arm A) or liquid formulation (Arm E) in post-radiation H3 K27M-mutant glioma (Arm A) or in newly diagnosed DIPG (Arm B) patients. Molecular assessments include intratumoral ONC201 concentrations (Arm C) and CSF H3 K27M DNA levels (Arm D). Enrollment as of April 30, 2020 is complete in Arm A (22) and Arm E (26) and continues in Arm B (18/24), Arm C (5/12), and Arm D (22/24). The RP2D of weekly 625mg ONC201 scaled by body weight was confirmed when administered as a capsule or a liquid formulation as a single agent or in combination with radiation without dose-limiting toxicity. The most frequent adverse events regardless of attribution to the drug were predominantly low grade: ONC201 capsule alone was headache (54.5%), nausea (36.4%), and fatigue (36.4%); ONC201 liquid formulation was vomiting (31.8%), headache (22.7%), VIth nerve disorder (22.7%); ONC201 capsules in combination with radiation (Arm B) was headache (47.1%), vomiting (52.9%), nausea (41.2%). Pharmacokinetic analysis in plasma of Arm A patients revealed T1/2: 8.4h; Tmax: 2.1h; Cmax: 2.3ug/mL; AUC0-tlast: 16.4ug/mL, with similar exposure across body weights. In conclusion, when scaled by body weight the ONC201 capsule or liquid formulation alone or in combination with radiation were associated with safety and pharmacokinetic profiles in pediatric H3 K27M-mutant diffuse midline glioma patients that are similar to the experience in adults.

BACKGROUND: Adult medulloblastoma (MB) is rare, accounting for 150–300 new cases in the US annually. Given the low incidence, prospective studies are challenging, and the role of adjuvant chemotherapy in standard risk patients has been controversial. Currently, the best evidence available (Level V) supports the use of upfront chemotherapy. A recent pilot prospective study (NOA-07) proved feasibility of craniospinal irradiation with vincristine, followed by cisplatin, lomustine and vincristine; 4 cycles were feasible in most patients. However, toxicity was substantial. In clinical practice, attempts to ameliorate the intensity of the treatment regimen are common, such as substitution of cisplatin by carboplatin, or removal of vincristine. It is not known if these modifications compromise outcome, and the optimal chemotherapy regimen for adult MB patients to balance efficacy and tolerability has not been established. METHODS: We analyzed patterns of use of chemotherapy retrospectively in a large single institution database of patients with adult medulloblastoma. To date, 136 patients (≥18 years at diagnosis) evaluated from January 1978 to April 2017 have been identified (additional patients are being analyzed). Median progression-free survival (mPFS), median overall survival (mOS), 5-year progression free survival (PFS-5) and 5 year-overall survival (OS-5) were estimated using the Kaplan-Meier method. RESULTS: Median age was 28 (18–63); female-to-male ratio 1.7:1; 69/136 (50.7%) were standard risk, and 53/136 (39.0%) were high risk (subtotal resection and/or metastasis) (indeterminate risk in 14). In patients without residual disease at initial diagnosis, 27/79 (34.2%) received chemotherapy upfront; carboplatin vs. cisplatin regimens in 8 vs. 11 patients; vincristine vs non-vincristine in 20 vs. 6 patients. The patients treated with upfront chemotherapy had significant improvement in outcome in comparison with those who did not receive upfront chemotherapy (PFS-5 of 56.6% vs. 84.2%, p=0.018 and OS-5 of 79.5% vs. 90.0%, p=0.050). There was no statistically significant difference between the survival of those who had received carboplatin vs. cisplatin (PFS-5 of 100% vs. 74.1%, p=0.197 and OS-5 of 100% vs. 85.7%, p=0.325). Addition of vincristine was not associated with improved outcome (PFS-5 92.9% vs. 55.6%, p=0.166 and OS-5 of 90.9% vs. 83.3%, p=0.090). CONCLUSION: To date, we have not found a statistically significant difference in outcome in patients without residual disease treated with carboplatin vs. cisplatin-based regimens, or between regimens containing vincristine and regimens not containing vincristine. Attenuated regimens of chemotherapy in adult medulloblastoma patients may decrease toxicity without compromising efficacy. Additional patients will be added to this cohort to further improve the accuracy of this study.

Choroid plexus (CP) carcinoma is a rare intraventricular brain tumor derived from the CP epithelium and occurs mainly in young children. CP carcinoma is a World Health Organization (WHO) grade III neoplasm. Despite multidisciplinary treatment approaches, including surgical resection, radiotherapy, and adjuvant chemotherapy, the outcome remains guarded and many of the survivors exhibit significant neurologic sequelae of both the tumor and its treatment. TP53 mutations are common in CP carcinomas and have been associated with poorer outcome. Recent studies have highlighted the potential of genome-wide methylation profiling, gene expression profiling, and p53 mutation status to provide additional layers of information to improve risk stratification in CP tumors. In this chapter, we discuss the current management of CP carcinoma and future therapeutic potentials in the era of new molecular discoveries in this rare tumor. Further studies are needed to standardize the treatment paradigm for this neoplasm.

Ganglioglioma (GG) is a rare mixed glial-neuronal neoplasm accounting for 0.5–5% of all pediatric central nervous system (CNS) tumors. Rarity of this tumor has precluded defining robust treatment guidelines. This retrospective study evaluates the prognostic factors and outcomes of this rare neoplasm. Retrospective analysis of 55 patients with GG was conducted to describe clinical findings, and outcomes. Kaplan–Meier survival and Cox-regression analyses were performed to assess the overall survival (OS) and progression-free survival (PFS). The mean age at diagnosis was 11.8 years (range 1–21 years) with a median follow-up period of 9.5 years. 53 patients (92.7%) had low grade GG and 2 patients had anaplastic GG. 25 patients had tumor progression, whose median PFS was 12 years. Six patients with low grade GG progressed to a higher grade, with median survival of 9.1 month after transformation. The 5 and 10 year PFS were 65 and 57%, respectively. The 5 and 10 year OS was 96 and 86% respectively. 8 of the 19 (42%) samples tested demonstrated positivity for the BRAF V600E mutation. Multivariate Cox regression analyses showed location and extent of resection were significant factors for PFS and presence of metastatsis attained significance for OS. This is the one of the largest retrospective study of pediatric GG. Identifying clinical variables, which could stratify these tumors into low- and high-risk groups might help to profile a risk-based therapeutic strategy. Collaborative multiinstitutional prospective studies are warranted to delineate treatment consensus and investigate prognostic factors.

Background The use of high-dose chemotherapy with autologous hematopoietic cell rescue (AuHCR) in Head Start III is a potentially curative approach for the management of young children with central nervous system neoplasms. We report the potential influence of quality and timing of radiation therapy on the survival of patients treated on the study. Procedure Between 2003 and 2009, 220 children with newly diagnosed central nervous system neoplasms were enrolled on the study. Radiation therapy was indicated following AuHCR for children between 6 and 10 years old or those younger than 6 years with residual tumor preconsolidation. Records were received for 42 patients and reviewed to determine adherence to protocol treatment volume and dose guidelines. Of these patients, seven were irradiated prior to consolidation, and additional four patients who initially avoided radiation therapy after AuHCR were subsequently treated at relapse. Results Of the 31 patients who were fully evaluable, 2 refused radiation therapy until recurrence and 4 progressed between recovery from AuHCR and radiation therapy. Of the remaining 25 patients, 8 had violations in their indication, dose, or treatment volume. All violations occurred in patients under 6 years of age. Two patients could have avoided radiation therapy. There were 6 violations in the 23 patients who received radiation therapy for guideline indications. Conclusion All protocol violations occurred in patients under 6 years of age and were associated with decreased overall survival as was the time to start radiotherapy of greater than 11 weeks. When indicated, starting radiation therapy soon after neutrophil and platelet recovery may improve the outcome for these high-risk children.

SUMMARY Diffuse intrinsic pontine glioma (DIPG) is an aggressive tumor that is universally fatal, and to-date we are at a virtual standstill in improving its grim prognosis. Dearth of tissue due to rarity of biopsy has precluded understanding the elusive biology and frustration continues in reproducing faithful animal models for translational research. Furthermore the intricate anatomy of the pons has forestalled locoregional therapy and drug penetration. Over the last few years, biopsy-driven targeted therapy, development of vitro and xenograft animal models for therapeutic testing, profiling immunotherapeutic strategies and locoregional infusion of drugs in brain stem tumors, now provide a sense of hope in the years ahead. This review aims to discuss current status and advances in the management of these tumors.

INTRODUCTION The new understanding of molecular pathways in cancer is paving the way towards personalized cancer medicine, especially in refractory disease. High-grade gliomas (HGG) are common pediatric brain tumors that tend to recur, with no available standard therapy upon recurrence. HGG are challenging tumors with illusive biology and poor outcome. We report here the molecular testing of 27 pediatric HGG patients. MATERIALS AND METHODS An analysis of pediatric patients with HGG treated at UT MD Anderson Cancer Center (MDACC) who underwent molecular genetic profiling using next generation sequencing with different genomic panels (AmpliSeq™Cancer Hotspot and Oncomine Panels – by Thermo Fisher Scientific). RESULTS 27 patients with HGG (median age 14 years, range 3–18 years old) underwent genomic profiling. Primary diagnoses were glioblastoma multiforme (n=22), anaplastic astrocytoma (n = 2), gliosarcoma (n= 1), anaplastic pleomorphic xanthoastrocytoma (n= 1) and anaplastic oligoastrocytoma (n= 1). There are 46 genes common to the panels used. The most common mutation was in TP53 (73%). Other mutations included PIK3CA (19%), IDH1 (11.5%), 7.7% for ATM, EGFR and PTEN, and 3.8% for BRAF, FGFR1 and FGFR2. 24 out of 27 patients were tested at initial diagnosis and 3 upon relapse/progression. Patients at initial diagnosis received standard of care therapy of radiation and temozolomide. Only 5 patients received targeted therapy upon progression/recurrence. Some challenges of genomically-matched therapy included lack of clinical trials accepting pediatric patients, unavailability of a liquid form of a drug, and insurance disapproval for off-label use. CONCLUSION The next generation of therapy for childhood cancers will be based upon in-depth molecular phenotyping that may facilitate the development of rational risk-adapted and target-based therapies. This cohort, though limited by sample size, highlights the opportunity to perform molecular testing and identification of alterations in actionable genes.

Background/rationale: Diffuse intrinsic pontine glioma (DIPG) in children remains essentially incurable with a median survival of 12 months. Radiation therapy is currently the standard treatment modality. To date chemotherapy or biologic agents have had no meaningful increase in survival, making it imperative to profile novel therapeutic combinations. Data from biopsied DIPG showed the PI3K/AKT/mTOR pathway as a major oncogenic player. At the gene level high PDGFR amplification (most commonly seen) and overexpression of the PI3K-Akt-mTOR pathway were noted in these tumors. Focal amplifications of genes within the receptor tyrosine kinase-Ras-phosphoinositol 3-kinase signaling pathway were found in 47% of DIPG. Thus targeting this pathways with mTOR inhibitors could hold therapeutic promise. Elevated expression of DNA repair proteins in the NHEJ and HRR pathway are known to induce resistance to radiation. Preclinical data shows inhibition of these pathways potentiates the sensitivity of these tumors to radiation. SAHA a pan HDAC inhibitor, has been associated with decreased expression of key DNA repair proteins in both the NHEJ and HRR pathways. Both temsirolimus (an mTOR inhibitor) and SAHA are well described in pediatric clinical trials with an established maximum tolerated dose (MTD). The efficacy of the combination of temsirolimus and SAHA has been well-established in other malignancies including prostate cancer, mantle lymphoma, and renal carcinoma. This is the first multi-targeted therapeutic trial in pediatric DIPG, using SAHA and temsirolimus in a combinatorial approach, targeting the key oncogenic pathway and molecules along with enhancing the radiation sensitivity. Correlative study: Stratum I (chemoradiotherapy phase): Histone acetylation will be quantified from peripheral blood mononuclear cell (PBMC) collected prior to the first dose of vorinostat and radiation and at the end of radiation. Stratum I and II (maintenance phase): Evaluation of histone acetylation, phosphorylated 70S6K and Akt on day 1 and 8 (prior to chemotherapy with temsirolimus) during cycle 1 and cycle 2. Methods Patients with a performance score of 50 or greater with newly diagnosed (Stratum 1) or progressive DIPG (stratum II) as confirmed by gadolinium enhanced MRI are eligible. Biopsy is not mandatory. Stratum I: Patients will receive radiation therapy concurrently with vorinostat on the days of radiation at a dose of 230mg/m2/dose, followed by adjuvant therapy with vorinostat and temsirolimus for 10 cycles if patients do not have progressive disease. Stratum II: Patients will receive vorinostat and temsirolimus for 12 cycles (28 day cycle), if patient does not have progressive disease. SAHA will be given once daily at 230 mg/m2 orally from day 1 to day 8, along with temsirolimus at 25mg/m2 intravenously on day 1 and day 8. This will be the dose level 1 and 2 dose escalations and 1 dose de-escalation will be allowed. A standard 3+3 design will be used and a minimum of 9 patients and a maximum of 18 patients will be enrolled. Trial is ongoing (30% of planned patients enrolled), with patients now in the second dose level (enrollment of this cohort started on September 2018). No dose limiting toxicity (DLT) were noted at the first dose level. Trial: NCT02420613 (currently recruiting). Note: This abstract was not presented at the meeting. Citation Format: Soumen Khatua, Joya Chandra, Miriam M. Morrell, Heather B. Meador, David I. Sandberg, Jeffrey Weinberg, Greg Fuller, Leena Ketonen, Jason M. Johnson, Kenneth R. Hess, Wafik Zaky. A Phase I study of Suberoylanilide Hydroxamic Acid (SAHA) with Temsirolimus in children with newly diagnosed or progressive diffuse intrinsic pontine glioma (DIPG) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT113.

Scientific background/rationale: The prognosis of recurrent/refractory medulloblastoma (MB), ependymoma (EP) and atypical teratoid/rhabdoid neoplasms (AT/RT) which constitutes the majority of malignant posterior fossa tumors (MPFT) in children, remains dismal with no defined effective therapy. Current treatment strategies have significant toxicities, thus profiling newer trials with clinical efficacy and minimal side-effects are imperative. Advantages of direct infusion of Natural Killer (NK) cells into the ventricles could enhance therapeutic efficacy by maximally concentrating them in the brain in close proximity to the tumor area, bypassing the blood brain barrier and alleviating toxicity often seen with systemic chemotherapy. We have shown efficacy of activated and propagated NK cells to lyse and kill the MPFT in vitro and tumor explants in mice models. We demonstrated in a pilot study for the first time in humans, the feasibility of infusions of biologic agents into the fourth ventricle. Infusing biologic agents into the lateral ventricles are well established in neurooncology. The current ongoing study is the first-in-human, loco-regional infusion of NK cells directly into the brain evaluating safety and efficacy in the context of a phase I trial with an intent to avoid the significant side-effects of systemic therapy. This novel trial, will hopefully be able to provide therapeutic efficacy and a meaningful increase in the survival of these children. Correlative studies: Cerebrospinal fluid (CSF) withdrawn during infusions of NK cells will be evaluated for the immunophenotype, function, persistence of NK cells and influx or presence of any other immune cells. Methods: NK cells are directly infused into the lateral or fourth ventricles, after placement of a catheter at that location. Recurrent or refractory MB, AT/RT and EP involving the brain and/or spine at original diagnosis or relapse with histological verification are eligible. Three to six evaluable patients, are entered at a dose level in this study for determination of maximum tolerated dose (MTD). A minimum of 9 patients and a maximum of 24 patients are planned to be enrolled. After autologous expanded NK cell product have been manufactured as per good manufacturing guidelines (GMP) and released, patients receive 3 cycles of NK cell infusions over 12 weeks. Each cycle consists of 1 infusion per week for 3 weeks followed by a rest week (week 4). Dosing is based on recipient body surface area (BSA) and 3 dose levels will be evaluated. Currently the trial is at the final cohort (third dose level), with no dose limiting toxicity (DLT) noted with the previous dose levels. 80% of the initial minimal accrual have been met. Also as a secondary aim we will evaluate the anti-tumor activity of the NK cell infusions within the confines of a phase I study. Trial (NCT02271711-recruiting) Citation Format: Soumen Khatua, Dean Lee, Laurence Cooper, Judy Moyes, David Sandberg, Zsila Sadighi, Heather Meador, Leena Ketonen, Michael E. Rytting, Jason M. Johnson, Dristhi Raagonanan, Diane D. Liu, Vidya Gopalakrishnan, Wafik Zaky. Phase I study of intraventricular infusions of autologous ex vivo expanded NK cells in children with recurrent/refractory malignant posterior fossa tumors of the central nervous system [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT216.

e21511 Background: NK cell therapy is a novel immunotherapeutic strategy used in cancer therapy. We conducted first-in-human, loco-regional infusion of autologous ex-vivo expanded NK cell directly into the brain in children with recurrent medulloblastoma (MB) and ependymoma (EP). Radiomics is considered an emerging method to predict treatment response as well as evaluate prognosis and tumor milieu. This is the first study evaluating the ability of radiomics to predict response to intraventricular infusions of NK cell in children with recurrent/refractory posterior fossa malignant brain tumors. Methods: We evaluated 7 patients (5 males: 2 females; mean age 11.8 years) with refractory/recurrent MB or EP (MBs = 3, EPs = 4), who were enrolled on a Phase-1 trial (NCT02271711) and received 3 cycles of intraventricular NK cell infusions. Patients were categorized based on their clinical response into responders (N = 2) and non-responders (N = 5). After semiautomatic segmentation of the tumor, 3,660 radiomic features were extracted from the baseline (before treatment) MRI scan. The least absolute shrinkage and selection operator regression was used for feature selection, and the radiomics signature was built using the unsupervised anomaly detection algorithm. The performance of the radiomics model was assessed using leave-one-out cross-validation. Results: The radiomic signature/model was comprised of 6 radiomic features and demonstrated high discriminatory performance in predicting response to NK cell therapy with an area under the curve, sensitivity, and specificity of 100% ( P = 0.09486). In addition, patients clustered into responders and non-responders using unsupervised hierarchical clustering. Conclusions: To our knowledge, this is the first study to identify the ability of radiomics to predict those who will likely benefit from NK cell therapy. Though this small study did not attain statistical significance, the robust discriminatory results warrant larger prospective studies, evaluating radiomics as a potential tool to identify responders to NK cell therapy at diagnosis.

Diffuse intrinsic pontine gliomas (DIPG) are inoperable and highly resistant tumors to chemotherapy and irradiation. DIPG has the worst prognosis among all pediatric brain tumors and the overwhelming majority of patients die within 6-18 months after diagnosis.We retrospectively reviewed the charts of six DIPG patients treated with chemoradiotherapy (daily carboplatin and oral etoposide in five patients and temozolomide in one patient) followed by maintenance chemotherapy consisting of irinotecan, temozolomide, and bevacizumab at our institution between January 2007 until December 2007.Event-free survival (EFS) and overall survival (OS) were 10.4 ± 3.08 and 14.6 ± 3.55 months, respectively. Side effects in the patients included hypertension in two, abdominal cramping and diarrhea in four, and neutropenia in five patients.This augmented regimen was associated with increased but tolerable toxicity and a modest increase in EFS and OS when compared with published literature in patients with DIPG (median EFS and OS of 6.1 and 9.6 months, respectively). More effective therapies are desperately needed.

Background Atypical teratoid/rhabdoid tumor (AT/RT) of the central nervous system (CNS) is a rare embryonal neoplasm of early childhood with dismal outcome and no current uniformly accepted treatment. Given its highly aggressive nature and predilection for dissemination at diagnosis, intensive multimodal therapy is required. Materials and Methods Nineteen children with newly diagnosed CNS AT/RT were treated on the head start (HS) III protocol. Treatment consisted of surgical resection, 5 cycles of induction chemotherapy, followed by consolidation with myeloablative chemotherapy and autologous hematopoietic progenitor cell rescue (AuHCR). Irradiation was given following recovery from consolidation based on patient age, disease extent at diagnosis, and treatment response to induction. Results Nineteen children (median age of 14 months) were treated on HS III between 2003 and 2009. Only four finished induction and three proceeded to consolidation. There are presently four survivors at 40, 42, 46, and 79 months from study enrollment. Eleven patients experienced tumor progression at a median time to progression of 4.1 months of whom 10 died with a median time from progression to death of 2.6 months. Five toxic deaths occurred, three of them while on the study. The 3-year event-free survival (EFS) and overall survival (OS) for the whole group was 21 ± 9% and 26 ± 10%, respectively. Five patients received irradiation at progression with only one long-term survivor. Conclusion A minority of children with CNS AT/RT treated on HS III may be long-term survivors without irradiation. More effective therapies are desperately needed. Pediatr Blood Cancer 2014;61:95–101. © 2013 Wiley Periodicals, Inc.

Pediatric high-grade glioma (pHGG) and brainstem gliomas are some of the most challenging cancers to treat in children, with no effective therapies and 5-year survival at ~2% for diffuse intrinsic pontine glioma (DIPG) patients. The standard of care for pHGG as a whole remains surgery and radiation combined with chemotherapy, while radiation alone is standard treatment for DIPG. Unfortunately, these therapies lack specificity for malignant glioma cells and have few to no reliable biomarkers of efficacy. Recent discoveries have revealed that epigenetic disruption by highly conserved mutations in DNA-packaging histone proteins in pHGG, especially DIPG, contribute to the aggressive nature of these cancers. In this review we pose unanswered questions and address unexplored mechanisms in pre-clinical models and clinical trial data from pHGG patients. Particular focus will be paid towards therapeutics targeting chromatin modifiers and other epigenetic vulnerabilities that can be exploited for pHGG therapy. Further delineation of rational therapeutic combinations has strong potential to drive development of safe and efficacious treatments for pHGG patients.

There is a paucity of literature reporting the outcome of intracranial sarcomas (IS) in children, adolescents, and young adults (CAYA). A multimodal therapeutic approach is commonly used, with no well-established treatment consensus. We conducted a retrospective review of CAYA with IS, treated at our institution, to determine their clinical findings, treatments, and outcomes. Immunohistochemistry (PDGFRA and EGFR) and DNA sequencing were performed on 5 tumor samples. A literature review of IS was also conducted. We reviewed 13 patients (median age, 7 years) with a primary diagnosis of IS between 1990 and 2015. Diagnoses included unclassified sarcoma (n = 9), chondrosarcoma (n = 2), and rhabdomyosarcoma (n = 2). Five patients underwent upfront gross total resection (GTR) of the tumor. The 5-drug regimen (vincristine, doxorubicin, cyclophosphamide, etoposide, and ifosfamide) was the most common treatment used. Nine patients died due to progression or recurrence (n = 8) or secondary malignancy (n = 1). The median follow-up period of the 4 surviving patients was 1.69 years (range 1.44-5.17 years). The 5-year progression-free survival and overall survival rates were 21 and 44 %, respectively. BRAF, TP53, KRAS, KIT, ERBB2, MET, RET, ATM, and EGFR mutations were detected in 4 of the 5 tissue samples. All 5 samples were immunopositive for PDGFRA, and only 2 were positive for EGFR. IS remain a therapeutic challenge due to high progression and recurrence rates. Collaborative multi-institutional studies are warranted to delineate a treatment consensus and investigate tumor biology to improve the disease outcome.

Background/rationale: Diffuse intrinsic pontine glioma (DIPG) in children remains essentially incurable with a median survival of 12 months. Radiation therapy is currently the standard treatment modality. To date chemotherapy or biologic agents have had no meaningful increase in survival, making it imperative to profile novel therapeutic combinations. Data from biopsied DIPG showed the PI3K/AKT/mTOR pathway as a major oncogenic player. At the gene level high PDGFR amplification and overexpression of the PI3K-Akt-mTOR pathway were noted in these tumors. Focal amplifications of genes within the PI3K-Akt-mTOR signaling pathway were found in 47% of DIPG. Thus targeting these pathways with mTOR inhibitors could hold promise. Elevated expression of DNA repair proteins in the NHEJ and HRR pathway are known to induce resistance to radiation. Preclinical data shows inhibition of these pathways potentiates the sensitivity of these tumors to radiation. Recent genomic and epigenetic insights demonstrates the role of histone deacetylase (HDAC) in these tumors. Vorinostat a pan HDAC inhibitor has been associated with decreased expression of key DNA repair proteins in both the NHEJ and HRR pathways and have been tested in clinical trial for children with DIPG. Both temsirolimus (an mTOR inhibitor) and vorinostat are well described in pediatric clinical trials with a determined maximum tolerated dose (MTD). The efficacy of the combination of temsirolimus and vorinostat has been well-established in other malignancies including prostate cancer, mantle lymphoma, and renal carcinoma. This is the first multi-targeted therapeutic trial in pediatric DIPG, using vorinostat and temsirolimus in a combinatorial approach, targeting the key oncogenic pathway and molecules along with enhancing the radiation sensitivity. Correlative study: Stratum I (chemoradiotherapy phase): Histone acetylation will be quantified from peripheral blood mononuclear cell (PBMC) collected prior to the first dose of vorinostat and radiation and at the end of radiation. Stratum I and II (maintenance phase): Evaluation of histone acetylation, phosphorylated 70S6K and Akt on day 1 and 8 (prior to chemotherapy with temsirolimus) during cycle 1 and cycle 2 will be performed. Methods: Patients with a performance score of 50 or greater with newly diagnosed (Stratum 1) or progressive DIPG (stratum II) as confirmed by gadolinium enhanced MRI, will be eligible. Biopsy is not mandatory. Stratum I: Patients will receive radiation therapy concurrently with vorinostat on the days of radiation at a dose of 230 mg/m2/dose orally, followed by maintenance phase with vorinostat and temsirolimus for 12 cycles if patients do not have progressive disease. Stratum I and Stratum II (maintenance phase): Patients will receive vorinostat and temsirolimus for 12 cycles (28 day cycle), if patient do not have progressive disease. Vorinostat will be given once daily orally at 230 mg/m2/dose orally from day 1 to day 8, along with temsirolimus at 25mg/m2 intravenously on day 1 and day 8. This will be dose level 1 with provisions for 2 higher dose levels and 1 lower dose level if needed. A standard 3+3 design will be used and a minimum of 9 patients and a maximum of 18 patients will be enrolled. Trial is continuing as planned and patient are on dose level 1. Trial: NCT02420613 (currently recruiting). Citation Format: Soumen Khatua, Vidya Gopalakrishnan, Joya Chandra, Leena Ketonen, David I. Sandberg, Jeffrey Weinberg, Fuller Gregory, Kenneth R. Hess, Natalie Slone, Heather Meador, Mirriam Morrell, Wafik Zaky. A phase I study of vorinostat and temsirolimus in children with newly diagnosed or progressive diffuse intrinsic pontine glioma (DIPG) [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 CT029. doi:10.1158/1538-7445.AM2017-CT029

Scientific background/rationale: The prognosis of recurrent/refractory medulloblastoma (MB), ependymoma (EP) and atypical teratoid/rhabdoid neoplasms (AT/RT), which constitutes the majority of malignant posterior fossa tumors (MPFT) in children, remain dismal with no defined effective therapy. Current treatment strategies have significant toxicities and thus profiling newer trials with clinical efficacy and minimal side-effects are imperative. Advantages of direct infusion of natural killer (NK) cells into the ventricles could enhance therapeutic efficacy by maximally concentrating them in the central nervous system (CNS) near the tumor area, bypassing the blood brain barrier and alleviating toxicity as seen with systemic chemotherapy. We have shown the efficacy of activated and propagated NK cells to lyse and kill the MPFT in vitro and tumor explants in mice models. Also, in a first-time human in vivo pilot study, we demonstrated the feasibility of infusions of biologic agents into the fourth ventricle. Infusing biologic agents through catheters placed in the lateral ventricles are well established in neurooncology. The current ongoing study is the first-in-human, loco-regional infusion of NK cells directly into the brain evaluating safety with intent to avoid the significant side-effects of systemic therapy. This novel trial will hopefully be able to provide therapeutic efficacy and a significant increase in the survival of these children. The current format of this trial incorporates changes including different dose, schedule, routes of intraventricular infusions of NK cells from the previously presented version of the trial, and thus submitted. Correlative studies: Cerebrospinal fluid (CSF) drawn during infusions of NK cells will be evaluated for the immunophenotype, function, persistence of NK cells and influx or presence of any other immune cells and correlating with tumor response. Methods: This trial (NCT02271711-recruiting) will proceed with infusions of NK cells directly into the lateral or fourth ventricles, after placement of a catheter at that location. Recurrent or refractory MB, AT/RT and EP involving the brain and/or spine at original diagnosis or relapse with histological verification will be eligible. Three to six evaluable patients may be entered at a dose level in this study for determination of maximum tolerated dose (MTD). A minimum of nine patients and a maximum of twenty-four patients will be enrolled. After autologous expanded NK cell product have been manufactured as per good manufacturing practice (GMP) guidelines and released, patients will receive three cycles of NK cell infusions over 12 weeks. Each cycle consists of one infusion per week for three weeks followed by a rest week (week 4). Dosing is based on recipient body surface area (BSA), and three dose levels will be evaluated. Currently, the trial is in the second cohort, with no dose limiting toxicity (DLT) noted with the previous dose level. 35% of the minimal accrual has been met. Also as a secondary aim, we will evaluate the antitumor activity of the NK cell infusions within the confines of a phase I study Citation Format: Soumen Khatua, Vidya Gopalakrishnan, Laurence Cooper, Dean Lee, David I. Sandberg, Michael Rytting, Jason J. Johnson, Leena Ketonen, Diane Liu, Judy Moyes, Wafik Zaky. Phase I study of intraventricular infusions of autologous exvivo expanded NK cells in children with recurrent/refractory malignant posterior fossa tumors of the central nervous system [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 CT033. doi:10.1158/1538-7445.AM2017-CT033

BACKGROUND: Glioblastoma multiforme (GBM) presenting as gliomatosis cerebri (GC) is a rare aggressive neoplasm of the central nervous system (CNS) with a median survival of less than one year. To-date no well-defined therapeutic strategy exists for these tumors. We report our experience of the likely benefit of using an individualized personalized therapeutic (IPT) approach to profile a new combinatorial treatment regimen in a child with GBM/GC of the CNS. CASE REPORT: An 8-year-old male with a Lansky score of 50 presented with headache, dysarthria and ataxia. MRI of the CNS showed tumor involvement of the thalamus, cerebellum, brain stem and spinal cord. Pathology of the biopsy performed was consistent with GBM. Diffuse positivity of the tumor for epidermal growth factor receptor (EGFR) was noted by immunohistochemistry. He received radiation therapy along with temozolomide followed by adjuvant therapy with temozolomide, irinotecan, and bevacizumab every 28 days. After 2 cycles, he demonstrated disease progression. Based on the diffuse EGFR expression profile of his tumor, Erlotinib (EGFR tyrosine-kinase inhibitor) was started orally daily. Marked response was noted clinically and by neuroimaging. However, following six cycles, MRI of the brain demonstrated a new lesion in the frontal lobe. Temsirolimus (m-TOR inhibitor) was added to Erlotinib. Currently he continues to tolerate this regimen, remains well with a Lansky scale of 80, 16 months post-diagnosis. DISCUSSION: EGFR-AKT-mTOR pathway is known to be up-regulated in GBM justifying targeting multiple oncogenic drivers and report the likely benefit of using erlonitib with temsirolimus. Prospective studies are warranted to standardize an IPT approach for such rare pediatric CNS tumors. Future studies will explore the potential benefit of this regimen targeting key molecules of this signaling pathway driving GBM tumorogenesis and evaluate its therapeutic efficacy in improving overall survival in comparison to historical controls.

BACKGROUND: Ganglioglioma (GG) are rare mixed glial-neuronal neoplasms of the central nervous system. METHODS: Retrospective review of 57 patients below 21 years diagnosed with GG at MD Anderson Cancer Center, Houston from 1992 to 2012 was performed. Patient demographics, clinical history, radiological features and treatment data were collected and analyzed. Kaplan-Meier and Cox-regression analysis were used to assess disease progression free survival (PFS) and symptom free survival (SFS) time after surgery. RESULTS: Median follow-up period was 6.08 years with mean age at presentation as 10.89 years. 3 patients had tumor recurrence after gross total resection (GTR) and 16 patients had sub-total resection (STR). Patients with GTR had a longer PFS time compared to patients with STR (5-year PFS 89% vs. 13%; p < 0.0001). Tumor type (cystic versus mixed cystic/solid) and location (supra-tentorial vs. infra-tentorial) of tumors correlated significantly with prolonged PFS (p = 0.014, p < 0.0001). Children 14 years or older were noted to have longer PFS than younger ages (p = 0.0053). Both PFS and SFS worsened with the adjuvant therapy use (p =

Medulloblastoma (MB) is the most common malignant brain tumor in children and accounts for 20% of all pediatric central nervous system tumors and 40% of the posterior fossa tumors [1]. Various seco...

Background: Vemurafenib (Vem) is approved by the US Food and Drug Administration for the treatment of BRAF V600-mutant melanoma. Vem also has demonstrated activity in BRAF V600-mutant non-melanoma cancers. However, with monotherapy, all patients eventually experience disease progression, and more effective treatments are needed. On the basis of preclinical studies showing that combined inhibition of the BRAF and PI3K/mTOR pathways may overcome the primary or innate resistance mechanisms in BRAF-mutant malignancies, we conducted a phase I trial combining Vem with the mTOR inhibitor everolimus (Eve). Objectives: Primary objectives of this open-label phase I trial were to evaluate safety and tolerability, and to determine the maximum tolerated dose (MTD) of the Vem and Eve combination in patients with BRAF-mutant advanced cancers; the secondary objective was to assess efficacy. Methods: Escalating doses of Vem twice daily (BID) and Eve once daily (QD) were combined using the standard 3 + 3 design, and then an expansion cohort was enrolled and treated at the MTD. Treatment was administered in 28-day cycles. MTD was defined as the highest dose studied in which incidence of dose-limiting toxicity (DLT) was less than 33%. Younger patients were enrolled at the accruing dose level, with body surface area-based dose adjustments for smaller children. Results: Twenty patients (14 male, 6 female) with BRAF-mutant (18 V600E, 1 V600K, 1 G469A) melanoma (n = 7) or central nervous system (n = 5), thyroid (n = 4), non-small cell lung (n = 1), colorectal (n = 1), appendiceal (n = 1), or unknown primary (n = 1) cancer were enrolled. The median age of the 18 adult patients was 64 years (range 16-85 years); the 2 pediatric patients were aged 10 and 13 years. Prior therapies included surgery (n = 18, 90%), radiation (n = 11, 55%), cytotoxic chemotherapy (n = 14, 70%), and a prior phase I trial (n = 10, 50%). Ten patients (50%) had prior treatment with BRAF/MEK inhibitor(s). Ten patients had received 2 or more lines of systemic therapies. No dose-limiting toxicity was observed at dose level 1 (Vem 720 mg BID, Eve 5 mg QD). Two DLTs (rash, fatigue) were observed at dose level 2 (Vem 720 mg BID, Eve 10 mg QD). Dose level 1 was determined to be the MTD. Grade >3 toxic effects included rash (n = 4), fatigue (n = 4), photosensitivity (n = 1), anemia (n = 1), hyperglycemia (n = 1), and hypertriglyceridemia (n = 1). After excluding 1 patient who withdrew consent before restaging, we found that 5 patients (26%) had a partial response (melanoma = 1, non-melanoma = 4), 9 (47%) had stable disease, and 5 (26%) had progression as the best response. Among 9 evaluable patients with a history of prior treatment with BRAF/MEK inhibitors, 2 had a partial response and 5 had stable disease. Two patients are continuing the treatment after 5 and 16 cycles. Conclusion: The combination of Vem (720 mg BID) and Eve (5 mg QD) is safe, well-tolerated, and has activity in patients with BRAF-mutant advanced cancers, including those previously treated with a BRAF/MEK inhibitor. Citation Format: Muhammad Rizwan Khawaja, Soumen Khatua, Daniel Karp, Filip Janku, David Hong, Javier Munoz, Apostolia Tsimberidou, Wafik Zaky, Steven I. Sherman, Patrick Hwu, Funda Meric-Bernstam, Vivek Subbiah. A phase I dose escalation trial of vemurafenib in combination with the mTOR inhibitor everolimus for melanoma and non-melanoma cancers with a BRAF aberration. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT052.

Emerging evidence confirms dysregulation of BRAF gene inducing oncogenesis of pediatric brain tumors. To-date few reports show short-lived efficacy using BRAF inhibitors in these tumors. This indicates the need to target diverse pathways to have sustained clinical efficacy. We present two cases where a combination of vemurafenib (BRAF inhibitor) with everolimus (mTOR inhibitor) as a part of an IRB approved protocol was used. A 10-year-boy diagnosed with a left parietal pleomorphic xanthoastrocytoma (PXA) demonstrated tumor progression despite radiotherapy and three surgical interventions over two years. The tumor showed BRAF mutation for which he received a combinatorial therapeutic approach using the above two drugs given orally every day on a 28 day cycle. He experienced a partial response after two cycles and continued response after 13 cycles. This therapy has been well-tolerated with only minor (Grade I) skin rash. The child remains clinically stable with a Lansky score of 100. The second case is a 13-year-old female diagnosed at 1 year of age with a right-sided optic pathway glioma. The biopsy was consistent with pilocytic astrocytoma. The tumor progressed through multiple chemotherapeutic regimens, including carboplatin, vincristine, vinblastine, celexocib. Molecular analysis performed at our institution demonstrated the tumor to harbor a BRAF mutation for which she is currently receiving the above therapeutic regimen. She is tolerating the therapy well, with mild mouth sores. Her tumor after four cycles shows ongoing response and stable vision. It is now known that these tumors can induce escape mechanisms conferring therapeutic resistance and short-lived efficacy, undermining single drug BRAF targeted approach. This is the first ongoing study targeting these pathways (RAF/MAPK/ERK) and PI3K/mTOR pathway in pediatric brain tumors with BRAF mutation. Larger prospective larger studies are warranted to overcome therapeutic limitations through optimal combination therapy targeting multiple signaling pathways.