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Background Entrectinib is a TRKA/B/C, ROS1, ALK tyrosine kinase inhibitor approved for the treatment of adults and children aged ≥12 years with NTRK fusion-positive solid tumors and adults with ROS1 fusion-positive non–small-cell lung cancer. We report an analysis of the STARTRK-NG trial, investigating the recommended phase 2 dose (RP2D) and activity of entrectinib in pediatric patients with solid tumors including primary central nervous system tumors. Methods STARTRK-NG (NCT02650401) is a phase 1/2 trial. Phase 1, dose-escalation of oral, once-daily entrectinib, enrolled patients aged Results At data cutoff, 43 patients, median age of 7 years, were response-evaluable. In phase 1, 4 patients experienced dose-limiting toxicities. The most common treatment-related adverse event was weight gain (48.8%). Nine patients experienced bone fractures (20.9%). In patients with fusion-positive tumors, ORR was 57.7% (95% CI 36.9-76.7), median duration of response was not reached, and median (interquartile range) duration of treatment was 10.6 months (4.2-18.4). Conclusions Entrectinib resulted in rapid and durable responses in pediatric patients with solid tumors harboring NTRK1/2/3 or ROS1 fusions.

PURPOSE Infant and young childhood medulloblastoma (iMB) is usually treated without craniospinal irradiation (CSI) to avoid neurocognitive late effects. Unfortunately, many children relapse. The purpose of this study was to assess salvage strategies and prognostic features of patients with iMB who relapse after CSI-sparing therapy. METHODS We assembled a large international cohort of 380 patients with relapsed iMB, age younger than 6 years, and initially treated without CSI. Univariable and multivariable Cox models of postrelapse survival (PRS) were conducted for those treated with curative intent using propensity score analyses to account for confounding factors. RESULTS The 3-year PRS, for 294 patients treated with curative intent, was 52.4% (95% CI, 46.4 to 58.3) with a median time to relapse from diagnosis of 11 months. Molecular subgrouping was available for 150 patients treated with curative intent, and 3-year PRS for sonic hedgehog (SHH), group 4, and group 3 were 60%, 84%, and 18% ( P = .0187), respectively. In multivariable analysis, localized relapse ( P = .0073), SHH molecular subgroup ( P = .0103), CSI use after relapse ( P = .0161), and age ≥ 36 months at initial diagnosis ( P = .0494) were associated with improved survival. Most patients (73%) received salvage CSI, and although salvage chemotherapy was not significant in multivariable analysis, its use might be beneficial for a subset of children receiving salvage CSI < 35 Gy ( P = .007). CONCLUSION A substantial proportion of patients with relapsed iMB are salvaged after initial CSI-sparing approaches. Patients with SHH subgroup, localized relapse, older age at initial diagnosis, and those receiving salvage CSI show improved PRS. Future prospective studies should investigate optimal CSI doses and the role of salvage chemotherapy in this population.

Purpose Pure germinomas account for 40% of pineal tumors and are characterized by the lack of appreciable tumor markers, thus requiring a tumor biopsy for diagnosis. MicroRNAs (miRNA) have emerged as potential non-invasive biomarkers for germ cell tumors and may facilitate the non-invasive diagnosis of pure pineal germinomas. Methods A retrospective chart review was performed of all patients treated at Children’s Cancer Hospital Egypt diagnosed with a pineal region tumor between June 2013 and March 2021 for whom a research blood sample was available. Plasma samples were profiled for miRNA expression and DESeq2 was used to compare between pure germinoma and other tumor types. Differentially expressed miRNAs were identified. The area under the curve of the receiver operating characteristic curve was constructed to evaluate diagnostic performance. Results Samples from 39 pediatric patients were available including 12 pure germinomas and 27 pineal region tumors of other pathologies, including pineal origin tumors [n = 17; pineoblastoma (n = 13), and pineal parenchymal tumors of intermediate differentiation (n = 4)], and others [n = 10; low grade glioma (n = 6) and atypical teratoid rhabdoid tumor (n = 4)]. Using an adjusted p value p = 0.0058, p = 0.0478 and p = 0.0366, respectively), and good discriminatory power between the two groups (AUC 90.7%, p

Primary central nervous system (CNS) germ cell tumors (GCT) are a rare heterogenous group of cancers, arising most commonly in the second decade of life. Through several clinical trials conducted around the world by various groups, the treatment approach for CNS GCT has advanced substantially with generally improved overall outcomes. In recent years, the goal of clinical trials has been focused on reduction of the radiotherapy burden and minimization of long-term toxicity. This review summarizes the current diagnostic and treatment regimens for CNS GCT, examines the controversies associated with these approaches, gaps in contemporary knowledge, and underscores the challenges we face. We also explore future directions in the management of CNS GCT with the ultimate overall aim of preserving curative outcomes, identifying novel biomarkers, and mitigating neurocognitive, endocrine, and psychological toxicity through prospective clinical studies.

Wnt-activated medulloblastoma (MB) confers an excellent prognosis. However, specific treatment strategies for patients with relapsed Wnt-MB are unknown. We report two patients with recurrent beta-catenin nucleopositive Wnt-MB successfully treated by incorporating marrow-ablative chemotherapy and autologous hematopoietic progenitor cell rescue (HDCx/AuHPCR). We also present a review of the literature for previously reported cases of relapsed Wnt-MB. We propose that patients with recurrent Wnt-MB may be treated using a multi-disciplinary approach that includes HDCx/AuHPCR with or without re-irradiation.

Metastatic atypical teratoid/rhabdoid tumors (AT/RTs) are aggressive central nervous system tumors that present during infancy and are associated with dismal outcomes. Patients receive multimodal treatment including surgical resection, systemic chemotherapy, and one or more of intrathecal chemotherapy (IT), marrow-ablative chemotherapy with autologous hematopoietic cell rescue (AuHCR) and radiation therapy (XRT). While data regarding treatment modalities for AT/RT patients exist, no comprehensive data have been published regarding the metastatic patients.We performed a meta-analysis of 1578 articles published through September 2018, including 44 studies with a total of 123 subjects. In addition, seven patients were included through chart review of patients treated at Nationwide Children's Hospital.Analysis of 130 patients revealed a 3-year overall survival (OS) of 25%. Age at diagnosis had a significant effect on survival (P = 0.0355); 3-year OS for infants less than 18 months was 21%, 18 to 36 months was 26%, and greater than 36 months was 36%. Location of the primary tumor, metastatic stage, and extent of surgical resection did not have a significant impact on OS. On univariate analysis, XRT (P0.0001), IT (P = 0.01), and AuHCR (P0.0001) were found to significantly improve survival. The most substantial effect was noted in patients who received AuHCR (3-year OS of 60% vs 9% in those who did not). On multivariable analysis, XRT (P = 0.0006), IT (P = 0.0124), and AuHCR (P0.0001) were independently associated with reduced risk of death.Although more research is warranted to make generalizable conclusions, these results suggest that treatment regimens for patients with metastatic AT/RTs should include AuHCR, XRT, and IT.

INTRODUCTION: Medulloblastoma is the most common malignant brain tumor in children, with 5-year overall survival (OS) ranging from 60%-95% depending on subgroup and risk status. The POG 8631/CCG 923 trial (accrual 1986-1990) found a 63% 5 year OS for patients with local disease after gross total resection treated with radiation at a dose of 23.4 Gy craniospinal radiation and posterior fossa boost to 54 Gy, vs. 80.5% 5-year OS for patients treated as per full ACNS0331 therapy including maintenance chemotherapy. Herein, we describe a long-term survival with standard-risk medulloblastoma who only received surgical resection and radiation therapy. CASE: A 17-year-old male presented with acute onset of hypertension, bradycardia, headache, and blurry vision and was found to have a heterogeneously enhancing posterior fossa mass with mass effect on the fourth ventricle and hydrocephalus on brain MRI. He underwent gross total resection of the tumor and histopathology revealed medulloblastoma with classic and large cell features. Fluorescence in situ hybridization (FISH) was negative for MYC, MYCN amplification, or HER2 gain. Cerebrospinal fluid cytology was negative for neoplastic cells, and spinal MRI did not reveal any drop metastases. The patient initiated therapy per ACNS0331 with craniospinal irradiation posterior fossa boost. He also received weekly vincristine. After completion of radiation therapy, the family declined further chemotherapy despite medical advice. He had no evidence of relapse most recently at 51 months from completion of therapy. Next generation sequencing and methylation testing are currently pending. CONCLUSION: Current efforts aim at optimizing therapy based on molecular subgrouping, to minimize long-term adverse events associated with current therapies. We report a unique case of an adolescent male with an standard-risk medulloblastoma, who achieved remission with only radiotherapy. Further molecular tumor analysis may elucidate the response of the tumor.

BACKGROUND: Primary intracranial germ cell tumors (GCTs) are rare heterogeneous tumors, with germinoma accounting for two-thirds of cases. Neoadjuvant chemotherapy with response-based reduced radiotherapy dose and field has become the standard management of localized CNS germinomas, however, treatment of primary metastatic disease has remained controversial. Furthermore, there is limited published research on the use of neoadjuvant chemotherapy in primary metastatic germinoma. METHODS: We performed a retrospective multi-institutional data collection and analysis of patients diagnosed with metastatic germinoma since 2000 to assess the overall survival (OS) and event-free survival (EFS) of the different treatment modalities administered. RESULTS: We identified 78 patients with germinoma, in two tertiary care centers, of which nine patients (11.5%; eight males) had metastatic disease. The median age at presentation was 13.3 years. All patients had a biopsy at presentation confirming the diagnosis. Three patients had positive CSF cytology (M1). Six patients received craniospinal irradiation (CSI) with boost to primary and metastatic sites, of which five patients received total CSI dose of 24 Gy, while the dose was unknown for one patient. One patient required one cycle of chemotherapy prior to CSI due to worsening visual changes, which subsequently resolved. One patient received two cycles followed by whole ventricular irradiation (WVI) of 23.4 Gy with a boost to the primary bed. One patient received WVI without neoadjuvant chemotherapy. One patient developed anoxic brain injury and only received chemotherapy. He died of recurrent progressive disease 15 months post-diagnosis. The median follow-up time was 77.5 months (range 15-130.5 months), with an OS of 88.9%. Further multi-institutional data collection and analysis is underway and will be presented at the meeting. CONCLUSION: We anticipate our results may elucidate the role of neoadjuvant chemotherapy in the treatment of metastatic germinoma, and whether when combined with lower CSI doses did not compromise EFS/OS.

BACKGROUND: The management of childhood central nervous system (CNS) tumors is complex and often faces numerous challenges in low- and middle- income countries (LMICs), including delayed diagnosis and limited treatment resources. Twinning initiatives between LMICs with high- income countries are feasible and proven to be highly effective at exchanging skills and expertise to improve diagnosis, treatment and care for children with brain tumors. METHODS: A monthly multidisciplinary international pediatric neuro-oncology tumor board via zoom videoconferencing was established in January 2021. This effort is a collaboration between Washington University School of Medicine, in St. Louis, Missouri, USA and nine international sites. Given the significant contributions of this international effort, it has since grown to include 20 institutions and cancer centers from 12 countries in the Middle East, Europe, Australia and South America. RESULTS: As of January 2022, we have held 11 tumor boards, 35 cases were reviewed, and have had 320 experts attend from several specialties – neuro-oncology, neurology, neurosurgery, neuroradiology and neuropathology. A multidisciplinary team of physicians reviewed each case and recommendations were given accordingly. We also started a quarterly neurofibromatosis (NF) meeting focused to leverage the expertise of dedicated specialists in the NF center. Two NF-focused meetings took place since establishing the program, and total of five cases were discussed. CONCLUSION: Virtual videoconferencing promotes a multi-disciplinary approach for the management of pediatric CNS tumors, and it allows access for medical expertise. We anticipate the current initiative will also provide a platform for future international research collaborations and deliver the optimal medical care for neuro-oncology patients globally. Multiple potential collaborative projects are currently underway.

BACKGROUND: Low-grade gliomas (LGG) are the most common solid tumor of childhood and can result in neurologic complications, including seizures, focal neurologic deficits, and learning difficulties. Molecularly targeted agents are increasingly being utilized to treat LGG, but the effect of these agents on accompanying neurologic complications are poorly understood. CASE: An 8-years old male with Neurofibromatosis Type 1 (NF1), medically refractory epilepsy and deep extensive glioma (extending from the optic pathway and involving the basal ganglia and corpus collosum) began selumetinib therapy due to radiographic and symptomatic tumor progression. Radiographic response (resolution of enhancement) was observed at 12 weeks of therapy, accompanied by improvement in seizure frequency, hemiparesis, and academic performance. Due to cardiotoxicity observed at that time (asymptomatic decreased ejection fraction and shortening fraction on echocardiogram), selumetinib was reduced to 50% dosing. On this reduced dose of selumetinib, seizures increased in frequency with subsequent worsening hemiparesis and recurrence of learning difficulties. One month later, dosing was escalated back to 100% due to interval resolution of cardiotoxicity, resulting in resolution of seizures and improvement in focal neurologic deficits and cognition. DISCUSSION: Dose-dependent response to MEK inhibition was observed without concurrent changes in anti-epileptic medications. The tumor was stable in size despite improved enhancement with treatment, suggesting that objective response by RANO criteria is not necessary for improved seizure control in LGG. Recent work has implicated the RAS/MEK/ERK pathway in neuronal precursor cells as a cause for epilepsy, suggesting that MEK inhibition of NF1-heterozygous neurons could be contributing to treatment response in this patient. Improvements in weakness and academic performance may have been due to improved seizure control or a direct effect of MEK inhibition on NF1-heterozygous neurons. CONCLUSION: MEK inhibition may have a clinically relevant anti-seizure effect for patients with pediatric LGG or NF1.

BACKGROUND: A standard-of-care has not been established for the management of patients with Down syndrome (DS) who develop primary central nervous system (CNS) germ cell tumors (GCTs) – the most common CNS neoplasm in DS – despite being more susceptible to treatment-related adverse events. METHODS: Data from large academic institutions were collected and a comprehensive review of the medical literature was conducted. RESULTS: Ten patients from six institutions (five USA, one Brazil) were reviewed. Additionally, thirty-one patients were identified in the literature from 1975-2021. Of the 41 total patients, mean age was ten years (range, birth to 35 years); males were predominant (61%). Basal ganglia were the most common tumor location (n=12; 29%), followed by posterior fossa (n=7; 17%). Sixteen patients had non-germinomatous germ cell tumors (NGGCTs) (39%), 14 had pure germinomas (34%), and eight had teratomas (20%); histology was unreported for two (5%). Nine patients (22%) experienced disease relapse, of which four died from tumor progression (one germinoma versus three teratoma). Fifteen patients (37%) experienced treatment-related complications - seven died (four germinoma versus three NGGCT). Of the germinoma patients, two died from chemotherapy-related sepsis, one from post-surgery cardiopulmonary failure, and one from Moyamoya following radiation-therapy (RT) only. Of the NGGCT patients, one died from chemotherapy-related sepsis, one from post-surgical infection, and one from pneumonia following surgery/chemotherapy/RT. Three-year overall survival (OS) was 66% for all histological types - 62% germinoma, 79% for NGGCT, and 53% for teratoma. Three-year OS for patients who received RT or chemotherapy was 71% and 75% respectively. Twenty-seven patients remain alive at latest follow-up (mean follow-up from diagnosis: 46.8 months). CONCLUSIONS: Patients with DS treated for CNS GCTs are at an increased risk of treatment-related adverse events. A different therapeutic approach may need to be considered for this patient population to mitigate treatment-related complications and long-term neurocognitive sequelae.

We aimed toidentify prognostic factors that may help better understand the behavior of relapsed central nervous system nongerminomatous germ cell tumors. We identified nine studies, including 101 patients; 33 patients (33%) were alive 12 months post-initial relapse. Sixty percent of patients with serum/cerebrospinal fluid (CSF) alpha-fetoprotein (AFP) level ≤25 ng/mL at initial diagnosis were survivors compared with 28% among patients with serum/CSF AFP level >25 ng/mL (P = 0.01). Seventy-one percent of patients who achieved complete response/continued complete response (CR/CCR) by the end of therapy at relapse were survivors compared with 7% among patients who had less than CR/CCR (P < 0.0001). Forty-eight percent of patients who received marrow-ablative chemotherapy followed by autologous hematopoietic cell rescue (HDCx/AuHCR) following relapse were survivors compared with 12% among patients who did not receive HDCx/AuHCR (P = 0.0001). Local relapse site, gross total surgical resection, and radiotherapy at relapse were not associated with improved outcomes.

ROS1 is a transmembrane receptor tyrosine kinase proto-oncogene that has been shown to have rearrangements with several genes in glioblastoma and other neoplasms, including intrachromosomal fusion with GOPC due to microdeletions at 6q22.1. ROS1 fusion events are important findings in these tumors, as they are potentially targetable alterations with newer tyrosine kinase inhibitors; however, whether these tumors represent a distinct entity remains unknown. In this report, we identify 3 cases of unusual pediatric glioma with GOPC-ROS1 fusion. We reviewed the clinical history, radiologic and histologic features, performed methylation analysis, whole genome copy number profiling, and next generation sequencing analysis for the detection of oncogenic mutation and fusion events to fully characterize the genetic and epigenetic alterations present in these tumors. Two of 3 tumors showed pilocytic features with focal expression of synaptophysin staining and variable high-grade histologic features; the third tumor aligned best with glioblastoma and showed no evidence of neuronal differentiation. Copy number profiling revealed chromosome 6q22 microdeletions corresponding to the GOPC-ROS1 fusion in all 3 cases and methylation profiling showed that the tumors did not cluster together as a single entity or within known methylation classes by t-Distributed Stochastic Neighbor Embedding.

Background Advanced diagnostic imaging has provided tremendous benefits; however, increased use of ionizing radiation modalities such as cranial computed tomography (CT) may be associated with an increased risk of developing central nervous system tumors. Methods A literature review identified studies published for more than the last 50 years from 1968 to 2018 that explored the association between head CT scans and developing central nervous system tumors in pediatrics. We reviewed seven studies that described and analyzed the risk of brain tumors. Results A positive correlation between exposure to CT scans and developing central nervous system tumors was evident in all cohorts. The strength of the association varied across the studies. Exclusion of patients with predisposing factors to central nervous system tumors was examined in four studies with a decreased risk to develop central nervous system tumors noted in three studies. Two studies reported nonsignificant reduction in the excess relative risk per milliGray of brain dose after adjusting for predisposing factors, whereas the reduction was significant in one study. The frequency of CT exposure was proportional to the risk of developing tumors in two studies although not significantly maintained in two other studies. Gender had no significant effect on the central nervous system tumor risk. The calendar year at the time of imaging showed decreasing risk in those exposed to CT in more recent years compared with prior decades. Conclusions Prospective epidemiologic studies are needed to examine the precise carcinogenic effect of exposure to ionizing radiation and help tailor further preventive measures.

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.

Outcomes in children and adolescents with recurrent or progressive high-grade glioma are poor, with a historical median overall survival of 5.6 months. Pediatric high-grade gliomas are largely immunologically silent or "cold," with few tumor-infiltrating lymphocytes. Preclinically, pediatric brain tumors are highly sensitive to oncolytic virotherapy with genetically engineered herpes simplex virus type 1 (HSV-1) G207, which lacks genes essential for replication in normal brain tissue.We conducted a phase 1 trial of G207, which used a 3+3 design with four dose cohorts of children and adolescents with biopsy-confirmed recurrent or progressive supratentorial brain tumors. Patients underwent stereotactic placement of up to four intratumoral catheters. The following day, they received G207 (10Twelve patients 7 to 18 years of age with high-grade glioma received G207. No dose-limiting toxic effects or serious adverse events were attributed to G207 by the investigators. Twenty grade 1 adverse events were possibly related to G207. No virus shedding was detected. Radiographic, neuropathological, or clinical responses were seen in 11 patients. The median overall survival was 12.2 months (95% confidence interval, 8.0 to 16.4); as of June 5, 2020, a total of 4 of 11 patients were still alive 18 months after G207 treatment. G207 markedly increased the number of tumor-infiltrating lymphocytes.Intratumoral G207 alone and with radiation had an acceptable adverse-event profile with evidence of responses in patients with recurrent or progressive pediatric high-grade glioma. G207 converted immunologically "cold" tumors to "hot." (Supported by the Food and Drug Administration and others; ClinicalTrials.gov number, NCT02457845.).

BackgroundPediatric cancers typically have a distinct genomic landscape when compared to adult cancers and frequently carry somatic gene fusion events that alter gene expression and drive tumorigenesis. Sensitive and specific detection of gene fusions through the analysis of next-generation-based RNA sequencing (RNA-Seq) data is computationally challenging and may be confounded by low tumor cellularity or underlying genomic complexity. Furthermore, numerous computational tools are available to identify fusions from supporting RNA-Seq reads, yet each algorithm demonstrates unique variability in sensitivity and precision, and no clearly superior approach currently exists. To overcome these challenges, we have developed an ensemble fusion calling approach to increase the accuracy of identifying fusions.ResultsOur ensemble fusion detection approach utilizes seven fusion calling algorithms: Arriba, CICERO, FusionMap, FusionCatcher, JAFFA, MapSplice, and STAR-Fusion, which are packaged as a fully automated pipeline using Docker and AWS serverless technology. This method uses paired end RNA-Seq sequence reads as input, and the output from each algorithm is examined to identify fusions detected by a consensus of at least three algorithms. These consensus fusion results are filtered by comparison to an internal database to remove likely artifactual fusions occurring at high frequencies in our internal cohort, while a “known fusion list” prevents failure to report known pathogenic events. We have employed the ensemble fusion-calling pipeline on RNA-Seq data from 229 patients with pediatric cancer or blood disorders studied under an IRB-approved protocol. The samples consist of 138 central nervous system tumors, 73 solid tumors, and 18 hematologic malignancies or disorders. The combination of an ensemble fusion-calling pipeline and a knowledge-based filtering strategy identified 67 clinically relevant fusions among our cohort (diagnostic yield of 29.3%), including RBPMS-MET, BCAN-NTRK1, and TRIM22-BRAF fusions. Following clinical confirmation and reporting in the patient’s medical record, both known and novel fusions provided medically meaningful information.ConclusionsOur ensemble fusion detection pipeline offers a streamlined approach to discover fusions in cancer, at higher levels of sensitivity and accuracy than single algorithm methods. Furthermore, this method accurately identifies driver fusions in pediatric cancer, providing clinical impact by contributing evidence to diagnosis and, when appropriate, indicating targeted therapies.

BACKGROUND: The optimal management of pediatric papillary tumors of the pineal region (PTPR) is not yet established. We report three cases, as an addition to the existing literature. PATIENT 1: A 22-month-old female presented with progressive ataxia and incoordination, found to have an enhancing solid and cystic mass centered within the pineal region, with associated obstructive hydrocephalus. Tumor biopsy revealed PTPR, prompting a subsequent subtotal resection. No adjuvant therapy was recommended. Patient has remained without evidence of disease progression for 92 months, since resection. PATIENT 2: An 8-year-old female presented with progressive headaches and new-onset generalized seizures, found to have a heterogeneously enhancing pineal lesion, with associated obstructive hydrocephalus. Following a biopsy demonstrating PTPR, patient underwent subtotal resection of the tumor. A second resection was completed 6 months later followed by focal irradiation. Targeted next-generation sequencing (NGS) demonstrated two non-targetable genomic alterations (CREBBP and MLL2). The patient remains without tumor recurrence, now 37 months, since irradiation. PATIENT 3: A 7-year-old male with Autism spectrum disorder presented with new-onset focal complex seizures. A brain MRI showed a heterogeneously enhancing lesion in the region of the pineal gland, with associated obstructive hydrocephalus. A tumor biopsy revealed PTPR, prompting a subsequent gross total resection (GTR). NGS demonstrated no reportable genomic alterations. Methylome profiling classified the tumor as PTPR, group B. Post-operative imaging with no residual tumor and he has remained without tumor progression, now eight months, since resection. CONCLUSION: PTPR are extremely rare in the pediatric setting, and were initially introduced in the WHO 2007 classification as grade II-III pineal gland tumors with distinct morphologic and immunohistochemical features. GTR is the mainstay of treatment but post-surgical management remains controversial. The clinical course is characterized by frequent local recurrence, hence, adjuvant chemotherapy and/or irradiation may be necessary upon disease progression.

BACKGROUND: The last two decades have witnessed several efforts to minimize the adverse sequelae of craniospinal irradiation (CSI), a standard of care treatment modality in medulloblastoma. This has been accomplished by adding chemotherapy to the treatment backbone. The use of pre-irradiation chemotherapy has also been previously reported. In one of the largest studies to date, we analyze treatment outcomes in children with standard and high-risk medulloblastoma treated with pre-irradiation chemotherapy followed by reduced-dose radiotherapy in SR and maintenance chemotherapy. METHODS: Data from the Polish Pediatric Neuro-oncology Group (PPNG) was analyzed in patients greater than 3 years of age with newly-diagnosed medulloblastoma. RESULTS : Among 138 patients, median age at diagnosis was 7.9 years and median follow-up was 5.5 years. Comprehensive molecular subgrouping was not available for all patients at the time of data collection. Of 60 standard-risk patients, there was pre-irradiation disease recurrence in one patient. One patient expired prior to radiation due to metastatic disease. Of 78 high-risk patients, one had pre-irradiation recurrence. Overall survival (OS) for high-risk patients at 3 and 5 years (± standard error) was 89.2 ± 4.0% and 81.3 ± 5.8%, respectively. OS for standard-risk patients at 3 and 5 years was 92.5 ± 3.8% and 88.2 ± 5.1%, respectively. Among high-risk patients, event-free survival (EFS) at 3 and 5 years was 82.5 ± 5.3% and 81.0 ± 5.6%. Among standard-risk patients, 3-year EFS was 89.2 ± 4.6% and 5-year EFS was 86.8 ± 5.3%. CONCLUSION : This study demonstrates promising survival outcomes in pediatric medulloblastoma patients treated with pre-irradiation chemotherapy followed by reduced-dose CSI and adjuvant chemotherapy. Such an approach may be helpful if delays in starting radiotherapy are expected, which is usually the case in many institutions around the globe.

INTRODUCTION: Ganglioglioma is a low grade neoplasm consisting of dysplastic neuronal and neoplastic glial cells and accounts for 5% of pediatric CNS tumors. Management often includes CNS diversion. There have been case reports in which platinum containing chemotherapy has been thought to contribute to CSF malabsorption leading to ascites. CASE: A 13 month old male developed progressive macrocephaly, developmental delay, chronic emesis, and intermittent bilateral cranial nerve VI palsy over the 5 months prior to presentation. MRI brain/spine was significant for an enhancing nodule in the left posterior lateral medulla, nodular thickening and enhancement along the brainstem down to the conus medullaris and in the tentorium, with associated hydrocephalus. Biopsy of the medullary nodule and of the enhancement were consistent with ganglioglioma with BRAF-KIAA1549 fusion, equivocal MYCN amplification, and no BRAF V600E mutation. A ventriculo-peritoneal shunt was placed at the time of biopsy. Therapy was initiated with vincristine (1.5 mg/m2) and carboplatin (175 mg/m2.) Following the 12 week induction phase of therapy, he developed increasing diarrhea, emesis, and abdominal ascites. Peritoneal fluid analysis had no malignant cells and low protein compared to CSF. Ascites was responsive to drainage but would rapidly re-accumulate. Ultimately the patient’s chemotherapy was discontinued after 2 maintenance cycles due to continued symptoms. Acetazolamide was trialed but discontinued due to side effects, so its efficacy could not be determined. He underwent shunt externalization followed by venticulo-atrial (VA) shunt re-internalization. He has not had ascites since that time, at 4 months from surgery. His CNS disease burden has been stable at 6 months off therapy. DISCUSSION: Ascites was most likely due to CSF malabsorption in the abdomen with a possible contribution from platinum containing chemotherapy and less likely secondary to malignant peritoneal cells. Resolution since VA shunt internalization makes alternate explanations less likely.

Diffuse gliomas are one of the most challenging pediatric brain tumors of the current era. The new WHO classification has brought in a paradigm shift in the diagnosis and management of diffuse gliomas. Although these tumors are not surgically resectable, an integrated molecular analysis could make them more amenable to targeted agents. We conducted a thorough systematic review and meta-analysis of therapies for diffuse gliomas in pediatric patients. Methods: Using PRISMA guidelines, PubMed, (Medline), Cochrane, and Google Scholar database searches are being conducted using search terms “diffuse midline glioma”, “diffuse midline astrocytoma” and “diffuse glioma management”. PubMed search filters used to find relevant articles were “human” species, “English” language, and “age birth to 18 years”. Results: Interim analysis using the PubMed database has revealed 387 articles of which 32 articles describe details of therapies used in pediatric patients. We found 8 case reports, 17 case series, and 7 clinical trials elucidating therapies for diffuse gliomas. Comprehensive analysis of modalities of therapies including neurosurgery, chemotherapy, and radiation therapy, along with survival analysis for these patients stratified by H3.3K27M mutant status is ongoing.

BACKGROUND: MRI-guided laser interstitial thermal therapy (LITT) is a minimally invasive, cytoreductive surgery useful for managing unresectable brain tumors. LITT disrupts the blood brain barrier (BBB) and facilitates chemotherapy delivery. We report the toxicity and outcome for pediatric brain tumors treated on a pilot trial of LITT and chemotherapy. The primary objectives were to quantify peritumoral BBB disruption following LITT and evaluate toxicity and efficacy. METHODS: The trial had two arms, A: patients with newly diagnosed gliomas underwent LITT followed by standard of care management, and B: patients with relapsed malignant brain tumors received 6 weeks of weekly doxorubicin post-LITT followed by maintenance etoposide. RESULTS: Between 2015 – 2018, six patients were enrolled: five on arm A (four with low-grade gliomas, one with high-grade glioma), one on Arm B with progressive anaplastic astrocytoma. All patients tolerated the procedure well; four experienced a transient hemiparesis post-LITT. The Arm B patient progressed and died of disease 2 months and 22 months post-LITT, respectively. The HGG patient received standard therapy and remains without disease progression 44 months post-LITT. One patient with LGG required additional treatment for disease progression 14 months post-LITT. Two patients with LGGs did not require additional therapy, now 51 and 41 months post-LITT. One patient was alive 24 weeks post-LITT and subsequently lost to follow-up. Peritumoral BBB disruption was analyzed in two ways: serum abundance of brain-derived proteins and MRI Dynamic contrast enhancement (DCE). Neuron-specific enolase were measurable in the serum of all patients, using ELISA up to 84 days post-LITT. DCE 2 weeks post-LITT demonstrated increased enhancement and FLAIR signal, consistent with BBB disruption and vasogenic edema. This effect was evident up to 4 months post-procedure. CONCLUSION: LITT is safe in children with brain tumors and can be combined with chemotherapy. DCE and serum brain-derived proteins can measure BBB disruption.

BACKGROUND: MEK inhibitor therapy is increasingly being utilized for the treatment of pediatric tumors, including low-grade glioma, plexiform neurofibroma and Langerhans cell histiocytosis. These drugs are well-tolerated but do have risk of toxicity, including cardiac toxicity. The purpose of this study is to better characterize MEK inhibitor-induced cardiac toxicity in pediatric patients. METHODS: Retrospective review of all patients who underwent MEK inhibitor mono-therapy for at least 3 months, 2015- 2021, age 25 years or less, at St. Louis Children’s hospital and Cardinal Glennon Children's hospital. RESULTS: We evaluated 31 patients, 19 (61%) with brain tumors and 12 (39%) without. Of the thirty-one, fifteen (48%) had NF1, 1 had Tuberous sclerosis. Cardiac toxicity consisted of asymptomatic sinus tachycardia, bradycardia, or decreased ejection fraction (EF). Thirteen patients (42%) experienced an asymptomatic decrease in left-ventricular ejection fraction (EF), Grade I-III. Time on therapy before decreased EF was 5 days to 21 months, median 2.8 months. Decreased EF developed in 5 of 13 patients receiving selumetinib and 8 of 18 receiving trametinib. Of the patients who developed decreased EF, 11 (85%) had brain tumors, 6 (46%) had NF1, and 89% had received prior systemic therapy. Out of the patients who had received no prior systemic therapy (6), 2 (33%) had decreased EF, while 11/25 (44%) of those who had received prior systemic therapy did. Drug was held temporarily for 6 patients, with dose limiting toxicity for 5 patients. Drug was discontinued for 1 patient after EF continued to decline despite dose reduction. Patients showed improvement in EF as early as 2 weeks after holding therapy. CONCLUSIONS: Cardiac toxicity in our patients was limited to asymptomatic reduction in ejection fraction, sinus bradycardia and tachycardia, reinforcing the need for appropriate monitoring via echocardiography. Prior systemic therapy was associated with decreased EF.

BACKGROUND: CNS Germinomas are highly radio-sensitive tumors with an excellent survival rate of more than 90%. The current standard of care combines chemotherapy with reduced-dose radiotherapy to minimize the adverse effects and long-term effects associated with radiotherapy. In the latest Children’s Oncology Group clinical trial (ACNS1123 stratum 2), patients with residual or progressive disease following chemotherapy can be considered for a “second-look” surgery to assess tumor viability. Patients with residual disease who do not undergo second-look surgery receive 24 Gy of whole ventricular radiation with a 12 Gy boost compared to 18 Gy plus boost given to patients in complete remission or without viable tumor on second-look. Conversely, the International Society of Paediatric Oncology (SIOP) protocol does not stratify based on response to chemotherapy, and the Korean SMC GCT trial uses 18 Gy CSI plus boost for all patients regardless of chemotherapy response. METHODS: Single center retrospective chart review of germinoma patients treated at St Louis Children’s Hospital between 2011 and 2021. RESULTS: We analyzed data for all 15 germinoma patients treated between 2011 and 2021. Five patients had residual disease following chemotherapy. Of these five, one had complete remission at the end of radiotherapy, one had partial response, and three had stable disease. All patients remain relapse-free with time of follow-up ranging between 6.3-109.3 months from the end of therapy (median 24 months). CONCLUSION: None of the five patients with residual disease following chemotherapy demonstrated disease progression following chemotherapy and radiotherapy. Future prospective clinical trials are needed in order to test the possibility of treating germinomas patients who have residual disease after chemotherapy with a low dose of radiotherapy similar to that used in patients with complete remission.

INTRODUCTION: Congenital intracranial teratomas (CITs) are rare tumors occurring in the first 60 days of life, often associated with dismal prognosis, posing challenges in both oncologic and surgical management. METHODS: We report a patient with a congenital mature teratoma diagnosed prenatally, who underwent successful surgical resection following neoadjuvant chemotherapy. We also performed an updated literature review on CIT outcomes. RESULTS: A newborn female, diagnosed prenatally with a complex midline intracranial echogenic mass, underwent postnatal brain MRI which demonstrated a supratentorial large complex enhancing mass with solid and cystic components, with associated obstructed hydrocephalus. Serum alpha-fetoprotein (AFP) and beta-human chorionic gonadotropin were normal for age. Tumor biopsy revealed mature teratoma. AFP obtained from cyst fluid during fenestration was significantly elevated at 8 weeks of life. Due to concerns for possible malignant transformation and in an attempt to alter tumor vascularity facilitating surgical resection, the patient received two cycles of neoadjuvant carboplatin and etoposide, followed by tumor resection without significant intraoperative bleeding. There was no evidence of immature components on final pathology. The patient remains without tumor recurrence, now 9 months, since surgical resection. Review of literature yielded 76 cases of CITs: eight patients with mature teratoma, of which six remained alive following tumor resection. Five patients with immature teratoma received chemotherapy prior to resection; three remained alive post-resection (follow-up range 3-20 years). DISCUSSION: CITs are typically associated with poor prognosis, with reported one-year survival of 7.2-12%. Surgical excision is the mainstay of treatment, often limited by intraoperative hemorrhage. Neoadjuvant chemotherapy has been employed as a successful strategy to reduce tumor volume and vascularity in a variety of pediatric brain tumors; more specifically, carboplatin and etoposide are utilized as neoadjuvant chemotherapy for non-germinomatous germ cell tumors to facilitate excision in older children. Their role in CITs requires further evaluation.

Background: The discovery of the driving oncogenic alterations in pediatric low-grade gliomas (pLGGs) has shifted our focus towards management with targeted therapies, especially in relapsing or progressive disease. Limited data is available on the durability of response to targeted therapy in pLGGs once the therapy has ceased. Methods: Multi-institutional retrospective chart review of patients with pLGGs younger than 25 years, between 2010-2021, was undertaken to evaluate the durability of response to targeted therapy and determine risk factors associated with disease progression after cessation of therapy. Results: Current analysis included 18 patients from two centers. Seven (39%) had neurofibromatosis type-1 (NF-1). Diagnoses included: optic pathway glioma (OPG) (6/18, 33%), pilocytic astrocytoma (8/18, 44%), diffuse fibrillary astrocytoma (1/18), ganglioglioma (1/18), glioneural neoplasm (2/18). Sixteen patients received at least one prior line of chemotherapy (range 1-5). Targeted agents included trametinib (50%), selumetinib (5%), binimetinib (22%), vemurafenib (11%) and everolimus (11%). Median time on therapy was 351 days (range 29-979 days). All, but one patient had residual intracranial findings at the end of therapy: eight patients (44%) had stable disease, while ten required additional therapy; 50% were NF-1 patients with OPG. Median time to progression was 203 days (range 29-615 days). Of those who did not require any additional therapies, 50% had suprasellar tumors. Genomic data was available for twelve patients; BRAF-KIAA1549 fusion was the most common genomic alteration. Others included mutations in KRAS, BRAF (V600E), PTPN11, SOX6-RAF1 fusion, NF-1, and a patient with FGFR1, KMT2C, and PTPN11 alterations. Conclusion: Preliminary analysis demonstrates that despite initial response, the majority of patients required additional line of therapy. Patients with NF-1 and OPGs tend to progress after discontinuing therapy, while suprasellar non-NF1 pLGGs tend to develop sustained response to targeted therapies. Additional multi-institutional analysis is underway and will be presented at the meeting.

BACKGROUND: Biologically targeted agents such as the BRAF inhibitor dabrafenib are now used to treat progressive low-grade glioma (LGG), but the effect of these agents on the neurologic symptoms that accompany LGGs is poorly understood. CASE: A 21-year-old male was diagnosed with medullary ganglioglioma (GG) after presenting with persistent vertigo and positional headaches. Immunohistochemistry was consistent with BRAF V600E mutation and dabrafenib was started. The patient had resolution of his neurologic symptoms within 3 weeks of treatment initiation; surveillance MRI several months later demonstrated interval decrease in tumor size. The patient remained on therapy for 2 years. Several days after planned drug discontinuation the patient had re-emergence of persistent vertigo that impaired his ability to work. Repeat imaging two months later demonstrated an increase in tumor size and solid enhancement along tumor margins. He was restarted on dabrafenib. Within one week, he again had complete resolution of his vertigo. DISCUSSION: Gangliogliomas are comprised of mixed neuronal and glial components and associated with epilepsy, headache and other localizing neurologic symptoms. In this report, we describe clinical and radiographic response from single-therapy dabrafenib in a patient with BRAF V600E+ GG, along with a very rapid resolution of neurologic symptoms upon initiation of the drug and recrudescence shortly following cessation of therapy. The symptoms subsided within a week of restarting dabrafenib, suggesting a separate, more rapid mechanism of symptom reversal than decline in tumor size. BRAF mutations have been identified in both the neuronal and glial components of ganglioglioma, suggesting that dabrafenib may provide symptomatic relief via inhibition of abberant neuronal processes. CONCLUSION: BRAF inhibitors can rapidly improve neurological symptoms via a rapid, not yet fully elucidated mechanism. Kinetics of this response suggest it is independent of effects on tumor volume and the degree of compression to tissue surrounding the tumor.

Intracranial growing teratoma syndrome (iGTS) is a rare phenomenon of paradoxical growth of a germ cell tumor (GCT) during treatment despite normalization of tumor markers. We sought to evaluate the frequency, clinical characteristics and outcome of iGTS in Western countries. Pediatric patients from 22 North American and Australian institutions diagnosed with iGTS between 2000 and 2017 were retrospectively evaluated. From a total of 777 cases of central nervous system (CNS) GCT, 39 cases of iGTS were identified for an overall frequency of 5%. Pineal region was a more frequent location for iGTS as compared to cases of GCT without iGTS (p

Background Surgical resection is the treatment of choice for pleomorphic xanthoastrocytoma, while chemotherapy and radiation therapy are typically used in patients with anaplasia, metastasis, or sometimes in subtotally resected cases, especially upon recurrence. Extracranial dissemination has been only rarely reported. We describe a five year old boy with the rare occurrence multiply recurrent and extracranially disseminated anaplastic pleomorphic xanthoastrocytoma. A complete resolution of his tumor was achieved for greater than two years thus far after administering everolimus. Methods We performed a comprehensive literature review of all pleomorphic xanthoastrocytoma cases; 359 cases were described, and 132 of these individuals were less than 18 years of age. Results Gross total resection was achieved in only 132 (36.7%) cases, while additional therapy was administered in 186 patients. Only four patients in additon to our own have been documented with extracranial dissemination (four of five in the pediatric population); two patients who succumbed to their disease underwent subtotal resection of the primary tumor. Conclusions We report the first patient with extracranially disseminated anaplastic pleomorphic xanthoastrocytoma to be successfully maintained on everolimus as a single oral chemotherapy agent with complete resolution of the tumor. Pleomorphic xanthoastrocytoma can rarely disseminate extracranially in the pediatric population, hence pathologists and neuro-oncologists should be aware of this possibility.

The lack of a standard treatment approach has contributed to poor outcomes of patients with recurrent central nervous system (CNS) mixed malignant germ cell tumors (MMGCT). There are no data in the literature supporting optimal re-induction chemotherapy regimens that should be used for patients with recurrent CNS MMGCT. We conducted a literature review to explore the response rate of patients with recurrent CNS MMGCT to different re-induction chemotherapy regimens by searching PubMed from 1985 through November 2017. Tumors were classified according to Japanese, European, and North American prognostic group classifications determined at initial presentation. Forty-two responses to various re-induction chemotherapy regimens reported in 38 patients were included. Two patients were inevaluable and their responses to re-induction chemotherapy were excluded. Thirty-five responses to various re-induction chemotherapy regimens were evaluable in 33 patients following a first relapse. Six (17%) responses were reported as complete or continuous complete responses, seven (20%) partial responses, two (6%) were stable disease, two (6%) were mixed responses, and 18 (51%) were progressive disease. Five of ten patients treated without platinum-based chemotherapy experienced tumor progression. There was a trend towards a higher rate of tumor progression among histological poor prognostic group patients, and among patients relapsing within 24 months of initial diagnosis; however, it was not statistically significant. The histological prognostic group and time to relapse may affect the response to re-induction chemotherapy. However, further studies with larger sample size are needed to examine these associations and determine the optimal re-induction chemotherapy regimens for patients with recurrent MMGCT.

Background Atypical teratoid/rhabdoid tumor (AT/RT) of the central nervous system (CNS) with synchronous or metachronous extra-CNS disease is a rare childhood malignancy with a dismal prognosis. Case Description We report a 7-week-old female with metastatic AT/RT and synchronous malignant rhabdoid tumor of the kidney who received an intensive multimodal approach combining surgical resection, intrathecal chemotherapy, and high-dose chemotherapy with autologous peripheral blood stem cell transplant (PBSCT). She is currently 24 months old without any evidence of disease. In addition, we completed an extensive literature review of cases with CNS AT/RT and synchronous or metachronous extra-CNS primary tumors. To date, 31 pediatric cases have been reported, and the median overall-survival was 6 months after diagnosis. The only 3 survivors received autologous PBSCT, and 2 of these patients had complete resection of their CNS tumor. Conclusions The rarity of CNS AT/RT with extra-CNS primary disease and the lack of standard treatment contribute to its reported dismal prognosis. We report a case of a long-term survivor with metastatic AT/RT and synchronous extra-CNS primary tumor. Maximal surgical resection, intrathecal chemotherapy, and consolidative autologous PBSCT may improve prognosis and avoid radiation.

Introduction: Pediatric high-grade gliomas (pHGGs) are routinely fatal with a median overall survival (OS) at recurrence of 5.6 months (mos). A safe, effective immunotherapy for pHGG has eluded investigators. Oncolytic HSV-1 G207 contains mutations that prevent a productive infection of normal cells but permit replication in tumor cells. In addition to direct tumor cell lysis, G207 activates innate/adaptive immune cells and promotes cross-presentation of tumor antigens to generate an anti-tumor immune response. A 5 Gy radiation dose increases viral replication and spread. We evaluated the safety and efficacy of G207 alone and combined with radiation in children with progressive supratentorial HGG (NCT02457845). Methods: We employed a 3 + 3 design with 4 cohorts. Children 3-18 years old with biopsy-confirmed HGG underwent stereotactic placement of up to four intratumoral catheters. The next day, we administered 107 or 108 plaque-forming units (pfu) of G207 by controlled rate infusion over 6 hours. Within 24 hours of G207, patients in dose level 3 and 4 received 5 Gy to the gross tumor volume. The primary objective was safety/tolerability. We assessed secondary objectives of virus shedding in blood, saliva and conjunctiva by PCR, response by MRI and evaluation of matched pre- and post-G207 tissue for tumor-infiltrating lymphocytes (TILs), and seroconversion by immunofluorescence assay. Results: 12 patients (age range 7-18) with progressive, IDH wild-type pHGG received G207. At screening, 10 patients had tumors with a bi-perpendicular sum ≥ 5.5 cm, 3 had multi-focal disease, 8 had failed ≥ 2 prior treatment regimens, and 4 had failed ≥ 3 regimens. 3-4 catheters (44 total) were placed safely throughout the cerebrum and resulted in no neurologic sequelae. G207 alone or with radiation was safe and tolerable in all patients with no dose-limiting toxicities, attributable grade 3 or 4 toxicities/serious adverse events, or evidence of virus shedding. 11 participants had radiographic, neuropathologic, and/or clinical responses. Median OS was 12.2 mos (95% CI 8.0, 16.4). Thus far, 36% of patients have lived >18 mos, the median OS for newly diagnosed pHGG. Compared to patients who seroconverted post-G207 (n=3), patients with baseline HSV-1 antibodies (n=3) had a shorter median survival: 5.1 mos (3.0, 7.2) vs 18.3 mos (9.2, 27.4). G207 significantly increased CD4+ and CD8+ TILs. Conclusions: G207 alone and combined with radiation was tolerable and safe with evidence of responses in children with pHGG. The promising median OS (12.2 mos) compares favorably with historical data (5.6 mos). Baseline HSV-1 seropositivity and seroconversion are potential biomarkers of treatment response that require further investigation. Importantly, G207 converted ‘cold' tumors to ‘hot' with a dramatic increase in TILs. A multi-institutional Phase II clinical trial of G207 in pHGG is forthcoming (NCT04482933). Citation Format: Gregory K. Friedman, James M. Johnston, Asim K. Bag, Joshua D. Bernstock, Rong Li, Inmaculada Aban, Kara Kachurak, Li Nan, Kyung-Don Kang, Stacie Totsch, Charles Schlappi, Allison M. Martin, Devang Pastakia, Sameer Farouk Sait, Yasmin Khakoo, Matthias A. Karajannis, Karina Woodling, Joshua D. Palmer, Diana S. Osorio, Jeffrey Leonard, Mohamed S. Abdelbaki, Avi Madan-Swain, T. Prescott Atkinson, Richard J. Whitley, John B. Fiveash, James M. Markert, G. Yancey Gillespie. Phase I immunovirotherapy trial of oncolytic HSV-1 G207 alone or combined with radiation in pediatric high-grade glioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT018.

BACKGROUND Patients with relapsed CNS NGGCTs experience poor outcomes. Our aim to explore prognostic factors that may guide future clinical trials. METHODS A review of clinical trials that included patients with relapsed CNS NGGCTs was performed. RESULTS Seventy-four patients were identified; only 14 patients (19%) were long-term survivors. Patients who relapsed >24 months after initial diagnosis had a survival rate of 47% compared with 15% of patients who relapsed in 25 ng/ml at relapse (p= 0.0015). Patients who achieved complete response/continued complete response (CR/CCR) by the end of therapy had a survival rate of 59% compared with 3% among patients who had less than CR/CCR by the end of therapy (p= 0.0001). Patients who received marrow-ablative chemotherapy followed by autologous hematopoietic cell rescue (HDCx/AuHCR) at relapse had a survival rate of 33% compared with 9% of patients who did not receive HDCx/AuHCR at relapse (p=0.056). The extent of surgical resection, receiving radiotherapy, and beta-human chorionic gonadotropin levels at relapse were not statistically associated with improved outcomes. CONCLUSION Timing of relapse (>24 months after initial diagnosis), serum/CSF AFP

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

BACKGROUND Wnt-MB infers an excellent prognosis, and metastatic disease is rare. However, specific treatment strategies and patterns of failure for patients with recurrent Wnt-MB are unknown. We report two cases of recurrent beta-catenin nucleopositive Wnt-MBs treated with an irradiation-sparing strategy, incorporating HDCx/AuHPCR. PATIENT 1: A nine-year-old female experienced local recurrence of a non-metastatic Wnt-MB nine months after gross total resection (GTR) followed by 18Gy craniospinal irradiation (CSI) with primary site boost to 54Gy, accompanied by weekly vincristine, followed by a maintenance regimen of nine cycles of cisplatin/lomustine/vincristine alternating with cyclophosphamide/vincristine every third cycle. GTR of the relapsed tumor was followed by three cycles of HDCx/AuHPCR. She is disease-free for over three years following relapse treatment. PATIENT 2: A 17-year-old male initially underwent GTR, followed by 23.4Gy CSI with 54Gy posterior fossa boost with concomitant weekly vincristine, followed by a maintenance regimen that included nine alternating cycles of vincristine/lomustine/cisplatin and cyclophosphamide/vincristine. Isolated right frontal horn metastatic recurrence developed 19 months post-treatment; three cycles of irinotecan/temozolomide/bevacizumab and gamma-knife radiosurgery produced complete response. A second isolated metastatic recurrence within the left frontal horn occurred 13 months post-treatment, which was treated with two cycles of cyclophosphamide/etoposide followed by two cycles of HDCx/AuHPCR. MRI of the brain showed no residual tumor one month post-treatment. He currently awaits follow-up stereotactic radiosurgery. CONCLUSION Patients with recurrent Wnt-MB may be treated with curative intent using a multi-disciplinary approach that includes HDCx/AuHPCR, and minimization or avoidance of re-irradiation.

BACKGROUND We report the responses, toxicities and long-term outcomes of gemcitabine, paclitaxel and oxaliplatin (GemPOx) regimen administered, in responsive patients, prior to single cycle marrow-ablative chemotherapy (thiotepa, etoposide and carboplatin) with autologous hematopoietic progenitor cell rescue (HDCx+AuHPCR). METHODS Since December 2009, 11 recurrent/refractory patients (10 MMGCT, 1 germinoma; 10 males; mean age 16.5 years, range 7–46 years) have been treated with up to four cycles of gemcitabine (800mg/M2), paclitaxel (170mg/M2) and oxaliplatin (100mg/M2) administered on one day at 14 days intervals. RESULTS All 11 patients were enrolled on a prospective multi-center trial, which was closed in October 2019. Three patients achieved complete remissions (tumor marker and/or imaging studies), five achieved partial remissions, two developed disease progression (PD), and one was withdrawn after one cycle for severe paclitaxel neurotoxicity followed by rapid tumor progression and death. One patient with PD after one cycle had pathologically-confirmed metastatic transformation to pure embryonal rhabdomyosarcoma, and rapidly expired. A second patient, with pure pineal choriocarcinoma, progressed after the second GemPOx cycle, ultimately died of tumor progression. Eight of the 11 responsive patients subsequently underwent HDCx+AuHPCR; five of these received some form of radiotherapy. Seven patients (six MMGCT, one germinoma) are alive and disease-free without recurrence for a mean of 94 months (range 74–118 months) since completion of therapy. CONCLUSION GemPOx is an effective re-induction regimen for patient with recurrent CNS germ cell tumors, with acceptable toxicities; when followed by marrow-ablative chemotherapy and subsequent irradiation/re-irradiation, the regimen produces encouraging long-term disease-free survival.

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

BACKGROUND We report a unique case of spinal ependymoma with classic histology and aggressive clinical behavior which harbored a focal MYC (8q24) amplification. CASE REPORT: A-12-year old male presented with a three months history of back pain and acute onset weakness with ataxia. A spine MRI revealed an avidly enhancing intradural, extramedullary mass occupying the dorsal spinal canal from C6 through T2. The tumor demonstrated mild diffusion restriction and was associated with severe cord compression and mild edema. He underwent gross total resection. Pathological diagnosis was classic grade II ependymoma. Eleven months later, he re-presented with acute onset lower extremity paresthesia and left-handed weakness. Spine MRI demonstrated tumor recurrence extending from C2 through T1-T2 with resultant severe cord compression, again demonstrating avid enhancement and restricted diffusion. He underwent subtotal resection of the mass and focal proton beam irradiation. MOLECULAR CHARACTERISTICS: The patient was enrolled on an institutional comprehensive genomic profiling protocol. The tumor’s copy number profile was complex, including homozygous loss of 17p and notably, amplification of the MYC oncogene. Using fluorescence in situ hybridization, we identified >20 copies of MYC in interphase cells, confirming the gene amplification, while two copies of MYCN (2p24) were seen. DNA methylation further classified this tumor as clustering near posterior fossa group A (score=0.6073) tumors. CONCLUSION We report a unique case of an adolescent male with aggressive spinal ependymoma harboring focal MYC amplification. Testing for MYC amplification may be reasonable in newly-diagnosed spinal ependymomas to aid in characterization.

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.

BACKGROUND BXQ-350 is a novel agent composed of the multifunctional, lysosomal activator protein Saposin C (SapC) and dioleoyl- phosphatidylserine (DOPS) and has demonstrated antitumor effects in both in vitro and in vivo preclinical models. Many tumors, including high-grade glioma and diffuse intrinsic pontine glioma (DIPG), and cells of tumor vasculature have aberrantly-exposed phosphatidylserine (PS)-rich domains on the cell surface. BXQ-350 is an anti-tumor agent in development from Bexion Pharmaceuticals, Inc. that selectively targets tumor cell PS, particularly those translocated to the outer leaflet of the plasma membrane in tumor cells. BXQ-350 activates and participates in various cellular processes, including apoptosis and necrosis, and may also exhibit novel mechanisms leading to cell death that require further investigation. METHODS Nine refractory solid (2) and central nervous system (7) tumor patients (5F:4M, age 4–23 years of age) were enrolled in a 2-site dose escalation Phase I first-in-pediatric trial (NCT03967093) which completed in 2019. All patients received at least one dose of BXQ-350 which was administered as an intravenous infusion. Dosing began at 1.8 mg/kg and escalated to the highest planned dose level of 3.2mg/kg. RESULTS There were no BXQ-350-related serious adverse events, dose limiting toxicities or withdrawals. The highest planned dose of 3.2 mg/kg was achieved safely but a maximum tolerated dose was not established. One osteosarcoma patient had progressive disease prior to completing cycle one of treatment and was removed from trial. Eight patients (DIPG-3, HGG-1, GBM-1, Pineoblasotoma-1, Ependymoma-1, Osteosarcoma-1) completed at least one cycle, with one DIPG patient completing cycle five. CONCLUSION BXQ-350 was well tolerated with no significant dose-limiting toxicities at the highest planed dose level. A pediatric Phase I trial in newly diagnosed patients is planned for 3rd quarter 2020.