Capmatinib is an effective treatment for MET-fusion driven pediatric high-grade glioma and synergizes with radiotherapy.

BACKGROUND: Pediatric-type diffuse high-grade glioma (pHGG) is the most frequent malignant brain tumor in children and can be subclassified into multiple entities. Fusion genes activating the MET receptor tyrosine kinase often occur in infant-type hemispheric glioma (IHG) but also in other pHGG and are associated with devastating morbidity and mortality. METHODS: To identify new treatment options, we established and characterized two novel orthotopic mouse models harboring distinct MET fusions. These included an immunocompetent, murine allograft model and patient-derived orthotopic xenografts (PDOX) from a MET-fusion IHG patient who failed conventional therapy and targeted therapy with cabozantinib. With these models, we analyzed the efficacy and pharmacokinetic properties of three MET inhibitors, capmatinib, crizotinib and cabozantinib, alone or combined with radiotherapy. RESULTS: Capmatinib showed superior brain pharmacokinetic properties and greater in vitro and in vivo efficacy than cabozantinib or crizotinib in both models. The PDOX models recapitulated the poor efficacy of cabozantinib experienced by the patient. In contrast, capmatinib extended survival and induced long-term progression-free survival when combined with radiotherapy in two complementary mouse models. Capmatinib treatment increased radiation-induced DNA double-strand breaks and delayed their repair. CONCLUSIONS: We comprehensively investigated the combination of MET inhibition and radiotherapy as a novel treatment option for MET-driven pHGG. Our seminal preclinical data package includes pharmacokinetic characterization, recapitulation of clinical outcomes, coinciding results from multiple complementing in vivo studies, and insights into molecular mechanism underlying increased efficacy. Taken together, we demonstrate the groundbreaking efficacy of capmatinib and radiation as a highly promising concept for future clinical trials.

Vorinostat, temozolomide or bevacizumab with irradiation and maintenance BEV/TMZ in pediatric high-grade glioma: A Children's Oncology Group Study.

Background: Outcomes for children with high-grade gliomas (HGG) remain poor. This multicenter phase II trial evaluated whether concurrent use of vorinostat or bevacizumab with focal radiotherapy (RT) improved 1-year event-free survival (EFS) compared to temozolomide in children with newly diagnosed HGG who received maintenance temozolomide and bevacizumab. Methods: Patients ≥ 3 and < 22 years with localized, non-brainstem HGG were randomized to receive RT (dose 54-59.4Gy) with vorinostat, temozolomide, or bevacizumab followed by 12 cycles of bevacizumab and temozolomide maintenance therapy. Results: Among 90 patients randomized, the 1-year EFS for concurrent bevacizumab, vorinostat, or temozolomide with RT was 43.8% (±8.8%), 41.4% (±9.2%), and 59.3% (±9.5%), respectively, with no significant difference among treatment arms. Three- and five-year EFS for the entire cohort was 14.8% and 13.4%, respectively, with no significant EFS difference among the chemoradiotherapy arms. IDH mutations were associated with more favorable EFS (P = .03), whereas H3.3 K27M mutations (P = .0045) and alterations in PIK3CA or PTEN (P = .025) were associated with worse outcomes. Patients with telomerase- and alternative lengthening of telomeres (ALT)-negative tumors (n = 4) had an EFS of 100%, significantly greater than those with ALT or telomerase, or both (P = .002). While there was no difference in outcomes based on TERT expression, high TERC expression was associated with inferior survival independent of the telomere maintenance mechanism (P = .0012). Conclusions: Chemoradiotherapy with vorinostat or bevacizumab is not superior to temozolomide in children with newly diagnosed HGG. Patients with telomerase- and ALT-negative tumors had higher EFS suggesting that, if reproduced, mechanism of telomere maintenance should be considered in molecular-risk stratification in future studies.

Computing Power and Sample Size for the False Discovery Rate in Multiple Applications.

The false discovery rate (FDR) is a widely used metric of statistical significance for genomic data analyses that involve multiple hypothesis testing. Power and sample size considerations are important in planning studies that perform these types of genomic data analyses. Here, we propose a three-rectangle approximation of a p-value histogram to derive a formula to compute the statistical power and sample size for analyses that involve the FDR. We also introduce the R package FDRsamplesize2, which incorporates these and other power calculation formulas to compute power for a broad variety of studies not covered by other FDR power calculation software. A few illustrative examples are provided. The FDRsamplesize2 package is available on CRAN.

Use of External Control Cohorts in Pediatric Brain Tumor Clinical Trials.

Why, when, and how to consider external control cohorts in pediatric brain tumor clinical trials.

High-grade glioma in infants and young children is histologically, molecularly, and clinically diverse: Results from the SJYC07 trial and institutional experience.

BACKGROUND: High-grade gliomas (HGG) in young children pose a challenge due to favorable but unpredictable outcomes. While retrospective studies broadened our understanding of tumor biology, prospective data is lacking. METHODS: A cohort of children with histologically diagnosed HGG from the SJYC07 trial was augmented with nonprotocol patients with HGG treated at St. Jude Children's Research Hospital from November 2007 to December 2020. DNA methylome profiling and whole genome, whole exome, and RNA sequencing were performed. These data were integrated with histopathology to yield an integrated diagnosis. Clinical characteristics and preoperative imaging were analyzed. RESULTS: Fifty-six children (0.0-4.4 years) were identified. Integrated analysis split the cohort into four categories: infant-type hemispheric glioma (IHG), HGG, low-grade glioma (LGG), and other-central nervous system (CNS) tumors. IHG was the most prevalent (n = 22), occurred in the youngest patients (median age = 0.4 years), and commonly harbored receptor tyrosine kinase gene fusions (7 ALK, 2 ROS1, 3 NTRK1/2/3, 4 MET). The 5-year event-free (EFS) and overall survival (OS) for IHG was 53.13% (95%CI: 35.52-79.47) and 90.91% (95%CI: 79.66-100.00) vs. 0.0% and 16.67% (95%CI: 2.78-99.74%) for HGG (p = 0.0043, p = 0.00013). EFS and OS were not different between IHG and LGG (p = 0.95, p = 0.43). Imaging review showed IHGs are associated with circumscribed margins (p = 0.0047), hemispheric location (p = 0.0010), and intratumoral hemorrhage (p = 0.0149). CONCLUSIONS: HGG in young children is heterogeneous and best defined by integrating histopathological and molecular features. Patients with IHG have relatively good outcomes, yet they endure significant deficits, making them good candidates for therapy de-escalation and trials of molecular targeted therapy.

Population pharmacokinetics of methotrexate and 7-hydroxymethotrexate and delayed excretion in infants and young children with brain tumors.

PURPOSE: The objectives of this study were to develop a population pharmacokinetic model of methotrexate (MTX) and its primary metabolite 7-hydroxymethotrexate (7OHMTX) in children with brain tumors, to identify the sources of pharmacokinetic variability, and to assess whether MTX and 7OHMTX systemic exposures were related to toxicity. METHODS: Patients received 2.5 or 5 g/m2 MTX as a 24-hour infusion and serial samples were analyzed for MTX and 7OHMTX by an LC-MS/MS method. Pharmacokinetic parameters were estimated using nonlinear mixed-effects modeling. Demographics, laboratory values, and genetic polymorphisms were considered as potential covariates to explain the pharmacokinetic variability. Association between MTX and 7OHMTX systemic exposures and MTX-related toxicities were explored using random intercept logistic regression models. RESULTS: The population pharmacokinetics of MTX and 7OHMTX were adequately characterized using two-compartment models in 142 patients (median 1.91 y; age range 0.09 to 4.94 y) in 513 courses. The MTX and 7OHMTX population clearance values were 4.6 and 3.0 l/h/m2, respectively. Baseline body surface area and estimated glomerular filtration rate were significant covariates on both MTX and 7OHMTX plasma disposition. Pharmacogenetic genotypes were associated with MTX pharmacokinetic parameters but had only modest influence. No significant association was observed between MTX or 7OHMTX exposure and MTX-related toxicity. CONCLUSIONS: MTX and 7OHMTX plasma disposition were characterized for the first time in young children with brain tumors. No exposure-toxicity relationship was identified in this study, presumably due to aggressive clinical management which led to a low MTX-related toxicity rate.

Application of the Rotterdam postoperative cerebellar mutism syndrome prediction model in patients undergoing surgery for medulloblastoma in a single institution.

OBJECTIVE: Postoperative cerebellar mutism syndrome (CMS) develops in up to 40% of children with medulloblastoma. The Rotterdam model (RM) has been reported to predict a 66% risk of CMS in patients with a score of ≥ 100. The aim of this study was to retrospectively apply the RM to an independent cohort of patients with newly diagnosed medulloblastoma and study the applicability of the RM in predicting postoperative CMS. METHODS: Participants had to have their first tumor resection at the authors' institution and be enrolled in the SJMB12 protocol (NCT01878617). All participants underwent structured serial neurological evaluations before and then periodically after completing radiation therapy. Imaging was reviewed by the study neurologist who was blinded to CMS status when reviewing the scans and retrospectively applied RM score to each participant. RESULTS: Forty participants were included (14 females and 26 males). Four (10%) patients had CMS. The median age at tumor resection was 11.7 years (range 3.5-17.8 years). Tumor location was midline in 30 (75%), right lateral in 6 (15%), and left lateral in 4 (10%). The median Evans index was 0.3 (range 0.2-0.4), and 34 (85%) patients had an Evans index ≥ 0.3. Five participants required a ventricular shunt. The median tumor volume was 51.97 cm3 (range 20.13-180.58 cm3). Gross-total resection was achieved in 35 (87.5%) patients, near-total resection in 4 (10%), and subtotal in 1. The median RM score was 90 (range 25-145). Eighteen participants had an RM score of ≥ 100, and of these 16.7% (n = 3) had CMS. Of the 22 patients with an RM score < 100, 1 child developed CMS (4.5%, CI 0.1%-22.8%); 3 of the 18 patients with an RM score ≥ 100 developed CMS (16.7%, CI 3.6%-41.4%). The observed rate of CMS in the cohort of children with an RM score ≥ 100 was significantly lower than the observed rate in the original RM cohort (66.7%, CI 51%-80.0%, p < 0.001). A greater risk of CMS in patients with an RM score ≥ 100 could not be confirmed (p = 0.31). CONCLUSIONS: At the authors' institution, the incidence of CMS in patients who had an RM ≥ 100 was significantly lower than the RM cohort. These findings raise questions regarding generalizability of RM; however, fewer cases of CMS and a relatively small cohort limit this conclusion.

Children's Oncology Group's 2023 blueprint for research: Central nervous system tumors.

Tumors of the central nervous system (CNS) are a leading cause of morbidity and mortality in the pediatric population. Molecular characterization in the last decade has redefined CNS tumor diagnoses and risk stratification; confirmed the unique biology of pediatric tumors as distinct entities from tumors that occur in adulthood; and led to the first novel targeted therapies receiving Food and Drug Administration (FDA) approval for children with CNS tumors. There remain significant challenges to overcome: children with unresectable low-grade glioma may require multiple prolonged courses of therapy affecting quality of life; children with high-grade glioma have a dismal long-term prognosis; children with medulloblastoma may suffer significant short- and long-term morbidity from multimodal cytotoxic therapy, and approaches to improve survival in ependymoma remain elusive. The Children's Oncology Group (COG) is uniquely positioned to conduct the next generation of practice-changing clinical trials through rapid prospective molecular characterization and therapy evaluation in well-defined clinical and molecular groups.

Phase I trial of panobinostat in children with diffuse intrinsic pontine glioma: A report from the Pediatric Brain Tumor Consortium (PBTC-047).

BACKGROUND: Diffuse intrinsic pontine glioma (DIPG) is a lethal childhood cancer with median survival of less than 1 year. Panobinostat is an oral multihistone deacetylase inhibitor with preclinical activity in DIPG models. Study objectives were to determine safety, tolerability, maximum tolerated dose (MTD), toxicity profile, and pharmacokinetics of panobinostat in children with DIPG. PATIENTS AND METHODS: In stratum 1, panobinostat was administered 3 days per week for 3 weeks on, 1 week off to children with progressive DIPG, with dose escalation following a two-stage continual reassessment method. After this MTD was determined, the study was amended to evaluate the MTD in children with nonprogressive DIPG/Diffuse midline glioma (DMG) (stratum 2) on an alternate schedule, 3 days a week every other week in an effort to escalate the dose. RESULTS: For stratum 1, 19 subjects enrolled with 17/19 evaluable for dose-finding. The MTD was 10 mg/m2/dose. Dose-limiting toxicities included thrombocytopenia and neutropenia. Posterior reversible encephalopathy syndrome was reported in 1 patient. For stratum 2, 34 eligible subjects enrolled with 29/34 evaluable for dose finding. The MTD on this schedule was 22 mg/m2/dose. DLTs included thrombocytopenia, neutropenia, neutropenia with grade 4 thrombocytopenia, prolonged intolerable nausea, and increased ALT. CONCLUSIONS: The MTD of panobinostat is 10 mg/m2/dose administered 3 times per week for 3 weeks on/1 week off in children with progressive DIPG/DMG and 22 mg/m2/dose administered 3 times per week for 1 week on/1 week off when administered in a similar population preprogression. The most common toxicity for both schedules was myelosuppression.

ATM inhibition enhances the efficacy of radiation across distinct molecular subgroups of pediatric high-grade glioma.

BACKGROUND: Pediatric high-grade glioma (pHGG) is largely incurable and accounts for most brain tumor-related deaths in children. Radiation is a standard therapy, yet the benefit from this treatment modality is transient, and most children succumb to disease within 2 years. Recent large-scale genomic studies suggest that pHGG has alterations in DNA damage response (DDR) pathways that induce resistance to DNA damaging agents. The aim of this study was to evaluate the therapeutic potential and molecular consequences of combining radiation with selective DDR inhibition in pHGG. METHODS: We conducted an unbiased screen in pHGG cells that combined radiation with clinical candidates targeting the DDR and identified the ATM inhibitor AZD1390. Subsequently, we profiled AZD1390 + radiation in an extensive panel of early passage pHGG cell lines, mechanistically characterized response to the combination in vitro in sensitive and resistant cells and evaluated the combination in vivo using TP53 wild-type and TP53 mutant orthotopic xenografts. RESULTS: AZD1390 significantly potentiated radiation across molecular subgroups of pHGG by increasing mutagenic nonhomologous end joining and augmenting genomic instability. In contrast to previous reports, ATM inhibition significantly improved the efficacy of radiation in both TP53 wild-type and TP53 mutant isogenic cell lines and distinct orthotopic xenograft models. Furthermore, we identified a novel mechanism of resistance to AZD1390 + radiation that was marked by an attenuated ATM pathway response which dampened sensitivity to ATM inhibition and induced synthetic lethality with ATR inhibition. CONCLUSIONS: Our study supports the clinical evaluation of AZD1390 in combination with radiation in pediatric patients with HGG.

Hypogonadism After Treatment for Medulloblastoma: Results From the SJMB03 Trial of Risk-Adapted Radiation Therapy.

PURPOSE: Our purpose was to estimate the cumulative incidence (CI) of hypogonadism in a cohort of pediatric patients treated for medulloblastoma with surgery, risk-adapted craniospinal irradiation, and dose-intensive chemotherapy. METHODS AND MATERIALS: Children and adolescents (n = 156) treated between 2003 and 2013 were evaluated for evidence of hypogonadism and infertility. Clinical information and mean radiation dose to the hypothalamus and gonads and cumulative doses of chemotherapy agents were recorded to estimate CI of hypogonadism and infertility with competing risks. RESULTS: The 5-year CI of hypogonadism was 71.25% (±6.76%) for women and 6.48% (±3.16%) for men (P < .0001) and 50.00% (±9.70%) for puberty age and 28.99% (±5.05%) for prepuberty age at treatment (P = .0068). The 5-year CI by gonadal radiation dose exposure (GRDE) was 61.11% (±12.13%) for high (>2 Gy), 61.18% (±12.92%) for intermediate (1-2 Gy), and 21.97% (±4.76%) for low (<1 Gy) (P < .0001). Sex, puberty status, GRDE, interval from treatment to puberty, and vincristine dose were associated with hypogonadism. Hypogonadism in female sex was highly correlated with GRDE, and dose to hypothalamus was significant when included in multivariable models or when used in models restricted to patients treated after the age of puberty. CI of infertility at 10 years was 55.36% (±14.07%) for women and 23.53% (±10.64%) for men (P = .0389) in a sample of 33 patients. CONCLUSIONS: In the setting of intensive chemotherapy, low-dose gonadal radiation exposure has a significant effect on gonadal function. Women and those achieving age of puberty at time of radiation therapy have a higher risk of hypogonadism. GRDE > 2 Gy was associated with hypogonadism for all groups and >1 Gy in prepubertal patients. Hypothalamus dose was significant when included in multivariable models that included postpubertal patients and those with lower GRDE.

Phase II study of alisertib as a single agent for treating recurrent or progressive atypical teratoid/rhabdoid tumor.

BACKGROUND: Recurrent atypical teratoid/rhabdoid tumor (AT/RT) is, most often, a fatal pediatric malignancy with limited curative options. METHODS: We conducted a phase II study of Aurora kinase A inhibitor alisertib in patients aged <22 years with recurrent AT/RT. Patients received alisertib once daily (80 mg/m2 as enteric-coated tablets or 60 mg/m2 as liquid formulation) on Days 1-7 of a 21-day cycle until progressive disease (PD) occurred. Alisertib plasma concentrations were measured in cycle 1 on Days 1 (single dose) and 7 (steady state) and analyzed with noncompartmental pharmacokinetics. Trial efficacy end point was ≥10 participants with stable disease (SD) or better at 12 weeks. RESULTS: SD (n = 8) and partial response (PR) (n = 1) were observed among 30 evaluable patients. Progression-free survival (PFS) was 30.0% ± 7.9% at 6 months and 13.3% ± 5.6% at 1 year. One-year overall survival (OS) was 36.7% ± 8.4%. Two patients continued treatment for >12 months. PFS did not differ by AT/RT molecular groups. Neutropenia was the most common adverse effect (n = 23/30, 77%). The 22 patients who received liquid formulation had a higher mean maximum concentration (Cmax) of 10.1 ± 3.0 µM and faster time to Cmax (Tmax = 1.2 ± 0.7 h) than those who received tablets (Cmax = 5.7 ± 2.4 µM, Tmax = 3.4 ± 1.4 h). CONCLUSIONS: Although the study did not meet predetermined efficacy end point, single-agent alisertib was well tolerated by children with recurrent AT/RT, and SD or PR was observed in approximately a third of the patients.

Endocrinopathy After Treatment for Medulloblastoma: Results From the SJMB03 Trial of Risk-Adapted Radiation Therapy.

PURPOSE: The objective of this study was to estimate the cumulative incidence of endocrinopathy in pediatric patients treated for medulloblastoma with surgery, risk-adapted photon craniospinal irradiation, and dose-intensive chemotherapy. METHODS AND MATERIALS: Children and adolescents (n = 156) treated between 2003 and 2013 were evaluated for evidence of endocrinopathy. Clinical information and mean radiation dose to hypothalamus and thyroid were calculated and used to estimate cumulative incidence of growth hormone deficiency, hypothyroidism, adrenal insufficiency, hypogonadism, and precocious puberty. RESULTS: The 5-year cumulative incidences were estimated for growth hormone deficiency, 68.9% (60.9%, 75.6%); hypothyroidism, 48.4% (95% confidence interval (CI), 40.2%-56.1%); adrenal insufficiency, 13.0% (95% CI, 8.3%-18.9%); hypogonadism, 33.9% (95% CI, 25.2%-42.7%); and precocious puberty, 2.0% (95% CI, 0.6%-5.4%). Growth hormone deficiency was associated with increased hypothalamus dose (hazard ratio [HR], 1.035; 95% CI, 1.010-1.061; P = .0055) in average-risk patients and cerebrospinal fluid shunt (HR, 2.532; 95% CI, 1.325-4.838; P = .0049) in high-risk patients. In average-risk patients, hypothyroidism was associated with younger age (HR, 0.902; 95% CI, 0.842-0.973; P = .0070), hypothalamus dose (HR, 1.039; 95% CI, 1.004-1.075; P = .0273), and thyroid dose (HR, 1.070; 95% CI, 1.008-1.136; P = .0263). In high-risk patients, hypothyroidism was associated with increased hypothalamus dose (HR, 1.068; 95% CI, 0.995-1.147; P = .0671) and thyroid dose (HR, 1.050; 95% CI, 1.000-1.104; P = .0515). Adrenal insufficiency was associated with increased hypothalamus dose (HR, 1.112; 95% CI, 1.058-1.170; P < .0001). Growth hormone deficiency incidence was higher when comparing patients treated with cerebrospinal fluid shunt versus those not having a shunt/extraventricular drain placed during initial surgery (HR, 1.712; 95% CI, 1.109-2.643). CONCLUSIONS: Incidence and time to onset of clinically significant endocrinopathy after photon craniospinal irradiation for pediatric medulloblastoma is influenced by radiation dose to target organs and patient age at time of treatment. Advanced radiation therapy methods and dose-reduction strategies are needed to reduce the incidence of endocrinopathy.

A high-dimensional mediation model for a neuroimaging mediator: Integrating clinical, neuroimaging, and neurocognitive data to mitigate late effects in pediatric cancer.

Pediatric cancer treatment, especially for brain tumors, can have profound and complicated late effects. With the survival rates increasing because of improved detection and treatment, a more comprehensive understanding of the impact of current treatments on neurocognitive function and brain structure is critically needed. A frontline medulloblastoma clinical trial (SJMB03) has collected data, including treatment, clinical, neuroimaging, and cognitive variables. Advanced methods for modeling and integrating these data are critically needed to understand the mediation pathway from the treatment through brain structure to neurocognitive outcomes. We propose an integrative Bayesian mediation analysis approach to model jointly a treatment exposure, a high-dimensional structural neuroimaging mediator, and a neurocognitive outcome and to uncover the mediation pathway. The high-dimensional imaging-related coefficients are modeled via a binary Ising-Gaussian Markov random field prior (BI-GMRF), addressing the sparsity, spatial dependency, and smoothness and increasing the power to detect brain regions with mediation effects. Numerical simulations demonstrate the estimation accuracy, power, and robustness. For the SJMB03 study, the BI-GMRF method has identified white matter microstructure that is damaged by cancer-directed treatment and impacts late neurocognitive outcomes. The results provide guidance on improving treatment planning to minimize long-term cognitive sequela for pediatric brain tumor patients.

Unified rhombic lip origins of group 3 and group 4 medulloblastoma.

Medulloblastoma, a malignant childhood cerebellar tumour, segregates molecularly into biologically distinct subgroups, suggesting that a personalized approach to therapy would be beneficial1. Mouse modelling and cross-species genomics have provided increasing evidence of discrete, subgroup-specific developmental origins2. However, the anatomical and cellular complexity of developing human tissues3-particularly within the rhombic lip germinal zone, which produces all glutamatergic neuronal lineages before internalization into the cerebellar nodulus-makes it difficult to validate previous inferences that were derived from studies in mice. Here we use multi-omics to resolve the origins of medulloblastoma subgroups in the developing human cerebellum. Molecular signatures encoded within a human rhombic-lip-derived lineage trajectory aligned with photoreceptor and unipolar brush cell expression profiles that are maintained in group 3 and group 4 medulloblastoma, suggesting a convergent basis. A systematic diagnostic-imaging review of a prospective institutional cohort localized the putative anatomical origins of group 3 and group 4 tumours to the nodulus. Our results connect the molecular and phenotypic features of clinically challenging medulloblastoma subgroups to their unified beginnings in the rhombic lip in the early stages of human development.

Molecular classification and outcome of children with rare CNS embryonal tumors: results from St. Jude Children's Research Hospital including the multi-center SJYC07 and SJMB03 clinical trials.

Methylation profiling has radically transformed our understanding of tumors previously called central nervous system primitive neuro-ectodermal tumors (CNS-PNET). While this marks a momentous step toward defining key differences, reclassification has thrown treatment into disarray. To shed light on response to therapy and guide clinical decision-making, we report outcomes and molecular features of children with CNS-PNETs from two multi-center risk-adapted studies (SJMB03 for patients ≥ 3 years; SJYC07 for patients < 3 years) complemented by a non-protocol institutional cohort. Seventy patients who had a histological diagnosis of CNS-PNET or CNS embryonal tumor from one of the new categories that has supplanted CNS-PNET were included. This cohort was molecularly characterized by DNA methylation profiling (n = 70), whole-exome sequencing (n = 53), RNA sequencing (n = 20), and germline sequencing (n = 28). Clinical characteristics were detailed, and treatment was divided into craniospinal irradiation (CSI)-containing (SJMB03 and SJMB03-like) and CSI-sparing therapy (SJYC07 and SJYC07-like). When the cohort was analyzed in its entirety, no differences were observed in the 5-year survival rates even when CSI-containing therapy was compared to CSI-sparing therapy. However, when analyzed by DNA methylation molecular grouping, significant survival differences were observed, and treatment particulars provided suggestions of therapeutic response. Patients with CNS neuroblastoma with FOXR2 activation (CNS-NB-FOXR2) had a 5-year event-free survival (EFS)/overall survival (OS) of 66.7% ± 19.2%/83.3% ± 15.2%, and CIC rearranged sarcoma (CNS-SARC-CIC) had a 5-year EFS/OS both of 57.1% ± 18.7% with most receiving regimens that contained radiation (focal or CSI) and multidrug chemotherapy. Patients with high-grade neuroepithelial tumor with BCOR alteration (HGNET-BCOR) had abysmal responses to upfront chemotherapy-only regimens (5-year EFS = 0%), but survival extended with salvage radiation after progression [5-year OS = 53.6% ± 20.1%]. Patients with embryonal tumor with multilayered rosettes (ETMR) or high-grade glioma/glioblastoma multiforme (HGG/GBM) did not respond favorably to any modality (5-year EFS/OS = 10.7 ± 5.8%/17.9 ± 7.2%, and 10% ± 9.0%/10% ± 9.0%, respectively). As an accompaniment, we have assembled this data onto an interactive website to allow users to probe and query the cases. By reporting on a carefully matched clinical and molecular cohort, we provide the needed insight for future clinical management.

Pediatric pineoblastoma: A pooled outcome study of North American and Australian therapeutic data.

Background: Pineoblastoma is a rare brain tumor usually diagnosed in children. Given its rarity, no pineoblastoma-specific trials have been conducted. Studies have included pineoblastoma accruing for other embryonal tumors over the past 30 years. These included only occasional children with pineoblastoma, making clinical features difficult to interpret and determinants of outcome difficult to ascertain. Patients and Methods: Centrally or independently reviewed series with treatment and survival data from North American and Australian cases were pooled. To investigate associations between variables, Fisher's exact tests, Wilcoxon-Mann-Whitney tests, and Spearman correlations were used. Kaplan-Meier plots, log-rank tests, and Cox proportional hazards models were used in survival analyses. Results: We describe a pooled cohort of 178 pineoblastoma cases from Children's Oncology Group (n = 82) and institutional series (n = 96) over 30 years. Children <3 years of age have significantly worse survival compared to older children, with 5-year progression-free survival (PFS) and overall survival (OS) estimates of 13.5 ± 5.1% and 16.2 ± 5.3%, respectively, compared with 60.8 ± 5.6% and 67.3 ± 5.0% for ≥3 years old (both P < .0001). Multivariable analysis showed male sex was associated with worse PFS in children <3 years of age (hazard ratio [HR] 3.93, 95% CI 1.80-8.55; P = .0006), suggestive of sex-specific risks needing future validation. For children ≥3 years of age, disseminated disease at diagnosis was significantly associated with an inferior 5-year PFS of 39.2 ± 9.7% (HR 2.88, 95% CI 1.52-5.45; P = .0012) and 5-year OS of 49.8 ± 9.1% (HR 2.87, 95% CI 1.49-5.53; P = .0016). Conclusion: Given the rarity of this tumor, prospective, collaborative international studies will be vital to improving the long-term survival of these patients.