A multi-institutional pediatric dataset of clinical radiology MRIs by the Children's Brain Tumor Network.

Pediatric brain and spinal cancers remain the leading cause of cancer-related death in children. Advancements in clinical decision-support in pediatric neuro-oncology utilizing the wealth of radiology imaging data collected through standard care, however, has significantly lagged other domains. Such data is ripe for use with predictive analytics such as artificial intelligence (AI) methods, which require large datasets. To address this unmet need, we provide a multi-institutional, large-scale pediatric dataset of 23,101 multi-parametric MRI exams acquired through routine care for 1,526 brain tumor patients, as part of the Children's Brain Tumor Network. This includes longitudinal MRIs across various cancer diagnoses, with associated patient-level clinical information, digital pathology slides, as well as tissue genotype and omics data. To facilitate downstream analysis, treatment-naïve images for 370 subjects were processed and released through the NCI Childhood Cancer Data Initiative via the Cancer Data Service. Through ongoing efforts to continuously build these imaging repositories, our aim is to accelerate discovery and translational AI models with real-world data, to ultimately empower precision medicine for children.

A phase 1/2 dose-finding, safety, and activity study of cabazitaxel in pediatric patients with refractory solid tumors including tumors of the central nervous system.

BACKGROUND: This phase 1/2 study (NCT01751308) evaluated cabazitaxel in pediatric patients. Phase 1 determined the maximum tolerated dose (MTD) in patients with recurrent/refractory solid tumors, including central nervous system (CNS) tumors. Phase 2 evaluated activity in pediatric recurrent high-grade glioma (HGG) or diffuse intrinsic pontine glioma (DIPG). PROCEDURE: In phase 1, a 3 + 3 dose-escalation study design was followed. Cabazitaxel was administered at a starting dose of 20 mg/m2 . Dose-limiting toxicities (DLTs) during cycle 1 were assessed to determine the MTD. Tumor response and cabazitaxel pharmacokinetics were also assessed. In phase 2, patients received cabazitaxel at the MTD determined in phase 1. Tumor responses were assessed every 9 weeks (modified Response Assessment in Neuro-oncology criteria). Progression-free survival and cabazitaxel pharmacokinetics were evaluated, and overall survival was estimated. RESULTS: In phase 1, 23 patients were treated, including 19 with CNS tumors. One patient had a partial response; five had stable disease for >3 cycles. Common adverse events included fatigue, diarrhea, nausea and vomiting, febrile neutropenia, and hypersensitivity reactions. Two of three DLTs (febrile neutropenia) occurred with a dose of 35 mg/m2 ; the MTD was 30 mg/m2 . Slightly higher cabazitaxel clearance was observed compared with adult trials. In phase 2, 16 patients (eight HGG and eight DIPG) were enrolled; 11 were evaluable for response and five withdrew (three due to anaphylaxis). All 11 patients progressed within four cycles. No responses were observed; the study was stopped due to futility. CONCLUSIONS: The safety profile of cabazitaxel was consistent with previous studies. The MTD (30 mg/m2 ) was higher than the adult MTD. Cabazitaxel did not demonstrate activity in recurrent/refractory HGG or DIPG.

A pediatric trial of radiation/cetuximab followed by irinotecan/cetuximab in newly diagnosed diffuse pontine gliomas and high-grade astrocytomas: A Pediatric Oncology Experimental Therapeutics Investigators' Consortium study.

BACKGROUND: Diffuse intrinsic pontine gliomas (DIPGs) and high-grade astrocytomas (HGA) continue to have dismal prognoses. The combination of cetuximab and irinotecan was demonstrated to be safe and tolerable in a previous pediatric phase 1 combination study. We developed this phase 2 trial to investigate the safety and efficacy of cetuximab given with radiation therapy followed by adjuvant cetuximab and irinotecan. METHODS: Eligible patients of age 3-21 years had newly diagnosed DIPG or HGA. Patients received radiation therapy (5,940 cGy) with concurrent cetuximab. Following radiation, patients received cetuximab weekly and irinotecan daily for 5 days per week for 2 weeks every 21 days for 30 weeks. Correlative studies were performed. The regimen was considered to be promising if the number of patients with 1-year progression-free survival (PFS) for DIPG and HGA was at least six of 25 and 14 of 26, respectively. RESULTS: Forty-five evaluable patients were enrolled (25 DIPG and 20 HGA). Six patients with DIPG and five with HGA were progression free at 1 year from the start of therapy with 1-year PFS of 29.6% and 18%, respectively. Fatigue, gastrointestinal complaints, electrolyte abnormalities, and rash were the most common adverse events and generally of grade 1 and 2. Increased epidermal growth factor receptor copy number but no K-ras mutations were identified in available samples. CONCLUSIONS: The trial did not meet the predetermined endpoint to deem this regimen successful for HGA. While the trial met the predetermined endpoint for DIPG, overall survival was not markedly improved from historical controls, therefore does not merit further study in this population.

Functional Subclone Profiling for Prediction of Treatment-Induced Intratumor Population Shifts and Discovery of Rational Drug Combinations in Human Glioblastoma.

PURPOSE: Investigation of clonal heterogeneity may be key to understanding mechanisms of therapeutic failure in human cancer. However, little is known on the consequences of therapeutic intervention on the clonal composition of solid tumors. EXPERIMENTAL DESIGN: Here, we used 33 single cell-derived subclones generated from five clinical glioblastoma specimens for exploring intra- and interindividual spectra of drug resistance profiles in vitro In a personalized setting, we explored whether differences in pharmacologic sensitivity among subclones could be employed to predict drug-dependent changes to the clonal composition of tumors. RESULTS: Subclones from individual tumors exhibited a remarkable heterogeneity of drug resistance to a library of potential antiglioblastoma compounds. A more comprehensive intratumoral analysis revealed that stable genetic and phenotypic characteristics of coexisting subclones could be correlated with distinct drug sensitivity profiles. The data obtained from differential drug response analysis could be employed to predict clonal population shifts within the naïve parental tumor in vitro and in orthotopic xenografts. Furthermore, the value of pharmacologic profiles could be shown for establishing rational strategies for individualized secondary lines of treatment. CONCLUSIONS: Our data provide a previously unrecognized strategy for revealing functional consequences of intratumor heterogeneity by enabling predictive modeling of treatment-related subclone dynamics in human glioblastoma. Clin Cancer Res; 23(2); 562-74. ©2016 AACR.

C11orf95-RELA fusions drive oncogenic NF-κB signalling in ependymoma.

Members of the nuclear factor-κB (NF-κB) family of transcriptional regulators are central mediators of the cellular inflammatory response. Although constitutive NF-κB signalling is present in most human tumours, mutations in pathway members are rare, complicating efforts to understand and block aberrant NF-κB activity in cancer. Here we show that more than two-thirds of supratentorial ependymomas contain oncogenic fusions between RELA, the principal effector of canonical NF-κB signalling, and an uncharacterized gene, C11orf95. In each case, C11orf95-RELA fusions resulted from chromothripsis involving chromosome 11q13.1. C11orf95-RELA fusion proteins translocated spontaneously to the nucleus to activate NF-κB target genes, and rapidly transformed neural stem cells--the cell of origin of ependymoma--to form these tumours in mice. Our data identify a highly recurrent genetic alteration of RELA in human cancer, and the C11orf95-RELA fusion protein as a potential therapeutic target in supratentorial ependymoma.

Pediatric brainstem gangliogliomas show BRAF(V600E) mutation in a high percentage of cases.

Brainstem gangliogliomas (GGs), often cannot be resected, have a much poorer prognosis than those located in more common supratentorial sites and may benefit from novel therapeutic approaches. Therapeutically targetable BRAF c.1799T>A (p.V600E) (BRAF(V600E) ) mutations are harbored in roughly 50% of collective GGs taken from all anatomical sites. Large numbers of pediatric brainstem GGs, however, have not been specifically assessed and anatomic-and age-restricted assessment of genetic and biological factors are becoming increasingly important. Pediatric brainstem GGs (n = 13), non-brainstem GGs (n = 11) and brainstem pilocytic astrocytomas (PAs) (n = 8) were screened by standard Sanger DNA sequencing of BRAF exon 15. Five of 13 (38%) pediatric GG harbored a definitive BRAF(V600E) mutation, with two others exhibiting an equivocal result by this method. BRAF(V600E) was also seen in five of 11 (45%) non-brainstem GGs and one of eight (13%) brainstem PAs. VE1 immunostaining for BRAF(V600E) showed concordance with sequencing in nine of nine brainstem GGs including the two cases equivocal by Sanger. The equivocal brainstem GGs were subsequently shown to harbor BRAF(V600E) using a novel, more sensitive, RNA-sequencing approach, yielding a final BRAF(V600E) mutation frequency of 54% (seven of 13) in brainstem GGs. BRAF(V600E) -targeted therapeutics should be a consideration for the high percentage of pediatric brainstem GGs refractory to conventional therapies.

Chondroitin sulfate proteoglycans potently inhibit invasion and serve as a central organizer of the brain tumor microenvironment.

Glioblastoma (GBM) remains the most pervasive and lethal of all brain malignancies. One factor that contributes to this poor prognosis is the highly invasive character of the tumor. GBM is characterized by microscopic infiltration of tumor cells throughout the brain, whereas non-neural metastases, as well as select lower grade gliomas, develop as self-contained and clearly delineated lesions. Illustrated by rodent xenograft tumor models as well as pathological human patient specimens, we present evidence that one fundamental switch between these two distinct pathologies--invasion and noninvasion--is mediated through the tumor extracellular matrix. Specifically, noninvasive lesions are associated with a rich matrix containing substantial amounts of glycosylated chondroitin sulfate proteoglycans (CSPGs), whereas glycosylated CSPGs are essentially absent from diffusely infiltrating tumors. CSPGs, acting as central organizers of the tumor microenvironment, dramatically influence resident reactive astrocytes, inducing their exodus from the tumor mass and the resultant encapsulation of noninvasive lesions. Additionally, CSPGs induce activation of tumor-associated microglia. We demonstrate that the astrogliotic capsule can directly inhibit tumor invasion, and its absence from GBM presents an environment favorable to diffuse infiltration. We also identify the leukocyte common antigen-related phosphatase receptor (PTPRF) as a putative intermediary between extracellular glycosylated CSPGs and noninvasive tumor cells. In all, we present CSPGs as critical regulators of brain tumor histopathology and help to clarify the role of the tumor microenvironment in brain tumor invasion.

Second tumors in pediatric patients treated with radiotherapy to the central nervous system.

OBJECTIVE: To determine the rate of second tumors in pediatric patients treated with radiotherapy to the central nervous system (CNS) with long-term follow-up. METHODS: We retrospectively reviewed the charts of 370 consecutive pediatric patients with solid tumors and leukemia treated at the University of Florida from 1963 to 2006 with curative CNS radiotherapy. The median age was 8.1 years (range, 0.2 to 19.0 y). One hundred seventy-two (47%), 79 (21%), and 119 (32%) patients received focal, whole-brain, and craniospinal irradiation, respectively. Variables analyzed for prognostic value included primary tumor histology, patient age at primary treatment, volume of tissue irradiated, dose to the tumor bed, treatment with chemotherapy, and location of the primary tumor. RESULTS: Eighteen second tumors were diagnosed in 16 patients. The actuarial incidences of second tumors were 3%, 8%, and 24% at 10, 20, and 30 years of follow-up, respectively. On univariate analysis, no single variable was found to be predictive of second tumor incidence. The most common second tumor after radiation for a primary solid CNS tumor was meningioma (63%), for which successful salvage was common (89%). Second gliomas were most common among patients treated for leukemia and were uniformly fatal. The most common cause of death among 5-year survivors was late relapse of their primary tumor. CONCLUSIONS: The risk of second tumors after CNS radiation is significant and does not plateau with long-term follow-up. Most second tumors after radiotherapy for solid CNS tumors are meningiomas that can be successfully salvaged.

Radiation-induced glioblastoma multiforme in children treated for medulloblastoma with characteristics of both medulloblastoma and glioblastoma multiforme.

Outcomes for average-risk medulloblastoma are excellent with 5-year event-free survival and overall survival>80%. Treatment failures include radiation-induced glioblastomas (RIG), which are often diagnosed solely on imaging. Recent studies suggest that RIGs differ from spontaneous glioblastoma multiforme (GBM), based on microarray gene-expression profiling. Retrospective review of children with average-risk medulloblastoma treated from 1996 to 2003 included 16 patients with 5 treatment failures. One died of disease progression, 1 died as a result of radiation necrosis, and 3 children died of pathology-confirmed GBM. Of these 3 GBMs, one was studied with electron microscopy, cytogenetics, and gene-expression microarray analysis. This tumor had focal medulloblastoma and similarity by gene-expression microarray with other RIGs. With both components in the recurrent tumor, we suggest it was in the process of transitioning from medulloblastoma to RIG, that is, "catching the tumor in the act." Some radiation-induced nervous system tumors may develop as a direct result of severe oncologic changes within the original tumor cells, with the tumor evolving into a different phenotypic tumor type. We recommend biopsy for tissue confirmation and genetic expression profile to shed light on the etiology of radiation-induced neoplasms.

Phase I and pharmacokinetic study of cetuximab and irinotecan in children with refractory solid tumors: a study of the pediatric oncology experimental therapeutic investigators' consortium.

PURPOSE: To determine the dose of cetuximab that can be safely combined with irinotecan for treatment of pediatric and adolescent patients with refractory solid tumors. PATIENTS AND METHODS: This open-label, phase I study enrolled patients ages 1 to 18 years with advanced refractory solid tumors, including tumors of the CNS. Patient cohorts by age group (children, ages 1 to 12 years; adolescents, ages 13 to 18 years) received escalating weekly doses of cetuximab (75, 150, 250 mg/m(2)) in a 3 + 3 design, plus irinotecan (16 or 20 mg/m(2)/d) for 5 days for 2 consecutive weeks every 21 days. The primary end points were establishing the maximum-tolerated dose (MTD), recommended phase II dose (RPIID), and pharmacokinetics of the combination. Preliminary safety and efficacy data were also collected. RESULTS: Twenty-seven children and 19 adolescents received a median of 7.1 and 6.0 weeks of cetuximab therapy, respectively. Cetuximab 250 mg/m(2) weekly plus irinotecan 16 mg/m(2)/d (pediatric) or 20 mg/m(2)/d (adolescent) have been established as the MTD/RPIID. Dose-limiting toxicities included diarrhea and neutropenia. Mild to moderate (grade 1 to 2) acneiform rash occurred in a majority of patients; no grade 3 to 4 rashes were observed. Cetuximab demonstrated dose-dependent clearance in both children and adolescents, similar to that in adults. There were two confirmed partial responses, both in patients with CNS tumors. Stable disease was achieved in 18 patients overall, including 10 patients with CNS tumors (38.5%). CONCLUSION: The cetuximab/irinotecan combination can be given safely to children and adolescents with cancer. Promising activity, particularly in CNS tumors, warrants phase II evaluation of this regimen.

Congenital craniopharyngioma and hypercalcemia induced by parathyroid hormone-related protein.

OBJECTIVE: To report a case of congenital craniopharyngioma and parathyroid hormone-related protein (PTHrP)-associated humoral hypercalcemia. METHODS: Details of this unusual case are reviewed, from detection of fetal hydrocephalus and a brain tumor, through cesarean delivery at 36 weeks of gestation, to subsequent laboratory studies, management, and confirmation of the diagnosis. RESULTS: Although PTHrP has been well documented as a cause of humoral hypercalcemia of malignancy (HHM) in adult patients with cancer, HHM is uncommon in children. In addition, HHM has rarely been ascribed to nonmalignant tumors. To the best of our knowledge, we report the first case of a neonate with congenital craniopharyngioma and refractory hypercalcemia (peak ionized calcium level of 1.92 mmol/L; normal, 1.05 to 1.3) attributed to an elevated PTHrP value of 8.6 pmol/L (normal, less than 4.7). Intact parathyroid hormone was appropriately undetectable (less than 10 pg/mL; normal, 15 to 65). Despite calcitonin treatment, the hypercalcemia persisted. Although pamidronate infusion stabilized the serum calcium level, the baby did not survive. CONCLUSION: The diagnosis of craniopharyngioma was confirmed at autopsy, and immunohistochemical studies substantiated that the craniopharyngioma produced PTHrP.

A new euglobulin clot lysis assay for global fibrinolysis.

Plasma fibrinolytic activity has been measured by the euglobulin clot lysis time (ELT) since the late 1950s. The euglobulin clot lysis assay (ECLA) method has been modified using a computerized kinetic spectrophotometric microtiter plate reader and measures optical density changes of recalcified euglobulin fraction of plasma samples over time. This method has been applied to normal healthy adults, children, pregnant women and newborn infants, which represent physiologic extremes of the ELT. The ECLA method adds measurements of maximum absorbance (Max Abs), area under the curve (AUC) and mean velocity to the standard clot lysis time. The resulting curves are unique to this method and have been analyzed and compared in order to establish normal ranges. Fibrinogen levels, plasminogen activator inhibitor-1 (PAI-1) antigen, PAI-1 activity and thrombin activatable fibrinolytic inhibitor (TAFI) antigen levels were measured in each individual of the four groups. Each protein measured within each study group except TAFI correlated with the lysis time, maximum absorbance and area under the curve. Considering all four groups together, PAI correlates most highly with lysis time, fibrinogen correlates the highest with Max Abs; fibrinogen and PAI-1 antigen have equally high correlations to AUC. Area under the curve is highly correlated with all coagulation parameters measured; the most significant contributor is fibrinogen. These observations are interesting, but at this time, it cannot be said that any of the test parameters are better than lysis time in distinguishing between these normal physiologic states.