Brain tumors are the leading cause of cancer-related death in children. For the past several decades, therapeutic strategies have centered on cytotoxic chemotherapy and radiation therapy due, in ...part, to limited understanding of genetic events that underlie tumor initiation and maintenance. Significant improvement in high-throughput genomic methods, such as next-generation sequencing, methylation array, and copy number array, in recent years has propelled the knowledge base from which novel therapies are derived. Translation of recent genomic findings into more effective therapies remains the most formidable challenge in improving the outcome for children with brain tumors.
Purpose
Amplification and high levels of NOTCH ligand expression have been identified in several types of pediatric brain tumors. A phase I trial of weekly MK-0752, an oral inhibitor of ...gamma-secretase, was conducted in children with recurrent central nervous system (CNS) malignancies to estimate the maximum tolerated dose, dose-limiting toxicities (DLT), pharmacokinetics (PK), and pharmacodynamics of weekly MK-0752.
Methods
MK-0752 was administered once weekly at 1000 and 1400 mg/m
2
using a rolling-6 design. PK analysis was performed during the first course. NOTCH and HES expression was assessed by immunohistochemistry and Western blot.
Results
Ten eligible patients were enrolled (median age 8.8 years; range 3.1–19.2) with diagnoses of brain stem glioma (
n
= 3), ependymoma (
n
= 2), anaplastic astrocytoma (
n
= 1), choroid plexus carcinoma (
n
= 2), medulloblastoma (
n
= 1), and primitive neuroectodermal tumor (
n
= 1). Nine were evaluable for toxicity. One DLT of fatigue occurred in the six evaluable patients enrolled at 1000 mg/m
2
/dose. No DLTs were experienced by three patients treated at 1400 mg/m
2
/dose. Non-dose-limiting grade 3 toxicities included lymphopenia, neutropenia, and anemia. Median number of treatment courses was 2 (range 1–10). Two patients continued on therapy for at least 6 months. The median (range) C
max
of MK-0752 was 88.2 μg/mL (40.6 to 109 μg/mL) and 60.3 μg/mL (59.2 to 91.9 μg/mL) in patients receiving 1000 and 1400 mg/m
2
/week, respectively. NOTCH expression was decreased in six of seven patients for whom tissue was available at 24 h post-MK-0752.
Conclusion
MK-0752 is well tolerated and exhibits target inhibition at 1000 and 1400 mg/m
2
/week in children with recurrent CNS malignancies.
Diffuse intrinsic pontine glioma (DIPG), a rare, often fatal childhood brain tumor, remains a major therapeutic challenge. In 2012, investigators, funded by the DIPG Collaborative (a philanthropic ...partnership among 29 private foundations), launched the International DIPG Registry (IDIPGR) to advance understanding of DIPG. Comprised of comprehensive deidentified but linked clinical, imaging, histopathological, and genomic repositories, the IDIPGR uses standardized case report forms for uniform data collection; serial imaging and histopathology are centrally reviewed by IDIPGR neuro-radiologists and neuro-pathologists, respectively. Tissue and genomic data, and cell cultures derived from autopsies coordinated by the IDIPGR are available to investigators for studies approved by the Scientific Advisory Committee. From April 2012 to December 2016, 670 patients diagnosed with DIPG have been enrolled from 55 participating institutions in the US, Canada, Australia and New Zealand. The radiology repository contains 3558 studies from 448 patients. The pathology repository contains tissue on 81 patients with another 98 samples available for submission. Fresh DIPG tissue from seven autopsies has been sent to investigators to develop primary cell cultures. The bioinformatics repository contains next-generation sequencing data on 66 tumors. Nine projects using data/tissue from the IDIPGR by 13 principle investigators from around the world are now underway. The IDIPGR, a successful alliance among philanthropic agencies and investigators, has developed and maintained a highly collaborative, hypothesis-driven research infrastructure for interdisciplinary and translational projects in DIPG to improve diagnosis, response assessment, treatment and outcome for patients.
We aimed to perform external validation of the recently developed survival prediction model for diffuse intrinsic pontine glioma (DIPG), and discuss its utility. The DIPG survival prediction model ...was developed in a cohort of patients from the Netherlands, United Kingdom and Germany, registered in the SIOPE DIPG Registry, and includes age <3 years, longer symptom duration and receipt of chemotherapy as favorable predictors, and presence of ring-enhancement on MRI as unfavorable predictor. Model performance was evaluated by analyzing the discrimination and calibration abilities. External validation was performed using an unselected cohort from the International DIPG Registry, including patients from United States, Canada, Australia and New Zealand. Basic comparison with the results of the original study was performed using descriptive statistics, and univariate- and multivariable regression analyses in the validation cohort. External validation was assessed following a variety of analyses described previously. Baseline patient characteristics and results from the regression analyses were largely comparable. Kaplan–Meier curves of the validation cohort reproduced separated groups of standard (n = 39), intermediate (n = 125), and high-risk (n = 78) patients. This discriminative ability was confirmed by similar values for the hazard ratios across these risk groups. The calibration curve in the validation cohort showed a symmetric underestimation of the predicted survival probabilities. In this external validation study, we demonstrate that the DIPG survival prediction model has acceptable cross-cohort calibration and is able to discriminate patients with short, average, and increased survival. We discuss how this clinico-radiological model may serve a useful role in current clinical practice.
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 nonmetastatic BGTGs, the 5‐ and 10‐year event‐free survivals (EFS) were 85.8% and 81.0%, respectively, while the 5‐ and 10‐year overall survivals (OS) were 100% and 95.5%, respectively (one patient fatality from unrelated cause). Median RT doses were as follows: CSI: 2250 cGy/cGy(RBE) (1980–2400); WBI: 2340 cGy/cGy(RBE) (1800–3000); WVI: 2340 cGy/cGy(RBE) (1800–2550); focal: 3600 cGy (3060–5400). Thirty‐eight patients (90.5%) received chemotherapy. There was no statistically significant difference in the EFS based on initial field extent (p = .84). Nevertheless, no relapses were reported in patients who received CSI or WBI. Chemotherapy alone had significantly inferior EFS compared to combined therapy (p = .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.
Inflammation has been identified as a hallmark of high-risk Group A (GpA) ependymoma (EPN). Chronic interleukin (IL)-6 secretion from GpA tumors drives an immune suppressive phenotype by polarizing ...infiltrating monocytes. This study determines the mechanism by which IL-6 is dysregulated in GpA EPN.
Twenty pediatric GpA and 21 pediatric Group B (GpB) EPN had gene set enrichment analysis for MSigDB Hallmark gene sets performed. Protein and RNA from patients and cell lines were used to validate transcriptomic findings. GpA cell lines 811 and 928 were used for in vitro experiments performed in this study.
The nuclear factor-kappaB (NF-κB) pathway is a master regulator of IL-6 and a signaling pathway enriched in GpA compared with GpB EPN. Knockdown of NF-κB led to significant downregulation of IL-6 in 811 and 928. NF-κB activation was independent of tumor necrosis factor alpha (TNF-α) stimulation in both cell lines, suggesting that NF-κB hyperactivation is mediated through an alternative mechanism. Leucine zipper downregulated in cancer 1 (LDOC1) is a known transcriptional repressor of NF-κB. In many cancers, LDOC1 promoter is methylated, which inhibits gene transcription. We found decreased LDOC1 gene expression in GpA compared with GpB EPN, and in other pediatric brain tumors. EPN cells treated with 5AZA-DC, demethylated LDOC1 regulatory regions, upregulated LDOC1 expression, and concomitantly decreased IL-6 secretion. Stable knockdown of LDOC1 in EPN cell lines resulted in a significant increase in gene transcription of v-rel avian reticuloendotheliosis viral oncogene homolog A, which correlated to an increase in NF-κB target genes.
These results suggest that epigenetic silencing of LDOC1 in GpA EPN regulates tumor biology and drives inflammatory immune phenotype.
The number of targeted therapies utilized in precision medicine are rapidly increasing. Neuro-oncology offers a unique challenge due to the varying blood brain barrier (BBB) penetration of each ...agent. Neuro-oncologists face a difficult task weighing the growing number of potential targeted therapies and their likelihood of BBB penetration. We developed the CNS TAP Working Group and performed an extensive literature review for the evidence-based creation of the CNS TAP tool, which was retrospectively validated by analyzing brain tumor patients who underwent therapy targeted based on genomic results from an academic sequencing study (MiOncoseq, n = 17) or private molecular profiling (Foundation One, n = 7). The CNS TAP tool scores relevant targeted agents by applying multiple variables (i.e., pre-clinical data, clinical data, BBB permeability) to patient specific genomic information and clinical trial availability. In the Michigan cohort, the CNS TAP tool predicted the selected agent 85.7% of the time. The CNS TAP tool predicted the agent independently selected by pediatric neuro-oncologists in the Colorado cohort 50% of the time. Patients with recurrent brain tumors treated with agents predicted by the CNS TAP tool demonstrated a median progression-free survival of 4 months and four patients with recurrent high-grade glioma maintained ongoing partial responses of at least 6 months. The CNS TAP tool is a formalized algorithm to assist clinicians select the optimal targeted therapy for neuro-oncology patients. The CNS TAP tool has relatively high concordance with selected therapies and clinical outcomes in patients receiving targeted therapy in this heterogeneous retrospective cohort were promising.
The goal of the present study was to determine whether the release of exosomes containing MYOC from trabecular meshwork (TM) cells is constitutive or regulated.
Conditioned media from TM cells were ...analyzed for MYOC-associated exosomes after treatment with IFN-gamma, porcine aqueous humor, dexamethasone, or a calcium ionophore in cells pretreated with dexamethasone. Aqueous humor was tested whole or fractionated by size exclusion filters. Exosomes from conditioned media were purified by differential centrifugation. Proteins in whole, exosome, and soluble fractions were separated by SDS-PAGE and analyzed for MYOC content by Western blot and densitometry.
Although treatment of TM cells with IFN-gamma increased the appearance of extracellular MYOC-associated exosomes, results were not significantly different from those of control (P = 0.13). In contrast, treatment with dexamethasone increased the appearance of MYOC in the exosome fraction by 376% (P < 0.01). The increase in MYOC-associated exosomes caused by dexamethasone was enhanced by an additional 379% after short-term exposure to ionomycin (P < 0.05). When cultured in media containing aqueous humor, MYOC-associated exosomes increased 514% over control (P < 0.01). Such an increase was diminished in cells treated with aqueous humor that was first passed through a 3-kDa or a 30-kDa, but not a 100-kDa, size exclusion filter.
The appearance of MYOC-associated exosomes in conditioned media from human TM cells is regulated by a corticosteroid, a calcium ionophore, and a component of aqueous humor, suggesting that TM cells respond to environmental cues by releasing MYOC-associated exosomes.
Abstract
Background
Embryonal tumor with multilayer rosettes (ETMR) is a rare CNS malignancy affecting young children that carries a very poor prognosis. Treatment with intensive surgical resection, ...radiotherapy, and high-dose chemotherapy is insufficient treatment in the vast majority of cases. Effective, biologically based therapies for this tumor are therefore desperately needed. The Dana-Farber Cancer Institute–modified IRS-III protocol incorporates preclinically active agents, such as doxorubicin and actinomycin D, into the treatment regimen for ETMR and may improve patient outcomes.
Methods
The authors present a case series of 5 children with ETMR treated with an IRS-III-based chemotherapy backbone.
Results
All 5 patients received a gross-total tumor resection. Patients received between 12 and 51 weeks of IRS-III therapy at the discretion of their treating physician. Four patients received focal radiation therapy, with the fifth patient instead receiving a cycle of high-dose chemotherapy with autologous stem cell rescue. Four patients have progression-free survival of more than 18 months. Chemotherapy treatment was reasonably tolerated by all 5 patients with one case of mild sinusoidal obstructive syndrome and one case of Grade 3 peripheral neuropathy.
Conclusions
The patient outcomes in this small cohort are far better than would be expected based on the historical survival for this tumor. Given the tremendous need for effective therapy for ETMR, further investigation of this approach is warranted. An international consensus protocol based on the IRS-III regimen has been developed and will be available through a multicenter clinical trial and a global treatment registry.