Current immunotherapeutic approaches to diffuse intrinsic pontine glioma

Diffuse intrinsic pontine glioma (DIPG) is an aggressive brain tumour that occurs in the pons of the brainstem and accounts for over 80% of all brainstem gliomas. The median age at diagnosis is 6–7 years old, with less than 10% overall survival 2 years after diagnosis and less than 1% after 5 years. DIPGs are surgically inaccessible, and radiation therapy provides only transient benefit, with death ensuing from relentless local tumour infiltration. DIPGs are now the leading cause of brain tumour deaths in children, with a societal cancer burden in years of life lost (YLL) of more than 67 per individual, versus approximately 14 and 16 YLL for lung and breast cancer respectively. More than 95 clinical drug trials have been conducted on children with DIPGs, and all have failed to improve survival. No single or combination chemotherapeutic strategy has been successful to date because of our inability to identify targeted drugs for this disease and to deliver these drugs across an intact blood-brain barrier (BBB). Accordingly, there has been an increased focus on immunotherapy research in DIPG, with explorations into treatments such as chimeric antigen receptor T (CAR-T) cells, immune checkpoint blockades, cancer vaccines, and autologous cell transfer therapy. Here, we review the most recent advances in identifying genetic factors influencing the development of immunotherapy for DIPG. Additionally, we explore emerging technologies such as Magnetic Resonance-guided Focused Ultrasound (MRgFUS) in potential combinatorial approaches to treat DIPG

Antigen p57/Kip2 as a potential negative regulator of human astrocytoma growth

This study was performed to determine the relationship between p57/Kip2 and the growth of human astrocytomas. Immunohistochemical staining for p57/Kip2, p53, p16, and Ki67 antigen was performed on paraffin-embedded tissue specimens obtained from 36 patients with astrocytoma. Expression of p57/Kip2, p53, p16, and Ki67 antigen was generally increased in association with the astrocytoma tumor grade. Expression of p16 was higher in patients whose tumors express p57/Kip2 in greater than 10% of tumor cells (p < 0.05). Expression of p53 also tended to be higher, but not to a statistically significant extent, in patients whose tumors express p57/Kip2 in greater than 10% of tumor cells. These findings suggest that p57/Kip2 inhibits the growth of human astrocytomas, and may function in parallel with p16 and p53. However, p57/Kip2 is, by itself, insufficient to arrest the cellular proliferation of human astrocytomas.ArticleJOURNAL OF CLINICAL NEUROSCIENCE. 16(12):1615-1618 (2009)journal articl

The use of high frequency oscillations to guide neocortical resections in children with medically-intractable epilepsy: How do we ethically apply surgical innovations to patient care?

AbstractPurposeResective surgical strategies are increasingly applied to treat medically-intractable epilepsy in children as uncontrolled seizures are associated with poor cognitive, developmental and behavioral outcomes. Innovative surgical strategies are, however, needed to improve outcomes and minimize the morbidity of such procedures.MethodThe current article utilizes an axiological approach to explore and highlight ethical issues in the use of high frequency oscillations (HFOs) to guide surgical resections in children with medically-intractable epilepsy. We frame our discussion in the context of the broader challenges in the application of surgical innovation to patient care.ResultsDespite a paucity of knowledge regarding their pathogenesis, limited evidence suggests the use of HFOs as biomarkers of epileptogenicity in resective procedures can improve seizure outcome. Clinicians must therefore weigh deficiencies in knowledge against the limited evidence supporting the utility of HFOs and make ethical decisions for the treatment of individual patients. Important ethical considerations for clinicians include the extent of deviation from established practice, the extent of evidence required to establish clinical validity, and the impact of technique implementation on equitable distribution of healthcare.ConclusionThe use of HFO signatures to guide neocortical resections represents a novel approach for the treatment of epilepsy. It is hoped that the issues discussed herein will contribute to and advance meaningful dialog on the ethical application of this surgical innovation to the treatment of a very vulnerable patient population

Predictors of seizure outcomes in children with tuberous sclerosis complex and intractable epilepsy undergoing resective epilepsy surgery: an individual participant data meta-analysis.

ObjectiveTo perform a systematic review and individual participant data meta-analysis to identify preoperative factors associated with a good seizure outcome in children with Tuberous Sclerosis Complex undergoing resective epilepsy surgery.Data sourcesElectronic databases (MEDLINE, EMBASE, CINAHL and Web of Science), archives of major epilepsy and neurosurgery meetings, and bibliographies of relevant articles, with no language or date restrictions.Study selectionWe included case-control or cohort studies of consecutive participants undergoing resective epilepsy surgery that reported seizure outcomes. We performed title and abstract and full text screening independently and in duplicate. We resolved disagreements through discussion.Data extractionOne author performed data extraction which was verified by a second author using predefined data fields including study quality assessment using a risk of bias instrument we developed. We recorded all preoperative factors that may plausibly predict seizure outcomes.Data synthesisTo identify predictors of a good seizure outcome (i.e. Engel Class I or II) we used logistic regression adjusting for length of follow-up for each preoperative variable.ResultsOf 9863 citations, 20 articles reporting on 181 participants were eligible. Good seizure outcomes were observed in 126 (69%) participants (Engel Class I: 102(56%); Engel class II: 24(13%)). In univariable analyses, absence of generalized seizure semiology (OR = 3.1, 95%CI = 1.2-8.2, p = 0.022), no or mild developmental delay (OR = 7.3, 95%CI = 2.1-24.7, p = 0.001), unifocal ictal scalp electroencephalographic (EEG) abnormality (OR = 3.2, 95%CI = 1.4-7.6, p = 0.008) and EEG/Magnetic resonance imaging concordance (OR = 4.9, 95%CI = 1.8-13.5, p = 0.002) were associated with a good postoperative seizure outcome.ConclusionsSmall retrospective cohort studies are inherently prone to bias, some of which are overcome using individual participant data. The best available evidence suggests four preoperative factors predictive of good seizure outcomes following resective epilepsy surgery. Large long-term prospective multicenter observational studies are required to further evaluate the risk factors identified in this review

Identification of alsterpaullone as a novel small molecule inhibitor to target group 3 medulloblastoma

© Impact Journals, LLC. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Advances in the molecular biology of medulloblastoma revealed four genetically and clinically distinct subgroups. Group 3 medulloblastomas are characterized by frequent amplifications of the oncogene MYC, a high incidence of metastasis, and poor prognosis despite aggressive therapy. We investigated several potential small molecule inhibitors to target Group 3 medulloblastomas based on gene expression data using an in silico drug screen. The Connectivity Map (C-MAP) analysis identified piperlongumine as the top candidate drug for non-WNT medulloblastomas and the cyclin-dependent kinase (CDK) inhibitor alsterpaullone as the compound predicted to have specific antitumor activity against Group 3 medulloblastomas. To validate our findings we used these inhibitors against established Group 3 medulloblastoma cell lines. The C-MAP predicted drugs reduced cell proliferation in vitro and increased survival in Group 3 medulloblastoma xenografts. Alsterpaullone had the highest efficacy in Group 3 medulloblastoma cells. Genomic profiling of Group 3 medulloblastoma cells treated with alsterpaullone confirmed inhibition of cell cycle-related genes, and down-regulation of MYC. Our results demonstrate the preclinical efficacy of using a targeted therapy approach for Group 3 medulloblastomas. Specifically, we provide rationale for advancing alsterpaullone as a targeted therapy in Group 3 medulloblastoma.This study was supported by the Canadian Cancer Society (Grant #2011-70051), the Pediatric Brain Tumor Foundation of the United States, the Brain Tumour Foundation of Canada, Meagan’s Walk, b.r.a.i.n.child and the Wiley Fund at the Hospital for Sick Children.info:eu-repo/semantics/publishedVersio

Rapid, reliable, and reproducible molecular sub-grouping of clinical medulloblastoma samples

The diagnosis of medulloblastoma likely encompasses several distinct entities, with recent evidence for the existence of at least four unique molecular subgroups that exhibit distinct genetic, transcriptional, demographic, and clinical features. Assignment of molecular subgroup through routine profiling of high-quality RNA on expression microarrays is likely impractical in the clinical setting. The planning and execution of medulloblastoma clinical trials that stratify by subgroup, or which are targeted to a specific subgroup requires technologies that can be economically, rapidly, reliably, and reproducibly applied to formalin-fixed paraffin embedded (FFPE) specimens. In the current study, we have developed an assay that accurately measures the expression level of 22 medulloblastoma subgroup-specific signature genes (CodeSet) using nanoString nCounter Technology. Comparison of the nanoString assay with Affymetrix expression array data on a training series of 101 medulloblastomas of known subgroup demonstrated a high concordance (Pearson correlation r = 0.86). The assay was validated on a second set of 130 non-overlapping medulloblastomas of known subgroup, correctly assigning 98% (127/130) of tumors to the appropriate subgroup. Reproducibility was demonstrated by repeating the assay in three independent laboratories in Canada, the United States, and Switzerland. Finally, the nanoString assay could confidently predict subgroup in 88% of recent FFPE cases, of which 100% had accurate subgroup assignment. We present an assay based on nanoString technology that is capable of rapidly, reliably, and reproducibly assigning clinical FFPE medulloblastoma samples to their molecular subgroup, and which is highly suited for future medulloblastoma clinical trials

Delineation of Two Clinically and Molecularly Distinct Subgroups of Posterior Fossa Ependymoma

Despite the histological similarity of ependymomas from throughout the neuroaxis, the disease likely comprises multiple independent entities, each with a distinct molecular pathogenesis. Transcriptional profiling of two large independent cohorts of ependymoma reveals the existence of two demographically, transcriptionally, genetically, and clinically distinct groups of posterior fossa (PF) ependymomas. Group A patients are younger, have laterally located tumors with a balanced genome, and are much more likely to exhibit recurrence, metastasis at recurrence, and death compared with Group B patients. Identification and optimization of immunohistochemical (IHC) markers for PF ependymoma subgroups allowed validation of our findings on a third independent cohort, using a human ependymoma tissue microarray, and provides a tool for prospective prognostication and stratification of PF ependymoma patients