Metabolic Regulation of the Epigenome Drives Lethal Infantile Ependymoma.

Posterior fossa A (PFA) ependymomas are lethal malignancies of the hindbrain in infants and toddlers. Lacking highly recurrent somatic mutations, PFA ependymomas are proposed to be epigenetically driven tumors for which model systems are lacking. Here we demonstrate that PFA ependymomas are maintained under hypoxia, associated with restricted availability of specific metabolites to diminish histone methylation, and increase histone demethylation and acetylation at histone 3 lysine 27 (H3K27). PFA ependymomas initiate from a cell lineage in the first trimester of human development that resides in restricted oxygen. Unlike other ependymomas, transient exposure of PFA cells to ambient oxygen induces irreversible cellular toxicity. PFA tumors exhibit a low basal level of H3K27me3, and, paradoxically, inhibition of H3K27 methylation specifically disrupts PFA tumor growth. Targeting metabolism and/or the epigenome presents a unique opportunity for rational therapy for infants with PFA ependymoma.

Neurosurgical Operative Cancellations in Canada: A Multicentre Retrospective Cohort Study.

INTRODUCTION: Operative cancellations adversely affect patient health and impose resource strain on the healthcare system. Here, our objective was to describe neurosurgical cancellations at five Canadian academic institutions. METHODS: The Canadian Neurosurgery Research Collaborative performed a retrospective cohort study capturing neurosurgical procedure cancellation data at five Canadian academic centres, during the period between January 1, 2014 and December 31, 2018. Demographics, procedure type, reason for cancellation, admission status and case acuity were collected. Cancellation rates were compared on the basis of demographic data, procedural data and between centres. RESULTS: Overall, 7,734 cancellations were captured across five sites. Mean age of the aggregate cohort was 57.1 ± 17.2 years. The overall procedure cancellation rate was 18.2%. The five-year neurosurgical operative cancellation rate differed between Centre 1 and 2 (Centre 1: 25.9%; Centre 2: 13.0%, p = 0.008). Female patients less frequently experienced procedural cancellation. Elective, outpatient and spine procedures were more often cancelled. Reasons for cancellation included surgeon-related factors (28.2%), cancellation for a higher acuity case (23.9%), patient condition (17.2%), other factors (17.0%), resource availability (7.0%), operating room running late (6.4%) and anaesthesia-related (0.3%). When clustered, the reason for cancellation was patient-related in 17.2%, staffing-related in 28.5% and operational or resource-related in 54.3% of cases. CONCLUSIONS: Neurosurgical operative cancellations were common and most often related to operational or resource-related factors. Elective, outpatient and spine procedures were more often cancelled. These findings highlight areas for optimizing efficiency and targeted quality improvement initiatives.

A Systematic Review of the Role of Gender in Securing and Maintaining Employment Among Youth and Young Adults with Disabilities.

Purpose There is a critical need for gender-specific vocational supports for young adults with disabilities as they transition to employment. We conducted a systematic review to explore the role of gender in securing and maintaining employment. Methods Systematic searches of seven databases identified 48 studies meeting our inclusion criteria. Using a narrative synthesis approach, these studies were analyzed in terms of the characteristics of the participants, methodology, results, and quality of the evidence. Results Among the 48 studies, 112,473 participants (56% male), mean age (of the total sample) was 21, represented across ten countries. Twenty-one studies reported that young men with disabilities had better employment outcomes than women with disabilities. Eight studies showed that females with disabilities had better employment outcomes than males. Five studies reported that there were no gender differences in employment outcomes for youth with various disabilities. With regards to maintaining employment, men with disabilities often work more hours and have better wages compared to women with disabilities. There are several gender-related barriers and facilitators to maintaining employment including social supports and gender role expectations. Conclusions Our findings highlight that there is a critical need for gender-specific vocational supports for young adults with disabilities.

Combination treatment with histone deacetylase and carbonic anhydrase 9 inhibitors shows therapeutic potential in experimental diffuse intrinsic pontine glioma.

Diffuse intrinsic pontine glioma (DIPG) remains a significant therapeutic challenge due to the lack of effective and safe treatment options. This study explores the potential of combining histone deacetylase (HDAC) and carbonic anhydrase 9 (CA9) inhibitors in treating DIPG. Analysis of RNA sequencing data and tumor tissue from patient samples for the expression of the carbonic anhydrase family and hypoxia signaling pathway activity revealed clinical relevance for targeting CA9 in DIPG. A synergy screen was conducted using CA9 inhibitor SLC-0111 and HDAC inhibitors panobinostat, vorinostat, entinostat, and pyroxamide. The combination of SLC-0111 and pyroxamide demonstrated the highest synergy and was selected for further analysis. Combining SLC-0111 and pyroxamide effectively inhibited DIPG cell proliferation, reduced cell migration and invasion potential, and enhanced histone acetylation, leading to decreased cell population in S Phase. Additionally, the combination therapy induced a greater reduction in intracellular pH than either agent alone. Data from this study suggest that the combination of SLC-0111 and pyroxamide holds promise for treating experimental DIPG, and further investigation of this combination therapy in preclinical models is warranted to evaluate its potential as a viable treatment for DIPG.

Global and local interference effects in ensemble encoding are best explained by interactions between summary representations of the mean and the range.

Through ensemble encoding, the visual system compresses redundant statistical properties from multiple items into a single summary metric (e.g., average size). Numerous studies have shown that global summary information is extracted quickly, does not require access to single-item representations, and often interferes with reports of single items from the set. Yet a thorough understanding of ensemble processing would benefit from a more extensive investigation at the local level. Thus, the purpose of this study was to provide a more critical inspection of global-local processing in ensemble perception. Taking inspiration from Navon (Cognitive Psychology, 9(3), 353-383, 1977), we employed a novel paradigm that independently manipulates the degree of interference at the global (mean) or local (single item) level of the ensemble. Initial results were consistent with reciprocal interference between global and local ensemble processing. However, further testing revealed that local interference effects were better explained by interference from another summary statistic, the range of the set. Furthermore, participants were unable to disambiguate single items from the ensemble display from other items that were within the ensemble range but, critically, were not actually present in the ensemble. Thus, it appears that local item values are likely inferred based on their relationship to higher-order summary statistics such as the range and the mean. These results conflict with claims that local information is captured alongside global information in summary representations. In such studies, successful identification of set members was not compared with misidentification of items within the range, but which were nevertheless not presented within the set.

Diffuse intrinsic pontine glioma: current insights and future directions.

Diffuse intrinsic pontine glioma (DIPG) is a lethal pediatric brain tumor and the leading cause of brain tumor-related death in children. As several clinical trials over the past few decades have led to no significant improvements in outcome, the current standard of care remains fractionated focal radiation. Due to the recent increase in stereotactic biopsies, tumor tissue availabilities have enabled our advancement of the genomic and molecular characterization of this lethal cancer. Several groups have identified key histone gene mutations, genetic drivers, and methylation changes in DIPG, providing us with new insights into DIPG tumorigenesis. Subsequently, there has been increased development of in vitro and in vivo models of DIPG which have the capacity to unveil novel therapies and strategies for drug delivery. This review outlines the clinical characteristics, genetic landscape, models, and current treatments and hopes to shed light on novel therapeutic avenues and challenges that remain.

MRI-guided focused ultrasound enhances drug delivery in experimental diffuse intrinsic pontine glioma.

Diffuse intrinsic pontine glioma (DIPG) is a surgically unresectable and devasting tumour in children. To date, there are no effective chemotherapeutics despite a myriad of clinical trials. The intact blood-brain barrier (BBB) is likely responsible for the limited clinical response to chemotherapy. MRI-guided focused ultrasound (MRgFUS) is a promising non-invasive method for treating CNS tumours. Moreover, MRgFUS allows for the temporary and repeated disruption of the BBB. Our group previously reported the feasibility of temporary BBB opening within the normal murine brainstem using MRgFUS following intravenous (IV) administration of microbubbles. In the current study, we set out to test the effectiveness of targeted chemotherapy when paired with MRgFUS in murine models of DIPG. Doxorubicin was selected from a drug screen consisting of conventional chemotherapeutics tested on patient-derived cell lines. We studied the RCAS/Tv-a model where RCAS-Cre, RCAS-PDGFB, and RCAS-H3.3K27M were used to drive tumourigenesis upon injection in the pons. We also used orthotopically injected SU-DIPG-6 and SU-DIPG-17 xenografts which demonstrated a diffusely infiltrative tumour growth pattern similar to human DIPG. In our study, SU-DIPG-17 xenografts were more representative of human DIPG with an intact BBB. Following IV administration of doxorubicin, MRgFUS-treated animals exhibited a 4-fold higher concentration of drug within the SU-DIPG-17 brainstem tumours compared to controls. Moreover, the volumetric tumour growth rate was significantly suppressed in MRgFUS-treated animals whose tumours also exhibited decreased Ki-67 expression. Herein, we provide evidence for the ability of MRgFUS to enhance drug delivery in a mouse model of DIPG. These data provide critical support for clinical trials investigating MRgFUS-mediated BBB opening, which may ameliorate DIPG chemotherapeutic approaches in children.

Epigenetic activation of a RAS/MYC axis in H3.3K27M-driven cancer.

Histone H3 lysine 27 (H3K27M) mutations represent the canonical oncohistone, occurring frequently in midline gliomas but also identified in haematopoietic malignancies and carcinomas. H3K27M functions, at least in part, through widespread changes in H3K27 trimethylation but its role in tumour initiation remains obscure. To address this, we created a transgenic mouse expressing H3.3K27M in diverse progenitor cell populations. H3.3K27M expression drives tumorigenesis in multiple tissues, which is further enhanced by Trp53 deletion. We find that H3.3K27M epigenetically activates a transcriptome, enriched for PRC2 and SOX10 targets, that overrides developmental and tissue specificity and is conserved between H3.3K27M-mutant mouse and human tumours. A key feature of the H3K27M transcriptome is activation of a RAS/MYC axis, which we find can be targeted therapeutically in isogenic and primary DIPG cell lines with H3.3K27M mutations, providing an explanation for the common co-occurrence of alterations in these pathways in human H3.3K27M-driven cancer. Taken together, these results show how H3.3K27M-driven transcriptome remodelling promotes tumorigenesis and will be critical for targeting cancers with these mutations.

Locoregional delivery of CAR T cells to the cerebrospinal fluid for treatment of metastatic medulloblastoma and ependymoma.

Recurrent medulloblastoma and ependymoma are universally lethal, with no approved targeted therapies and few candidates presently under clinical evaluation. Nearly all recurrent medulloblastomas and posterior fossa group A (PFA) ependymomas are located adjacent to and bathed by the cerebrospinal fluid, presenting an opportunity for locoregional therapy, bypassing the blood-brain barrier. We identify three cell-surface targets, EPHA2, HER2 and interleukin 13 receptor α2, expressed on medulloblastomas and ependymomas, but not expressed in the normal developing brain. We validate intrathecal delivery of EPHA2, HER2 and interleukin 13 receptor α2 chimeric antigen receptor T cells as an effective treatment for primary, metastatic and recurrent group 3 medulloblastoma and PFA ependymoma xenografts in mouse models. Finally, we demonstrate that administration of these chimeric antigen receptor T cells into the cerebrospinal fluid, alone or in combination with azacytidine, is a highly effective therapy for multiple metastatic mouse models of group 3 medulloblastoma and PFA ependymoma, thereby providing a rationale for clinical trials of these approaches in humans.

Gender matters in the transition to employment for young adults with physical disabilities.

PURPOSE: The purpose of this study was to explore the role of gender in the transition to employment for young adults with physical disabilities. METHODS: This study drew on in-depth interviews with a purposive sample of 33 participants (23 youth and 10 clinicians). The youth in our sample included 13 females (mean age 22.9) and 10 males (mean age 21.3) who had various types of physical disabilities. The person-environment-occupation (PEO) model informed our analysis. RESULTS: Our research showed several similarities and some differences between young males and females with physical disabilities as they transition to employment and adulthood at the person, environment, and occupational level. At the person level, issues included managing their condition, self-advocacy, and willingness to ask for help. At the environment level, themes focused on parental and social support, accommodations, stigma and discrimination, and transportation challenges. Finally, in the occupation component of the PEO model, we found that males and females with disabilities had different levels of engagement in employment. Although most clinicians commented on gender differences, many reported that they did not tailor their clinical practice accordingly. CONCLUSIONS: Gender sensitive vocational approaches are needed for youth with disabilities as they transition to employment. Implications for rehabilitation Clinicians, educators, and parents should encourage independence and self-advocacy skills among youth so that they are prepared to ask for accommodations that they need to succeed in a work environment. Clinicians and educators should present a variety of career and job options to youth, including science, technology, engineering, and math disciplines, an area where youth with disabilities, particularly females, are under-represented. Males may feel less able to self-advocate and seek support and may need additional assistance from clinicians, educators, and parents. Clinicians should tailor their vocational rehabilitation practices to the gender-specific needs of youth with disabilities. Clinicians and parents should ensure that both males and females have the resources and supports they need to be successful in their transition to employment.

A systematic review of post-secondary transition interventions for youth with disabilities.

Purpose: Youth with disabilities have lower rates of enrollment and completion of post-secondary education compared with youth without disabilities. The objective of this systematic review is to understand the best practices and components of post-secondary transition programs for youth with disabilities. Method: Systematic searches of six international databases identified 18 studies meeting our inclusion criteria (youth with a disability, aged 15-30; focusing on post-secondary education program or intervention, published from 1997 to 2017). These studies were analyzed with respect to the characteristics of the participants, methodology, results, and quality of the evidence. Results: Among the 18 studies, 2385 participants (aged 13-28, mean 17.7 years) were represented across three countries (US, Canada, and Australia). Although the outcomes of the post-secondary transition programs varied across the studies, all of them reported an improvement in at least one of the following: college enrollment, self-determination, self-confidence, social and vocational self-efficacy, autonomy, social support, career exploration, and transition skills. The post-secondary transition programs varied in duration, length, number of sessions, and delivery format which included curriculum-based, online, immersive residential experience, mentoring, simulation, self-directed, technology-based, and multi-component. Conclusions: Our findings highlight that post-secondary transition programs have the potential to improve self-determination, transition skills, and post-secondary outcomes among youth with disabilities. Implications for rehabilitation Post-secondary education interventions have a beneficial influence on post-secondary and related transition outcomes in youth with disabilities. Clinicians and educators should consider having multiple components, involving several sessions that include a curriculum, immersive college residential experience, mentoring, and/or simulations in their interventions for optimum program outcomes. More research is needed to explore the types of interventions that work best for whom and the optimal age (including exploring the socio-demographic characteristics), setting, and delivery format.

Cone beam CT for perioperative imaging in hearing preservation Cochlear implantation - a human cadaveric study.

BACKGROUND: Knowledge of the cochlear implant array's precise position is important because of the correlation between electrode position and speech understanding. Several groups have provided recent image processing evidence to determine scalar translocation, angular insertion depth, and cochlear duct length (CDL); all of which are being used for patient-specific programming. Cone beam computed tomography (CBCT) is increasingly used in otology due to its superior resolution and low radiation dose. Our objectives are as followed: 1.Validate CBCT by measuring cochlear metrics, including basal turn diameter (A-value) and lateral wall cochlear duct length at different angular intervals and comparing it against microcomputed CT (uCT).2.Explore the relationship between measured lateral wall cochlear duct length at different angular intervals and insertion depth among 3 different length electrodes using CBCT. METHODS: The study was performed using fixed human cadaveric temporal bones in a tertiary academic centre. Ten temporal bones were subjected to the standard facial recess approach for cochlear implantation and imaged by CBCT followed by uCT. Measurements were performed on a three-dimensional reconstructed model of the cochlea. Sequential insertion of 3 electrodes (Med-El Flex24, 28 and Soft) was then performed in 5 bones and reimaged by CBCT. Statistical analysis was performed using Pearson's correlation. RESULTS: There was good agreement between CBCT and uCT for cochlear metrics, validating the precision of CBCT against the current gold standard uCT in imaging. The A-value recorded by both modalities showed a high degree of linear correlation and did not differ by more than 0.23 mm in absolute values. For the measurement of lateral wall CDL at various points along the cochlea, there was a good correlation between both modalities at 360 deg and 720 deg (r = 0.85, p < 0.01 and r = 0.79, p < 0.01). The Flex24 electrode displayed consistent insertion depth across different bones. CONCLUSIONS: CBCT reliably performs cochlear metrics and measures electrode insertion depth. The low radiation dose, fast acquisition time, diminished metallic artifacts and portability of CBCT make it a valid option for imaging in cochlear implant surgery.