Citations

Background: Access to high-quality airway equipment is critical for effective otolaryngological and emergency care. In sub-Saharan Africa (SSA), challenges in the procurement infrastructure may hinder equipment availability, impacting patient outcomes. Given the paucity of literature investigating equipment procurement in SSA, this study aims to map out the multilevel barriers to procurement of airway equipment in SSA to inform opportunities for improvement. Methods: A qualitative study design was employed using semi-structured interviews and open-ended survey responses. Participants included otolaryngologists in SSA, manufacturing company representatives and international policymakers, selected through purposive sampling to ensure representation of various roles in the procurement process. Six interviews, one focus group and six survey responses with regional healthcare providers (n = 13), manufacturing representatives (n = 3) and international policymakers (n = 2) explored supply chain dynamics, regulatory challenges, manufacturing capabilities, financial constraints and policy frameworks. Data were analysed using thematic analysis to identify recurrent themes and interrelationships. Results: Systemic barriers exist in the procurement process, including fragmented supply chains, inconsistent regulatory enforcement, limited local manufacturing capacity and insufficient funding mechanisms. Otolaryngologists emphasised frequent delays in equipment availability, while manufacturers reported logistical challenges and regulatory hurdles. Policymakers noted gaps in infrastructure and regional coordination. Emerging themes suggest opportunities for streamlining procurement processes, fostering local production and enhancing collaboration to improve supply chain efficiency. Conclusion: This study underscores the multifaceted challenges in airway equipment procurement in SSA and highlights the need for integrated approaches involving stakeholders across the supply chain. Contribution: Findings provide actionable insights to inform policy development and capacity-building initiatives with the goal of enhancing access to life-saving airway equipment and improving healthcare outcomes.

Background Individuals with intellectual and developmental disabilities experience substantial disparities across the cancer care continuum, including delayed diagnosis, limited access to supportive resources, and heightened psychosocial distress. These challenges are intensified in high-acuity settings where care models are not adapted to their developmental and cognitive needs. Methods We describe an interdisciplinary, patient-centered approach to the care of a 34-year-old patient with developmental delay and metastatic adenocarcinoma. Key strategies emphasized education, preparation, and communication tailored to her cognitive abilities. Collaboration with her family informed effective strategies to reduce distress and improve compliance. Results Tailored interventions – including simplified communication, visual supports, and continuity of providers – improved the patient’s coping, reduced distress, and enabled completion of comprehensive oncologic evaluation and treatment. Conclusions This case demonstrates that structured, interdisciplinary, patient-centered approaches to care can mitigate disparities and support equitable, compassionate care for individuals with intellectual and developmental disabilities facing serious illness.

Abstract Purpose/Objective(s) To report outcomes for disseminated Medulloblastoma (stage M1-M3) who received radiation (RT) on the Pediatric Proton/Photon Consortium Registry (PPCR). Materials/Methods 71 patients were included with either M1 (6), M2 (21), or M3 (44) Medulloblastoma on PPCR. Survival (OS, Overall; EFS, Event Free) analyses were performed using the Kaplan Meier method and log rank p-values from RT start. Median follow up was calculated using the reverse Kaplan Meier method. Results Median age at RT was 7.5 years (range 2.4-21.89) and the median follow up was 4.3 years. Histology was classic (52), diffuse anaplasia (12), focal anaplasia (5), desmoplastic nodular (1), or other (1). Treatment included surgery, chemotherapy with or without stem cell support, and RT. 54 patients had gross total resection (GTR) or near total resection (NTR); 14 had subtotal resection (STR). Pre-RT chemotherapy was given in 69 (97.1%) patients; 23 had myeloablative chemotherapy with stem cell support. The 5 and 10-year OS of the entire cohort were 73% and 65%, and 5 and 10-year EFS were 65% and 59%. Patients with progression prior to RT (10 patients) had inferior OS (5-year OS 44%) compared to patients without progression pre-RT (5-year OS 78%, p = 0.045). There was a trend for better OS (p = 0.07) and improved EFS (p = 0.043) for M2 stage. GTR/NTR did not impact OS (p = 0.75) or EFS (p = 0.97) compared to STR. Craniospinal (CSI) radiation (70 patients, 99%) doses were: £ 23.4Gy (11.4%), 23.5Gy-36Gy (11.4%), or ³ 36Gy (74.3%). Patients receiving CSI ³ 36Gy had superior OS (p = 0.043), with 5 and 10-year OS of 82% and 71% compared to 5 and 10-year OS of 52% and 52% for lower dose CSI. Conclusion Full dose CSI (36Gy) for M1-M3 medulloblastoma was associated with excellent long-term survival this series, whereas lower dose CSI and progression prior to RT had inferior outcomes.

Abstract Medulloblastoma (MB) is one of the most prevalent malignant brain tumors in children, with tremendous cognitive and neuroendocrine disability among survivors. Group 3 (G3) MBs have poor overall survival at < 50%, higher frequency of metastasis, and no targeted therapies. Amplification of MYC and activation of TGFβ signaling are frequent in G3MB. Remarkably, some tumors have no reported mutations, suggesting roles for epigenetic mechanisms in driving disease. We have generated novel humanized models for G3MB by transducing neuroepithelial stem cells (NESC) derived from human induced pluripotent stem (iPSC) cells with TGFβ effectors alone and/or in combination with MYC, prioritizing combinations observed in patients. We determined that both MYC and TGFβ effectors drove tumor formation in vivo with the combination driving more aggressive tumors and higher frequency of metastasis. NESC-derived tumors clustered with human G3/G4MB, indicating our models recapitulated human disease. To decipher mechanisms of resistance, we integrated CUT&RUN for MYC genomic localization and histone PTMs with RNA-sequencing and discovered MYC-bound neural developmental genes repressed in MYC and TGFβR1-driven lines. Further interrogation identified JARID1B, a MYC binding partner, as a regulator of many of these repressed neural genes. We postulate that deregulation of MYC and context-specific targeting to the chromatin template culminates in transcriptional alterations that promote aggressive G3MB. To further investigating therapeutic vulnerabilities, we have performed a in vivo whole genome CRISPRi screen to reveal important drivers of malignancy, one of the first of it’s kind in brain tumors. We are functionally validating key candidate sgRNAs that were differentially significant in primary tumors and may also have key roles in driving metastasis. Excitingly, many sgRNAs identified from the screen were chromatin modifiers and may be important co-factors of MYC-mediated regulation on the epigenome. Collectively, our studies provide a critical framework for understanding mechanisms of resistance and the epigenetic landscape of MYC- and TGFβ-driven MB.

Abstract Diffuse leptomeningeal glioneuronal tumors (DLGNT) are rare central nervous system tumors. Our understanding of the clinical course, prognostic factors, and optimal treatment strategies remains limited. Histologic, molecular, and clinical data were collected and analyzed for 25 patients with DLGNT reviewed at St. Jude Children’s Research Hospital. The median age at diagnosis was 6 years (11 months-20 years). Nineteen (72%) patients were male. The disease was localized at diagnosis in 12 (48.0%) patients, with most tumors localized in the spinal cord. BRAF fusion was present in 22 (95.6%) of 23 patients who had material for testing. Of 18 patients who had tissue for DNA methylation profiling, 3 (16.7%) matched to DLGNT MC-1, 3 (16.7%) to DLGNT MC-2, and 12 (66.7%) did not match to a DLGNT subclass. Median follow-up was 63 months. Twenty-four (96.0%) patients received adjuvant therapy after initial diagnosis or at progression. Thirty-five cytotoxic chemotherapy and 24 single-agent targeted therapy regimens were used in 22 and 13 patients, respectively. With targeted therapy, 3 (12%) patients had partial responses. Eleven (44.0%) received radiotherapy. Median progression-free survival (PFS) after a patient’s first chemotherapy, targeted therapy, or radiotherapy regimen was 44 months (1-77), 11 months (4-39), and 16.5 months (9-23), respectively. The 5-year PFS was 18.7%±9.2, while the 5-year overall survival (OS) was 82.4%±9.2. The 5-year OS was lower in patients older than 9 years at diagnosis (60.0%±21.9 vs 91.7%±8.0, p = 0.02). Ki67 >4% was associated with worse PFS (0%±0 vs 24.6%±11.9 at 5 years, p = 0.03). Initial disease dissemination (localized vs. disseminated) and 1q gain status do not influence PFS or OS. PFS for DLGNT remains poor across all treatment modalities, including targeted therapies, despite the high frequency of BRAF fusions. Due to its rarity, establishing optimal therapeutic strategies for DLGNT requires additional treatment and outcome data and prospective multi-institutional trials.

Abstract One of the most significant unmet clinical challenges in paediatric oncology is the development of novel therapeutic strategies for recurrent medulloblastoma (R-MB). MYC-driven MBs are defined as classically cold tumours with a low incidence of infiltrating immune cells, resulting in a therapeutic challenge. The identification of cell-cell interactions between tumour and immune cells may provide insight into critical intercellular communications and manipulations occurring within the tumour immune microenvironment (TME). We hypothesised that the key cell-cell interactions in MYC-driven primary and recurrent MB may reveal dominant immune-suppressive mechanisms and uncover targetable therapeutic vulnerabilities. Paired primary-recurrent bulk RNA-sequencing data, confirmed myeloid cells as the most infiltrating immune cell type in group3-MB and group4-MB. Comprehensive spatial phenotypic and cell-cell communication analyses corroborated this discovery, validating an increased incidence of macrophages in the matched-recurrent tumours. Subsequently, we used innovative algorithms for 10X MB single-cell data to predict interactions between tumour-cell ligands and immune-cell receptors within the TME; macrophages emerged as the core immune-cells involved in interactions throughout the TMEs, with the most significant ligand-receptor interaction and inflammatory response between MIF and CD74. In-depth immunohistochemistry analyses of primary and recurrent group3 and group4 tumours, and exhaustive tissue microarrays demonstrated expression of both CD74 and MIF, with limited expression of CD74 within the brain. To investigate the therapeutic potential of CD74, we developed recurrent, immune competent MYC-driven medulloblastoma mouse models. Comprehensive deconvolution analysis confirmed the TME integrity of our models to mirror that of the human disease. Locoregional delivery and repeat dosing of a bioactive-CD74 peptide demonstrated complete tumour clearance in our immune-competent mouse models of primary and recurrent MB, demonstrating the significant therapeutic potential of targeting the CD74-MIF axis in MYC-driven primary and recurrent MB. Key cellular interactions and therapeutic vulnerabilities within the tumour microenvironment of MYC-driven medulloblastoma (MB) have been identified, highlighting the CD74-MIF axis as a target for next-generation immunotherapies.

Abstract EZHIP (EZH inhibitory protein) is a cancer-testis antigen (CTA) typically restricted to germline cells, where it inhibits Polycomb repressive complex 2 (PRC2)-mediated deposition of the repressive histone mark H3K27me3. Its aberrant expression in H3K27M mutation-negative diffuse midline gliomas (DMGs) and ependymomas leads to PRC2 inhibition and widespread epigenomic dysregulation. H3K27M-mutant gliomas are similarly characterized by global loss of H3K27me3 due to inhibition of PRC2 by the oncohistone H3K27M, positioning EZHIP as a functional epigenetic mimetic of this mutation.To explore its role in tumorigenesis, we overexpressed EZHIP in the H3K27 wild-type DMG cell lines that lack H3K27M mutations. EZHIP overexpression resulted in a significant reduction in H3K27me3 levels, indicating PRC2 inhibition. In a Nestin-TVA mouse model of DMG, the introduction of EZHIP into neural stem cells via the RCAS-EZHIP-P2A-PDGFβ vector led to the development of aggressive, high-grade diffuse gliomas. The tumorigenic potential of EZHIP was further supported by Western blot analysis of EZHIP-expressing neural stem cells, which revealed increased expression of stem cell markers, including Nanog, GFAP, and Nestin, consistent with a stem-like transcriptional state. RNA and ATAC sequencing of EZHIP-overexpressing DMG cell lines, compared to their isogenic wild-type counterparts, revealed a substantial increase in the number of upregulated genes typically repressed by PRC2, indicating widespread transcriptional activation associated with PRC2 inhibition. Comparative transcriptional analysis further showed that EZHIP-induced gene expression changes more closely resembled those in PRC2 knockout cells rather than in cells harboring the H3K27M mutation. Together, these findings highlight the complex role of EZHIP in disrupting PRC2-mediated gene silencing, promoting gliomagenesis, and altering the epigenomic landscape. While EZHIP and H3K27M mutations share some mechanistic similarities in inhibiting PRC2, key differences in their downstream effects suggest distinct contributions to tumor development. These findings advance our understanding of EZHIP-driven gliomas and reveal potential therapeutic vulnerabilities that could inform future treatments.

Abstract Background Hydrocephalus, the abnormal buildup of cerebrospinal fluid (CSF) in the brain’s ventricles, makes pediatric neurosurgery difficult. Endoscopic Third Ventriculostomy (ETV) and Ventriculoperitoneal Shunting (VPS) are the basic treatments, however unsuccessful ETV management is disputed. This study aims to compare RE-ETV with VPS in pediatric hydrocephalus patients after unsuccessful ETV. Methods A comprehensive literature review was performed using PubMed, Embase, and Cochrane Library. The review covered pediatric RE-ETV or VPS trials following ETV failure. Success rates, complications, failure timings, and reoperation rates were extracted. The Cochrane Collaboration’s risk of bias instrument (RoB 2.0) and Critical Appraisal Skills Programme (CASP) were utilized to assess quality of studies. Results 40 articles were chosen for comprehensive full-text evaluation. Nine publications specifically addressing the topic of Re-ETV and/or VPS placement after the failure of original ETV were identified as acceptable for the review. A data set of 663 patients was assessed. Re-ETV was carried out in 220 patients (33.18%) and VPS Placement was done in 443 patients (66.81%). The primary ETV failure rates ranged from 16.6% to 60.89%. There was a larger failure rate of Re-ETV (74.98%) compared to VPS (22.26%) showing that VPS is often more effective as a secondary intervention. The presence of bleeding during primary ETV suggested more benefit from VPS placement rather than Re-ETV (p < 0.05). Conclusions VPS is more commonly employed than RE-ETV in pediatric patients after unsuccessful ETV. Although RE-ETV provides a less invasive technique, it has a greater failure rate. However, owing to inadequate evidence on VPS failure post-ETV, additional research is recommended. Future research should concentrate on enhancing the evidence foundation to aid clinical decision-making in treating hydrocephalus post-ETV failure.