Brown, Desmond

AbstractAbstract Background Central nervous system (CNS) tumors are a significant cause of morbidity and mortality in Sub-Saharan Africa (SSA). This project aimed to assess and map out the current neuro-oncology capacity in SSA, brain tumor registries, and biobanks. Methods This cross-sectional study utilized an online survey to gather data from healthcare professionals involved in CNS tumor care across SSA through the Society for Neuro-Oncology SSA (SNOSSA). The survey captured information on the availability of neuro-oncology practitioners, neuropathology, molecular diagnostics, cancer registries, and biobanking. Results A total of 145 respondents representing 70 healthcare institutions across 22 countries participated. Of the 70 institutions, specialties included neurosurgery (89%, 62/70), anatomic pathology (74%, 52/70), and medical oncology (71%, 50/70). For radiologic evaluation, 64% (45/70) of responding institutions reported having both CT and MRI. Access to molecular testing through immunohistochemistry or next-generation sequencing was available in 46% (32/70) of responding institutions. Multidisciplinary tumor boards were available for CNS cases in 86% (60/70) of responding institutions. Brain tumor-specific registries were available in 29% (20/70) of responding institutions, and 10% (7/70) maintained brain tumor biorepositories. Conclusion This study demonstrates that SSA has substantial potential in neuro-oncology care practice capacity and facilities. The most significant gaps were in neuropathology and molecular testing, which makes widespread implementation of the WHO 2021 diagnosis challenging. Understanding the prevalence of CNS tumor subtypes in SSA is difficult due to the low number of brain tumor registries and biobanks.

Abstract Background Brain tumors represent a significant global health challenge, with rising incidence and mortality impacting individuals worldwide and contributing to cancer-related morbidity and mortality. In Africa, this burden is exacerbated by limited access to advanced diagnostics, treatment options, and multidisciplinary care, compounded by the absence of standardized cancer registration and tumor biobanking. The introduction of molecular diagnostics, as outlined in the 2021 World Health Organization central nervous system (CNS) tumor classification, adds complexity to brain tumor management, particularly in regions with scarce resources. Methods To address these issues, the Brain Tumor Consortium for Africa (BTCA) was established in 2023, bringing together experts to improve CNS tumor diagnosis, patient care, and research. The initial project, conducted via an electronic questionnaire, aimed to assess neuro-oncology capacity across Sub-Saharan Africa. Results The study revealed significant gaps, with a limited number of institutions incorporating molecular subtyping into their diagnostic algorithms. The consortium’s efforts focus on enhancing local data use, informing public policy, and promoting collaboration to advance neuro-oncology practices in Africa. By fostering a network enlisting the expertise of collaborators in the fields of neurosurgery, neurology, neuropathology, anatomic pathology, and medical and radiation oncology, the BTCA seeks to improve brain tumor management through better diagnostics, infrastructure, and policy advocacy. Future directions include expanding molecular diagnostic capabilities, standardizing brain tumor biobanking, enhancing data collection, and advocating for improved brain tumor care in national health agendas. Conclusions The BTCA represents a pioneering model of collaboration and innovation in addressing the unique challenges of brain tumor care in Africa.

Abstract Brain tumors constitute significant morbidity and mortality in sub-Saharan Africa (SSA). There is no previous large-scale effort focusing on brain tumor genetics in SSA. This project aims to map out the current neuro-oncology capacity in terms of workforce and available services in SSA. This is an ongoing online survey among a cross section of neuro-oncology practitioners spread across SSA countries to capture information on the distribution, number of available neuro-oncology care practitioners, capacity for neuropathology and molecular diagnosis, management of brain tumors, cancer registration, and tumor biobanking. The survey was disseminated by the Society for Neuro-oncology in SSA (SNOSSA). There were 83 respondents representing 15 countries and 52 health institutions: 46 tertiary, 4 secondary, 1 private and 1 other. Here, we present data on the 52 institutions. The prevalence of specialties was 87% neurosurgery, 75% anatomic pathology, 69% medical oncology, 64% neurology, 60% radiation oncology, and 39% neuropathology. For radiologic evaluation, 81% of institutions were reported to have both CT and MRI, 17% CT only, and one institution neither. For molecular testing, 46% have access to IHC or NGS testing, whereas 52% were reported to have neither. A neuro-oncology tumor board was reported at 58% of institutions. A general cancer registry is available in 64% of institutions, 31% have a brain tumor specific registry and 10% have a brain tumor biorepository. This study shows that SSA has substantial potential in neuro-oncology care practice capacity and facilities. Most significant gaps remain in areas such as neuropathology and molecular testing, which makes widespread implementation of the WHO 2021 diagnosis challenging. Understanding the prevalence of CNS tumor subtypes is also difficult due to low number of brain tumor registries and biobanks in SSA. The present findings reveal strategic opportunities, especially in neuropathology, tumor registries, biobanks, and infrastructure for IHC and NGS in SSA.

Abstract Glioblastoma is the most common malignant primary brain tumor and is universally fatal. Treatment involves maximal safe resection with adjuvant chemoradiation. Poor prognosis in glioblastoma is multifactorial, and local and systemic immunosuppression is an important factor. Extracellular vesicles (EVs) are small, membrane-bound particles released by cells into the external environment. They play a key role in intercellular communication. In glioblastomas, EVs regulate immunosuppression through induction of myeloid-derived suppressor cells (MDSCs) in a process dependent on the PD-1/PD-L1 and IL-6 axes. Primary cilia are microtubule-based organelles that play crucial roles in various cellular processes and signal transduction cascades. We recently showed that primary cilia modulate IL-6 expression and consequently, MDSC induction. Comparative proteomic analysis of EVs derived from human glioblastoma cells devoid of cilia showed loss of ICAM-1 expression compared to control glioblastoma cells. ICAM-1 (Intercellular Adhesion Molecule-1) is a cell surface glycoprotein that mediates cell-cell adhesion and immune responses. In this study, we showed that depletion of primary cilia in human glioblastoma cells result in increased PD-L1 but loss of IL-6 and ICAM-1. RNAi-meidated loss of ICAM-1 was synergistic with primary cilia depletion in preventing MDSC inductionn normal human monocytes exposed to glioblastoma-derived EVs. Exogenous IFN-g was sufficient to restore IL-6 levels and MDSC induction despite loss of primary cilia and ICAM-1 suggesting that primary cilia act upstream of IFN-g, IL-6 and ICAM-1 in glioblastoma-mediated MDSC induction. This study is the first to connect primary cilia signal transduction to IL-6 and ICAM-1 expression and to MDSC induction. The evidence suggests a potential parallel primary cilia regulatory cascade independent of the PD-L1 axis that controls tumor-mediated immunosuppression. These results may inform novel therapeutic strategies aimed at increasing efficacy of immunotherapy in the glioblastoma and other neoplastic processes.

OBJECTIVE Following resection of posterior superior frontal gyrus (PSFG) tumors, patients can experience supplementary motor area (SMA) syndrome consisting of contralateral hemiapraxia and/or speech apraxia. Given the heterogeneity of PSFG tumors, the authors sought to determine the risk of postoperative deficits and assess predictors of outcomes for all intraparenchymal PSFG tumors undergoing surgery (biopsy or resection), regardless of histology. METHODS This was a retrospective single-center cohort study of adult PSFG-region tumors undergoing biopsy or resection by a single surgeon. RESULTS A total of 106 consecutive patients undergoing 123 procedures (21 biopsies, 102 resections) fulfilled inclusion and exclusion criteria. Anaplastic astrocytomas were the most frequent among resected tumors (39% vs 29%), while glioblastomas were most common among biopsies (38% vs 27%) (p < 0.0001). The biopsy cohort was more likely to have tumor involvement outside the PSFG (90% vs 62%) (p = 0.011), most commonly in the motor cortex (67% vs 31%) (p = 0.005). Seizures were the most common presenting symptom in the resection cohort (p = 0.017), while motor deficits were more common in the biopsy cohort (58% vs 29%) (p < 0.001). Immediate postoperative neurological deficits occurred in 71 cases (58%), but only 3 of the deficits were permanent at 6 months of follow-up (2%). Postoperative SMA syndrome occurred in 48 cases (47%) and was significantly associated with involvement of the motor cortex (p = 0.018) or cingulate gyrus (p = 0.023), which were also significant in multivariate analysis as risk factors for SMA syndrome. However, postoperative SMA syndrome was not significantly associated with overall survival (p = 0.51). There were no perioperative deaths, but corpus callosum involvement (p < 0.001), contrast enhancement (p = 0.003), and glioblastoma pathology (p = 0.038) predicted worse overall survival in patients undergoing resection. CONCLUSIONS Nearly half of all patients undergoing resection of PSFG-region tumors experience a postoperative SMA syndrome. Individuals with corpus callosum and/or motor cortex involvement may be at an increased risk of experiencing SMA syndrome. However, these deficits are usually transient, and the risk of permanent new deficits is very low (3%). Preoperative characteristics including corpus callosum involvement and tumor enhancement—in addition to pathology—might serve as predictors of overall survival within this patient population.

Abstract Glioblastoma is the most common primary malignant brain tumor. Despite maximal safe resection, followed by chemoradiation, median survival is 15 months, and 5-year survival is 6.8%. Efficacy of immunotherapy is limited by glioblastoma-mediated immunosuppression. Extracellular vesicles (EVs) are a heterogeneous group of small membrane-bound particles that are released from all cell types. Glioblastoma-derived EVs regulate the tumor microenvironment and tumor progression in a paracrine manner. They also regulate glioblastoma-mediated systemic immunosuppression in an IL6- and PDL1-dependent manner by inducing myeloid-derived suppressor cells (MDSCs) ultimately resulting in T cell depletion. Primary cilia are ubiquitous microtubule-based organelles that project from the mother centriole and are present on glioblastoma cells. Inhibition of ciliogenesis–through knockdown of KIF3A, IFT88, or ARL13B (structural ciliary proteins required for ciliogenesis)–abolishes IL6 induction in response to chemoradiation and significantly reduces the induction of MDSCs in normal human donor monocytes exposed to glioblastoma-derived EVs. Inhibition of ciliogenesis does not affect the biophysical properties of EVs but our data instead suggest significant alterations in EV packaging and content in response to ciliary loss. These data suggest a novel role for primary cilia in packaging of EV contents and connects these organelles with tumor EV-mediated immunosuppression in glioblastomas. These findings have potential implications for improving the efficacy of immunotherapy in glioblastoma–a universally fatal disease.

Abstract INTRODUCTION Brain tumors constitute significant morbidity and mortality in sub-Saharan Africa (SSA). Improvements in neuro-oncology practice and research have seen increased diagnosis of brain tumors. However, to our knowledge, there have been no previous projects on brain tumor genetics in SSA. To understand the feasibility of developing brain tumor biobanking and registries, this project aims to start by mapping out the current neuro-oncology capacity in terms of workforce and available services. METHODOLOGY We will conduct a descriptive questionnaire-based online survey among a cross section of neuro-oncology practitioners spread across SSA countries. The dissemination of the survey questionnaire will be facilitated by the Society for Neuro-oncology in SSA (SNOSSA). The Google designed questionnaire will capture information on the distribution, and number of available neuro-oncology care practitioners, capacity for brain tumor diagnosis and management, cancer registration, tumor biobanking, and research. CLINICAL IMPACT AND CONCLUSION This study will generate robust data from SSA, which can be used to improve future research and promote advocacy towards brain tumor diagnosis and management. This work will also serve as a pilot study for subsequent research that will focus on the development of brain tumor-specific registries and biorepositories in SSA.

OBJECTIVE Idiopathic normal pressure hydrocephalus (iNPH) results in significant morbidity in the elderly with symptoms of dementia, gait instability, and urinary incontinence. In well-selected patients, ventriculoperitoneal shunt (VPS) placement often results in clinical improvement. Most postshunt assessments of patients rely on subjective scales. The goal of this study was to assess the utility of remote activity monitoring to provide objective evidence of gait improvement following VPS placement for iNPH. METHODS Patients with iNPH were prospectively enrolled and fitted with 5 activity monitors (on the hip and bilateral thighs and ankles) that they wore for 4 days preoperatively within 30 days of surgery and for 4 days within 30 days postoperatively. Monitors collected continuous data for number of steps, cadence, body position (upright, prone, supine, and lateral decubitus), gait entropy, and the proportion of each day spent active or static. Data were retrieved from the devices and a comparison of pre- and postoperative movement assessment was performed. The gait data were also correlated with formal clinical gait assessments before and after lumbar puncture and with motion analysis laboratory testing at baseline and 1 month and 1 year after VPS placement. RESULTS Twenty patients fulfilled the inclusion and exclusion criteria (median age 76 years). The baseline median number of daily steps was 1929, the median percentage of the day spent inactive was 70%, the median percentage of the day with a static posture was 95%, the median gait velocity was 0.49 m/sec, and the median number of steps required to turn was 8. There was objective improvement in median entropy from pre- to postoperatively, increasing from 0.6 to 0.8 (p = 0.002). There were no statistically significant differences for any of the remaining variables measured by the activity monitors when comparing the preoperative to the 1-month postoperative time point. All variables from motion analysis testing showed statistically significant differences or a trend toward significance at 1 year after VPS placement. Among the significantly correlated variables at baseline, cadence was inversely correlated with percentage of gait cycle spent in the support phase (contact with ground vs swing phase). CONCLUSIONS This pilot study suggests that activity monitoring provides an early objective measure of improvement in gait entropy after VPS placement among patients with iNPH, although a more significant improvement was noted on the detailed clinical gait assessments. Further long-term studies are needed to determine the utility of remote monitoring for assessing gait improvement following VPS placement.

Abstract Glioblastoma is the most common and aggressive primary brain tumor. Median survival is 15 months despite surgery, radiation, and chemotherapy. Immunotherapy is promising but glioblastoma-mediated immunosuppression remains a barrier. Recently, extracellular vesicles (EVs) have been implicated in glioblastoma-mediated immunosuppression through expression of the immune checkpoint molecules PD-L1 and IDO1 which have been implicated in T cell function suppression and decreased proliferation in some cancers. Our data demonstrate that PD-L1 and IDO1 expression are increased in most nucleated cells following IFN-γ exposure. IFN-γ exposure did not alter EV production or expression of common EV markers but increased PD-L1 and IDO1 expression in EVs from differentiated but not stem-like GBM cells. Differentiated glioblastoma cell derived EVs induced myeloid-derived suppressor cell and non-classical monocyte differentiation from normal monocytes. This was increased following IFN-γ exposure and was dependent upon both PD-L1 and IDO1 expression but not stem-like GBM cell. Monocytes exposed to differentiated but not stem-like GBM cell EVs inhibited T cell proliferation in a similar manner (increased with IFN-γ exposure, decreased with PD-L1 or IDO1 knockdown). Thus, IFN-γ exposure results in super-induction of immunosuppressive EVs from differentiated but not stem-like GBM cells that increase MDSC and NCM differentiation in normal monocytes and increase their ability to inhibit T cell proliferation. These effects are dependent upon PD-L1 and IDO1 up-regulation induced by IFN-γ. This may be an important mechanism GBMs utilize to suppress anti-tumor T cell responses that are typically accompanied by increased IFN-γ expression.