Citations

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.

Abstract BACKGROUND The diagnosis and management of patients with brain tumors currently uses WHO defined morphologic and molecular features. However, neuro-oncology practice in low resource settings relies solely on histomorphology. This study aims to reclassify glioma cases diagnosed in the Department of Anatomic and Molecular Pathology Lagos University Teaching Hospital using the WHO 2021 classification. METHODS Fifty-six cases of glioma diagnosed between 2013 to 2021 were evaluated. Morphologic diagnosis was reassessed. Five-micron sections were obtained for immunohistochemistry (IHC), and genetic testing (DNA and RNA) after manual macrodissection for tumor enrichment used 10-µm sections. IHC for IDH1-R132H, ATRX, BRAF-V600E, p53, Ki67 and H3-K27M and Oncoscan chromosomal microarray analysis were performed. NGS mutation/fusion analysis and EPIC methylation array profiling are in progress. RESULTS Of the 56 cases evaluated, median age was 22 years (range, 1-60); 71% were male. The initial morphologic diagnoses included 21 pilocytic astrocytoma, 11 glioblastoma, 9 ependymoma, 7 diffuse astrocytoma, 3 anaplastic astrocytoma, 2 high-grade gliomas, 1 oligodendroglioma, 1 diffuse midline glioma, and 1 pleomorphic xanthoastrocytoma (PXA). Histomorphologic re-evaluation revealed discordant diagnosis in 29% (16/56) of cases. Of the 56 cases, 73% (41/56) had usable DNA yield and 38% (21/56) had DNA yield of ≥750ng. Chromosomal microarray analysis was completed for 50% (28/56) cases. The revised WHO 2021 diagnosis was: 5 glioblastoma IDH-wildtype, 5 pilocytic astrocytoma, 4 glioma NEC, 3 posterior fossa ependymoma, group B, 3 PXA, 3 astrocytoma IDH-mutant, 2 pediatric low-grade gliomas, 2 supratentorial ependymoma, ZFTA fusion-positive, 1 posterior fossa ependymoma, group A. In 71% (20/28) of cases with molecular testing, diagnosis was revised using WHO 2021 criteria. CONCLUSION Most cases had usable DNA. Overall, histologic re-evaluation and molecular based on the WHO 2021 criteria refined the diagnosis in 48% (27/56) of cases.

Abstract Glioblastoma (GBM) is the most common and aggressive primary brain tumor. Temozolomide (TMZ) is the only drug currently been used for treatment of newly diagnosed GBM patients but the benefit from this agent has been hampered by the primary and secondary resistance. Thus, there is a strong need for uncovering the mechanisms of TMZ resistance. The DNA repair protein O6-methylguanine-DNA-methyltransferase (MGMT) is the main driver of primary TMZ resistance and lacking MGMT expression due to promoter hypermethylation has been associated with a significant survival prolongation. However, the MGMT-independent resistance mechanisms remain poorly understood. To investigate TMZ resistance mechanisms, we developed in vivo TMZ resistant models using GBM patient derived xenografts (PDXs) by treating animals bearing flank PDXs with clinically relevant 3-cyles of TMZ. The recurrent tumors were all resistant to TMZ through multiple mechanisms, including MGMT re-expression, elevated homologous recombination (HR) and/or non-homologous end joining (NHEJ) repair activities, and loss of mismatch repair (MMR). However, other tumors developed resistance due to unknown mechanisms. To identify novel modulators of TMZ sensitivity, we performed genome wide screening using shRNA library, and we identified over 600 druggable targets. Validation experiments identified RBBP4 gene as one of the candidates involved in TMZ sensitivity. Silencing RBBP4 in GBM cells sensitized both MGMT-methylated and -unmethylated GBM cells to TMZ. Mechanistically, RBBP4 interacts with p300 to form a chromatin remodeling complex that control expression of DNA damage repair genes, and silencing RBBP4 or p300 significantly blocked the recovery of TMZ induced DNA double strand breaks causing cell death. We also found the nuclear pore exporter XPO1 is the modulator of TMZ sensitivity, and the XPO1 inhibitor Selinexor is currently being evaluated for GBM treatment in a clinical trial. Collectively, our work has uncovered multiple mechanisms of TMZ resistance that are potential targets for GBM therapy.

Exoskeletons are ergonomic devices that can support workers to improve performance and worker safety. This study created an apparatus that simulated a head-and-neck exoskeleton designed for surgeons to test the effects of varying tension forces on muscle activation (splenius capitis, splenius cervices, and erector spinae), body part discomfort, dexterity, cognition, and overall usability of the device. Eight participants were involved in twelve trials over two days and held static postures (looking down at 45° or 90°) for 20 minutes with 10-minute breaks between trials. Six trials utilized tension forces, which were recorded every two minutes and then averaged for each trial. A bivariate regression analysis ( on each metric vs. average tension forces demonstrated that increasing tension forces led to decreased muscle activity of the left splenius capitis, change in general body pain, change in neck discomfort, and the rate of discomfort developing, and improved usability scores.

Abstract Background Routine childhood immunization against varicella-zoster virus has led to a dramatic reduction in the incidence of primary varicella. However, there are rare, yet significant cases reported of reactivated Oka-strain varicella, primarily in immunocompromised hosts.Case Presentation A 16-year-old female with Hodgkin’s lymphoma developed a tender vesicular rash shortly after completing chemotherapy. Swabs obtained from the vesicles were positive for varicella-zoster virus. By the time of hospitalization, the patient developed a disseminated rash involving multiple dermatomes. Subsequent polymerase chain reaction confirmed Oka vaccine-strain varicella-zoster virus. The patient had previously received a primary series against varicella in 2008 and 2012, 11 years before her diagnosis of Hodgkin’s lymphoma. The patient was treated with parenteral acyclovir upon hospitalization and was monitored clinically for cutaneous disease progression as well as sequelae. After 8 days of inpatient treatment, her rash had stopped spreading with no new lesions. All earlier lesions had crusted over. No serious sequelae of disease such as pneumonitis, hepatitis, encephalitis, or meningitis occurred, and she made a complete recovery.Conclusions There are individual and community-wide benefits to childhood immunization against varicella. This case highlights an unusual presentation of disseminated vaccine-strain varicella-zoster virus in an adolescent with secondary immunodeficiency 11 years after completing primary immunization. In addition, this case informs pediatricians of complications that can arise in immunized subjects if they become immunosuppressed years later. Providers should be cognizant of potential vaccine virus reactivation in their differential. Considerations for work-up and management should include infection control and viral resistance in refractory cases.

Abstract The IFIH1 gene, encoding melanoma differentiation-associated protein 5 (MDA5), is an indispensable innate immune regulator involved in the early detection of viral infections. Previous studies described MDA5 dysregulation linking it to weakened immunological responses, and increased susceptibility to microbial infections and autoimmune disorders. Monoallelic gain-of-function of the IFIH1 gene has been associated with multisystem disorders, namely Aicardi-Goutieres and Singleton-Merten syndromes, while biallelic loss of this gene causes immunodeficiency. In this study, nine patients suffering from different cases of recurrent infections, inflammatory diseases, severe COVID-19, or multisystem inflammatory syndrome in children (MIS-C) were identified with putative loss-of-function IFIH1 variants by whole exome sequencing. All patients revealed signs of lymphopenia and an increase in inflammatory markers, including CRP, amyloid A, ferritin, and IL-6. One patient with a pathogenic homozygous variant c.2807 + 1G > A was the most severe case showing immunodeficiency and glomerulonephritis. The c.1641 + 1G > C variant was identified in the heterozygous state in patients suffering from periodic fever, COVID-19, or MIS-C, while the c.2016delA variant was identified in two patients with inflammatory bowel disease or MIS-C. Expression analysis showed that PBMCs of one patient with a c.2016delA variant had a significant decrease in ISG15, IFNA and IFNG transcript levels, compared to normal PBMCs, upon stimulation with Poly(I:C), suggesting that MDA5 receptor truncation disrupts the immune response. Our findings accentuate the implication of rare monogenic IFIH1 loss-of-function variants in altering the immune response, and severely predisposing patients to inflammatory and infectious diseases, including SARS-CoV-2 related disorders.