Central Nervous System Tumors In Adults Research Articles

Innovative Approaches in Glioblastoma Treatment: The Role of Optune in Enhancing Patient Survival

Glioblastoma multiforme (GBM) is the most common form of malignant primary brain and CNS (central nervous system) tumors in adults. Prognosis is generally poor and the current standard for treatment often fails to meet expectations. In recent years, Optune has garnered attention for its novel approach to cancer treatment. Utilizing biophysical principles, Optune employs tumor-treating fields (TTFields) to preferentially disrupt cells undergoing mitosis. In this review, we examine Optune’s current role in progressing cancer treatments through its unique mechanism of action. We consider its future application with other carcinomas and current drawbacks and adoption from a biological and economic standpoint.

Characteristics and Survival of Patients with WHO Grade 4 Diffuse Glioma in Dharmais National Referral Cancer Hospital

Background: The WHO grade 4 diffuse glioma are extremely aggressive and account for over 60% of adult Central Nervous System (CNS) tumors. The diagnosis and management pose significant challenges due to the need for comprehensive evaluation and holistic treatment approaches. This study aims to determine the clinical characteristics of WHO grade 4 diffuse glioma in Indonesia and the overall survival as a secondary goal. Methods: This is a retrospective cohort study of all WHO grade 4 glioma patients from 2017 to 2022 at Dharmais National Cancer Hospital, Jakarta, Indonesia. Demographic characteristics were presented descriptively. Kaplan-Meier plot was used to evaluate the median survival. Results: Twenty-eight patients were eligible for this study. The median age group is 45 years old, with equal male and female prevalence. Headache was the most prevalent primary symptom. The therapy following surgery was radiotherapy (RT) with chemosensitizer (82.1%) and RT alone (14.3%) with both followed by adjuvant chemotherapy. There was one patient (3.6%) underwent palliative therapy. The median survival of all patients was 10 months, whereas 10 months in RT with the chemo-sensitizer group and 1 month in RT only group. There was no statistically significant difference between RT with and without chemotherapy sensitizer in terms of survival rates. Conclusions: Our study reports a younger median age of WHO Grade 4 diffuse glioma. Male subjects were equivalent to females. Median OS was 10 months and were longer in RT with the chemosensitizer group. Further multicentered and at the genetic level investigation was needed, to achieve optimal outcomes.

478P Molecular characterization of adult non-glioblastoma central nervous system (CNS) tumors to identify potential targettable alterations

478P Molecular characterization of adult non-glioblastoma central nervous system (CNS) tumors to identify potential targettable alterations

Abstract 2231: Impact of sociodemographic and clinical factors on symptom burden in the young adult primary central nervous system tumor population

Abstract Purpose: The goal of this analysis was to provide insight into differences in perceived symptom burden and general health status between young adults (YA; 18-39 years of age) and older adults (OA; ≥ 40 years of age) with primary central nervous system (PCNS) tumors. Determining differences in characteristics that impact symptom burden and general health status in YA will allow for tailored survivorship programs that meet the unique needs of this population. Methods: Data were retrospectively analyzed from the National Cancer Institute Neuro-Oncology Branch’s Natural History Study (NCT02851706 PI: T.S. Armstrong), which is an observational prospective cohort study designed to follow and collect PROs and clinical information on patients diagnosed with PCNS tumors throughout their disease trajectory. Differences in patient-reported outcomes (general health status [EQ-5D-3L], symptom burden [MDASI-BT and MDASI-SP], anxiety/depression [PROMIS], and perceived cognition [Neuro-QOL]) and demographic and clinical data were assessed using chi-square tests, one-way ANOVAs, and Students’ t-tests. Linear regression with backward elimination determined which characteristics impacted perceived symptom burden and general health status as evidenced by MDASI-BT and EQ-5D-3L, respectively. Results: The sample included 271 YA (82% with a primary brain tumor [PBT]; median age 31 [range, 18-39]) and 516 OA (88% with a PBT; median age 54 [range, 40-85]). YA were more likely to be single (P<0.001), employed (P<0.001), and make < $50,000 per year (P=0.014). More YA reported pain (P=0.008), nausea (P<0.001), drowsiness (P=0.043), and vomiting (P=0.001) than OA. More YA presented with vision problems (25% of YA, 16% of OA), whereas more OA presented with cognitive deficits (17% of YA, 25% of OA). Compared to YA, 7% more OA with PBTs and 19% more OA with primary spinal tumors (PST) were diagnosed in outpatient clinics, whereas the majority of YA with PBTs (47%) were diagnosed in an emergency room. Among demographic and clinical characteristics, only Karnofsky Performance Scale score was a predictor of general health status (P<0.001) in YA with PCNS tumors and symptom interference (P=0.014) in YA with PBTs. YA reported more affective, cognitive, neurologic, treatment-related, generalized disease, and gastrointestinal symptom burden than OA, with the affective factor being the most severe among the symptom factors reported. Among individuals with PSTs, 20% more YA reported moderate-severe anxiety (P=0.050) and 32% more YA reported moderate-severe perceived cognitive deficits (P=0.023) than OA. Conclusion: YA patients were more likely to be single, employed, have a lower income, and report more symptom burden than OA. These findings underscore the need for tailored survivorship programs providing additional psychosocial support and resources to address symptom presentation in YA. Citation Format: Kimberly Reinhart, Tricia Kunst, Jennifer Reyes, Alvina Acquaye-Mallory, Ewa Grajkowska, Byram H. Ozer, Marta Penas-Prado, Jing Wu, Eric Burton, Lisa Boris, Marissa Panzer, Tina Pillai, Lily Polskin, Mark R. Gilbert, Elizabeth Vera, Terri S. Armstrong. Impact of sociodemographic and clinical factors on symptom burden in the young adult primary central nervous system tumor population [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2231.

Current approaches in glioblastoma multiforme immunotherapy.

Glioblastoma multiform (GBM) is the most prevalent CNS (central nervous system) tumor in adults, with an average survival length shorter than 2years and rare metastasis to organs other than CNS. Despite extensive attempts at surgical resecting, the inherently permeable nature of this disease has rendered relapse nearly unavoidable. Thus, immunotherapy is a feasible alternative, as stimulated immune cells can enter into the remote and inaccessible tumor cells. Immunotherapy has revolutionized patient upshots in various malignancies and might introduce different effective ways for GBM patients. Currently, researchers are exploring various immunotherapeutic strategies in patients with GBM to target both the innate and acquired immune responses. These approaches include reprogrammed tumor-associated macrophages, the use of specific antibodies to inhibit tumor progression and metastasis, modifying tumor-associated macrophages with antibodies, vaccines that utilize tumor-specific dendritic cells to activate anti-tumor T cells, immune checkpoint inhibitors, and enhanced T cells that function against tumor cells. Despite these findings, there is still room for improving the response faults of the many currently tested immunotherapies. This study aims to review the currently used immunotherapy approaches with their molecular mechanisms and clinical application in GBM.

Abstract A014: ClpP drives efficacy and mediates acquired resistance with imipridones ONC201 and ONC206 in glioma in vitro

Abstract A014: ClpP drives efficacy and mediates acquired resistance with imipridones ONC201 and ONC206 in glioma <i>in vitro</i>

The Significance of the Redox Gene in the Prognosis and Therapeutic Response of Glioma.

Glioblastoma (GBM) is a fatal adult central nervous system tumor. Due to its high heterogeneity, the survival rate and prognosis of patients are poor. Thousands of people die of this disease every year all over the world. At present, the treatment of GBM is mainly through surgical resection and the combination of later drugs, radiotherapy, and chemotherapy. An abnormal redox system is involved in the malignant progression and treatment tolerance of glioma, which is the main reason for poor survival and prognosis. The construction of a GBM redox-related prognostic model may be helpful in improving the redox immunotherapy and prognosis of GBM. Based on glioma transcriptome data and clinical data from The Cancer Genome Atlas, databases, a risk model of redox genes was constructed by univariate and multivariate Cox analysis. The good prediction performance of the model was verified by the internal validation set of The Cancer Genome Atlas, and the external data of Chinese Glioma Genome Atlas. The results confirmed that the higher the risk score, the worse the survival of patients. Age and isocitrate dehydrogenase status were significantly correlated with risk scores. The analysis of immune infiltration and immunotherapy found that there were significant differences in the immune score, matrix score, and ESTIMATE score between high and low-risk groups. reverse transcription polymerase chain reaction and immunohistochemical staining of glioma samples confirmed the expression of the hub gene. Our study suggests that the 5 oxidative-related genes nitricoxidesynthase3 , NCF2 , VASN , FKBP1B , and TXNDC2 are hub genes, which may provide a reliable prognostic tool for glioma clinical treatment.

Chimeric Antigen Receptor T Cell and Chimeric Antigen Receptor NK Cell Therapy in Pediatric and Adult High-Grade Glioma—Recent Advances

High-grade gliomas (HGG) account for approximately 10% of central nervous system (CNS) tumors in children and 25% of CNS tumors in adults. Despite their rare occurrence, HGG are a significant clinical problem. The standard therapeutic procedure in both pediatric and adult patients with HGG is the surgical resection of the tumor combined with chemotherapy and radiotherapy. Despite intensive treatment, the 5-year overall survival in pediatric patients is below 20–30%. This rate is even lower for the most common HGG in adults (glioblastoma), at less than 5%. It is, therefore, essential to search for new therapeutic methods that can extend the survival rate. One of the therapeutic options is the use of immune cells (T lymphocytes/natural killer (NK) cells) expressing a chimeric antigen receptor (CAR). The objective of the following review is to present the latest results of preclinical and clinical studies evaluating the efficacy of CAR-T and CAR-NK cells in HGG therapy.

GSTM1 null genotype underpins recurrence of NF2 meningiomas.

Meningiomas are the most common primary central nervous system (CNS) tumor in adults, comprising one-third of all primary adult CNS tumors. Although several recent publications have identified molecular alterations in meningioma including characteristic mutations, copy number alterations, and gene expression signatures, our understanding of the drivers of meningioma recurrence is limited. To identify gene expression signatures of 1p-22q-NF2- meningioma recurrence, with concurrent biallelic inactivation of NF2 and loss of chr1p that are heterogenous but enriched for recurrent meningiomas. Transcriptomic alterations present in recurrent versus primary 1p-22q-NF2- meningiomas were identified using RNA sequencing (RNA-seq) data in a clinically annotated cohort. Recurrent 1p-22q-NF2- meningiomas were enriched for a newly identified GSTM1 null genotype compared to primary meningiomas that showed variable GSTM1 expression and independent external validation was performed. The GSTM1 null genotype is a novel biomarker of 1p-22q-NF2- meningioma recurrence that resolves heterogeneity in existing meningioma subtypes and may be used to guide future clinical management decisions on extent of treatment to improve patient outcomes.

Abstract LB_A04: Quantitative digital spatial protein profiling of non-small cell lung cancer brain metastasis

Abstract Metastatic brain tumor is the most common form of adult central nervous system (CNS) tumor, and the majority of the cerebral metastasis originate from lung cancer. Along with recent combination strategies applying immune checkpoint inhibitor, evaluating tumor microenvironment of the brain metastasis (BM) needs to be unveiled. In this study, we tried to disclose immune context information of BM of non-small cell lung cancer (NSCLC) by using highly multiplex NanoString digital spatial profiling (DSP) method. Seven cases of NSCLC and metastatic brain tumor were evaluated. To detect proteins at quantitative and high multiplex with spatial resolution, NanoString optical barcoding technology was used to digitally profile protein expression in FFPE samples. Immuno-oncology protein targets, including immune cell markers and checkpoint proteins are included. DSP identified differentially expressed proteins between primary NSCLC and BM. Proteins associated with immune regulation, evasion, and adaptive immunity, such as IDO-1, PD1, PDL1, STAT3, PTEN, and CD44 revealed decreased expression in patients with BM (P&amp;lt;0.01). The expression of pS6 was significantly increased in BM (P&amp;lt;0.01), which is associated with activation induced T-cell death. This study demonstrated differentially expressed proteins in BM associated with immune regulation and evasion via NanoString DSP platform. This study highlighted the localized expression of immune-related proteins of BM in patients with NSCLC. Moreover, our results presented the possibility of using digitally quantified and spatially allocated novel method in BM eliminating the subjectivity and variability associated with the immunohistochemistry techniques. Citation Format: Tae Jung Kim. Quantitative digital spatial protein profiling of non-small cell lung cancer brain metastasis [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr LB_A04.

The unique immune ecosystems in pediatric brain tumors: integrating single-cell and bulk RNA-sequencing.

The significant progress of immune therapy in non-central nervous system tumors has sparked interest in employing the same strategy for adult brain tumors. However, the advancement of immunotherapy in pediatric central nervous system (CNS) tumors is not yet on par. Currently, there is a lack of comprehensive comparative studies investigating the immune ecosystem in pediatric and adult CNS tumors at a high-resolution single-cell level. In this study, we comprehensively analyzed over 0.3 million cells from 171 samples, encompassing adult gliomas (IDH wild type and IDH mutation) as well as four major types of pediatric brain tumors (medulloblastoma (MB), ependymoma (EPN), H3K27M-mutation (DIPG), and pediatric IDH-mutation glioma (P-IDH-M)). Our approach involved integrating publicly available and newly generated single-cell datasets. We compared the immune landscapes in different brain tumors, as well as the detailed functional phenotypes of T-cell and myeloid subpopulations. Through single-cell analysis, we identified gene sets associated with major cell types in the tumor microenvironment (gene features from single-cell data, scFes) and compared them with existing gene sets such as GSEA and xCell. The CBTTC and external GEO cohort was used to analyze and validate the immune-stromal-tumor patterns in pediatric brain tumors which might potentially respond to the immunotherapy. From the perspective of single-cell analysis, it was observed that major pediatric brain tumors (MB, EPN, P-IDH-M, DIPG) exhibited lower immune contents compared with adult gliomas. Additionally, these pediatric brain tumors displayed diverse immunophenotypes, particularly in regard to myeloid cells. Notably, the presence of HLA-enriched myeloid cells in MB was found to be independently associated with prognosis. Moreover, the scFes, when compared with commonly used gene features, demonstrated superior performance in independent single-cell datasets across various tumor types. Furthermore, our study revealed the existence of heterogeneous immune ecosystems at the bulk-RNA sequencing level among different brain tumor types. In addition, we identified several immune-stromal-tumor patterns that could potentially exhibit significant responses to conventional immune checkpoint inhibitors. The single-cell technique provides a rational path to deeply understand the unique immune ecosystem of pediatric brain tumors. In spite of the traditional attitudes of "cold" tumor towards pediatric brain tumor, the immune-stroma-tumor patterns identified in this study suggest the feasibility of immune checkpoint inhibitors and pave the way for the upcoming tide of immunotherapy in pediatric brain tumors.

Vascularization ability of glioma stem cells in different three-dimensional microenvironments.

Glioblastoma (GBM) is among the most common and aggressive adult central nervous system tumors. One prominent characteristic of GBM is the presence of abnormal microvessels. A significant correlation between angiogenesis and prognosis has been observed. Accurately reconstructing this neovascularization and tumor microenvironment through personalized in vitro disease models presents a significant challenge. However, it is crucial to develop new anti-angiogenic therapies for GBM. In this study, 3D bioprinted glioma stem cell (GSC)-laden hydrogel scaffolds, hybrid GSC hydrogels and cell-free hydrogel scaffolds were manufactured to investigate the vascularization ability of GSCs in varying 3D microenvironments. Our results demonstrated that the bioactivity of GSCs in the 3D bioprinted GSC-laden hydrogel scaffold was preferable and stable, and the amounts of vascular endothelial growth factor A and basic fibroblast growth factor were the highest in the microenvironment. When the three different models were co-cultured with human umbilical vein endothelial cells, the expression of angiogenesis-related markers was the most abundant in the bioprinted GSC-laden hydrogel scaffold. Additionally, xenograft tumors formed by bioprinted GSC-laden hydrogel scaffolds more closely resembled human gliomas regarding color, texture and vascularization. Notably, in xenograft tumors derived from 3D bioprinted GSC-laden hydrogel scaffolds, the number of human CD105+ cells was significantly higher, and human endothelial vascular lumen-like structures were observed. This indicates that the 3D bioprinted GSC-laden hydrogel scaffold is a suitable model for mimicking the glioma microenvironment and studying tumor angiogenesis.

Intraoperative Integrated Diagnostic System for Malignant Central Nervous System Tumors.

The 2021 World Health Organization (WHO) classification of central nervous system (CNS) tumors uses an integrated approach involving histopathology and molecular profiling. Because majority of adult malignant brain tumors are gliomas and primary CNS lymphomas (PCNSL), rapid differentiation of these diseases is required for therapeutic decisions. In addition, diffuse gliomas require molecular information on single-nucleotide variants (SNV), such as IDH1/2. Here, we report an intraoperative integrated diagnostic (i-ID) system to classify CNS malignant tumors, which updates legacy frozen-section (FS) diagnosis through incorporation of a qPCR-based genotyping assay. FS evaluation, including GFAP and CD20 rapid IHC, was performed on adult malignant CNS tumors. PCNSL was diagnosed through positive CD20 and negative GFAP immunostaining. For suspected glioma, genotyping for IDH1/2, TERT SNV, and CDKN2A copy-number alteration was routinely performed, whereas H3F3A and BRAF SNV were assessed for selected cases. i-ID was determined on the basis of the 2021 WHO classification and compared with the permanent integrated diagnosis (p-ID) to assess its reliability. After retrospectively analyzing 153 cases, 101 cases were prospectively examined using the i-ID system. Assessment of IDH1/2, TERT, H3F3AK27M, BRAFV600E, and CDKN2A alterations with i-ID and permanent genomic analysis was concordant in 100%, 100%, 100%, 100%, and 96.4%, respectively. Combination with FS and intraoperative genotyping assay improved diagnostic accuracy in gliomas. Overall, i-ID matched with p-ID in 80/82 (97.6%) patients with glioma and 18/19 (94.7%) with PCNSL. The i-ID system provides reliable integrated diagnosis of adult malignant CNS tumors.

DUBing Primary Tumors of the Central Nervous System: Regulatory Roles of Deubiquitinases.

The ubiquitin proteasome system (UPS) utilizes an orchestrated enzymatic cascade of E1, E2, and E3 ligases to add single or multiple ubiquitin-like molecules as post-translational modification (PTM) to proteins. Ubiquitination can alter protein functions and/or mark ubiquitinated proteins for proteasomal degradation but deubiquitinases (DUBs) can reverse protein ubiquitination. While the importance of DUBs as regulatory factors in the UPS is undisputed, many questions remain on DUB selectivity for protein targeting, their mechanism of action, and the impact of DUBs on the regulation of diverse biological processes. Furthermore, little is known about the expression and role of DUBs in tumors of the human central nervous system (CNS). In this comprehensive review, we have used publicly available transcriptional datasets to determine the gene expression profiles of 99 deubiquitinases (DUBs) from five major DUB families in seven primary pediatric and adult CNS tumor entities. Our analysis identified selected DUBs as potential new functional players and biomarkers with prognostic value in specific subtypes of primary CNS tumors. Collectively, our analysis highlights an emerging role for DUBs in regulating CNS tumor cell biology and offers a rationale for future therapeutic targeting of DUBs in CNS tumors.

Childhood, adolescent, and adult primary brain and central nervous system tumor statistics for practicing healthcare providers in neuro-oncology, CBTRUS 2015-2019.

The Central Brain Tumor Registry of the United States (CBTRUS), in collaboration with the Centers for Disease Control and Prevention (CDC) and National Cancer Institute (NCI), is the largest aggregation of histopathology-specific population-based data for primary brain and other central nervous system (CNS) in the US. CBTRUS publishes an annual statistical report which provides critical reference data for the broad neuro-oncology community. Here, we summarize the key findings from the 2022 CBTRUS annual statistical report for healthcare providers. Incidence data were obtained from the CDC's National Program of Cancer Registries (NPCR) and NCI's Surveillance, Epidemiology, and End Results Program for 52 central cancer registries (CCRs). Survival data were obtained from 42 NPCR CCRs. All rates are per 100 000 and age-adjusted using the 2000 US standard population. Overall median survival was estimated using Kaplan-Meier models. Survival data for selected molecularly defined histopathologies are from the National Cancer Database. Mortality data are from the National Vital Statistics System. The average annual age-adjusted incidence rate of all primary brain and other CNS tumors was 24.25/100 000. Incidence was higher in females and non-Hispanics. The most commonly occurring malignant and predominately non-malignant tumors was glioblastoma (14% of all primary brain tumors) and meningioma (39% of all primary brain tumors), respectively. Mortality rates and overall median survival varied by age, sex, and histopathology. This summary describes the most up-to-date population-based incidence, mortality, and survival, of primary brain and other CNS tumors in the US and aims to serve as a concise resource for neuro-oncology providers.

TRIB1 confers therapeutic resistance in GBM cells by activating the ERK and Akt pathways

GBM (Glioblastoma) is the most lethal CNS (Central nervous system) tumor in adults, which inevitably develops resistance to standard treatments leading to recurrence and mortality. TRIB1 is a serine/threonine pseudokinase which functions as a scaffold platform that initiates degradation of its substrates like C/EBPα through the ubiquitin proteasome system and also activates MEK and Akt signaling. We found that increased TRIB1 gene expression associated with worse overall survival of GBM patients across multiple cohorts. Importantly, overexpression of TRIB1 decreased RT/TMZ (radiation therapy/temozolomide)-induced apoptosis in patient derived GBM cell lines in vitro. TRIB1 directly bound to MEK and Akt and increased ERK and Akt phosphorylation/activation. We also found that TRIB1 protein expression was maximal during G2/M transition of cell cycle in GBM cells. Furthermore, TRIB1 bound directly to HDAC1 and p53. Importantly, mice bearing TRIB1 overexpressing tumors had worse overall survival. Collectively, these data suggest that TRIB1 induces resistance of GBM cells to RT/TMZ treatments by activating the cell proliferation and survival pathways thus providing an opportunity for developing new targeted therapeutics.

Secondary tumors following radiation therapy and chemotherapy : Incidence of cavernous hemangiomas

There is arisk of developing secondary central nervous system (CNS) tumors after cranial radiation therapy. Meningiomas and pituitary tumors are also increasingly treated with radiation therapy, which means that the risk of secondary tumors from radiation in children and adults must be communicated. Studies in children show that radiation causes a7- to 10-fold increase in subsequent CNS tumors with acumulative incidence over 20years ranging from 1.03 to 28.9. The latency period for the occurrence of secondary tumors ranged from 5.5 to 30years, with gliomas developing after 5-10years and meningiomas around 15years after irradiation. The latency period for secondary CNS tumors in adults ranged from 5to 34years. After radiation treatment, tumors can rarely occur as secondary sequelae, mostly meningiomas and gliomas, but also cavernomas. The treatment and long-term results of radiation-induced CNS tumors showed no worse results than primary CNS tumors over the course of time.

Abstract 2233: Clinical validation of a methylation array-based diagnostic assay for improved classification of CNS tumors

Abstract Current cIMPACT-NOW and WHO guidelines state that the accurate diagnosis of many central nervous system (CNS) tumors must not only incorporate traditional histological findings but also include additional molecular data derived from sequence and methylation profiling techniques. To address this clinical need, our group has adapted and clinically validated the CNS tumor classifier that was pioneered and developed by the German Cancer Research Network (DKFZ) and University Hospital Heidelberg for both adult and pediatric CNS tumors. The classifier analyzes whole genome methylation data derived from the Illumina EPIC array system with a machine learning algorithm trained on a large reference set to provide a tumor family and class (a more granular classification than family) along with calibrated scores to aid in determining confidence in the assigned classifications. Around this core algorithm, we have generated a computational and reporting pipeline to generate a mid-throughput clinical diagnostic assay. We have validated this assay using a combination of adult and pediatric CNS tumor samples and have established reliable run-level and sample-level quality control metrics with empirically defined thresholds. With these thresholds, approximately 90% of samples with a neoplastic content of 70% or greater were “classifiable”, such that a result could be returned by the CNS tumor diagnostic assay. The performance of the assay was exceptional, with a sensitivity, specificity and accuracy each greater than 98% as determined with a validation sample set of 105 specimens. Further, 4 discordant calls between the original diagnosis and the output of the new methylation-based diagnostic were identified and underwent further histopathologic review. This additional analysis led to the re-classification of 2 specimens due to molecular analysis, highlighting the clinical utility of the assay. The new assay is currently offered for clinical testing under the name JAX OncoMethyl ArrayTM and addresses a clear need in the field of CNS tumor diagnostics. Citation Format: Melissa Soucy, Nick Renzette, Xinming Zhuo, Prasanti Nuni, Kristi Herlth, Kevin Kelly, Gregory Omerza, Lei Li. Clinical validation of a methylation array-based diagnostic assay for improved classification of CNS tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2233.

Barriers to employment for young adult central nervous system tumor survivors: The role of career readiness and core self-evaluations

BACKGROUND: Although the majority of childhood cancer survivors make successful transitions to adulthood, research suggests that a significant group experiences ongoing medical concerns, such as psychological distress, that significantly impact the achievement of crucial social roles including employment. OBJECTIVE: The purpose of this study was to examine the relationship between career decision making, core self-evaluations, and perceived internal and external barriers to employment in a sample of young adult central nervous system tumor survivors. METHOD: A sample of 110 young adult survivors of pediatric central nervous system tumors was surveyed. Mediation analysis with structural equational modeling was used to correlate a number of different measures (Career Decision Making [CTI], Perceived Employment Barriers [PEB], and Core-Self Evaluations [CSE]). RESULTS: The presence of both significant direct and indirect effects of career decision making on perceived employment barriers implied that there was a partial mediating effect of core self-evaluations on the association between career readiness and employment barriers. CONCLUSION: Career decision-making is a robust construct that can be applied to young adult central nervous system tumor survivors in effort to gain more insight into the vocational psychological factors that impact career development and employment in this group. Core self-evaluations was found to be a mediator between career decision making and perceived career barriers.

Specific gene expression signatures of low grade meningiomas.

Meningiomas are the most common primary central nervous system (CNS) tumors in adults, representing approximately one-third of all primary adult CNS tumors. Although several recent publications have proposed alternative grading systems of meningiomas that incorporate genomic and/or epigenomic data to better predict meningioma recurrence and progression-free survival, our understanding of driving forces of meningioma development is still limited. To define gene expression signatures of the most common subtypes of meningiomas to better understand cellular processes and signaling pathways specific for each tumor genotype. We used RNA sequencing (RNA-seq) to determine whole transcriptome profiles of twenty meningiomas with genomic alterations including NF2 inactivation, loss of chr1p, and missense mutations in TRAF7, AKT1 and KLF4. The analysis revealed that meningiomas with NF2 gene inactivation expressed higher levels of BCL2 and GLI1 compared with tumors harboring TRAF7 missense mutations. Moreover, NF2 meningiomas were subdivided into two distinct groups based on additional loss of chr1p. NF2 tumors with intact chr1p were characterized by the high expression of tumor suppressor PTCH2 compared to NF2 tumors with chr1p loss. Taken together with the high expression of BCL2 and GLI1, these results suggest that activation of Sonic Hedgehog pathway may contribute to NF2 meningioma development. In contrast, NF2 tumors with chr1p loss expressed high levels of transcription factor FOXD3 and its antisense RNA FOXD3-AS1. Examination of TRAF7 tumors demonstrated that TRAF7 regulates a number of biomechanically responsive genes (KRT6a, KRT16, IL1RL1, and AQP3 among others). Interestingly, AKT1 and KLF4 meningiomas expressed genes specific for PI3K/AKT signaling pathway, suggesting overlapping gene signatures between the two subtypes. In addition, KLF4 meningiomas had high expression of carcinoembryonic antigen family members CEACAM6 and CEACAM5. Each group of meningiomas displayed a unique gene expression signature suggesting signaling pathways potentially implicated in tumorigenesis. These findings will improve our understanding of meningioma tumorigenesis and prognosis.