Aggressive Central Nervous System Research Articles

Abstract 4992: Baseline and alteration in pre vs post standard of care management serum-derived inflammatory markers are associated with radiation treatment volumes and patient outcomes in patients with GBM in a large-scale proteomic panel

Abstract Glioblastomas (GBM) are the most aggressive central nervous system tumors with near universal recurrence following resection and chemoradiation (CRT). Inflammation plays a multifaceted role in GBM development and progression through disruption of the brain barrier, immunosuppression, angiogenesis, and release of inflammatory mediators. Previously established serum inflammatory markers (IM) have been studied in baseline measures obtained prior to surgical resection, making it difficult to establish patterns for potential treatment-induced alteration of IM. We tested the hypothesis that serum-derived IM measured post-resection, prior to and following completion of CRT, may be related to residual tumor burden and response to treatment. IM was analyzed in serum collected pre and post-CRT from 82 individuals with a pathologic confirmed diagnosis of GBM using aptamer-based SOMAScan® proteomic assay. Clinical variables were collected or derived from electronic health records and included RT (radiation therapy) gross tumor volumes GTVT1 (enhancing tumor volume on T1 gadolinium MRI pre CRT), GTVT2 ( T2 FLAIR tumor volume on MRI pre CRT), the volume receiving the higher prescribed RT dose (60Gy) (PTVHD) and lower dose (46Gy) (PTVLD), and outcomes (overall survival (OS), progression-free survival (PFS)). Cox regression analyses were performed with pre and post IM levels significant associations (p<0.05) were identified. GTVT1 and PTVHD correlated positively with pre-CRT Fibrinogen level and negatively with alteration in CD23. GTVT2 and PTVLD correlated negatively with Kininogen alteration (p<0.05 for all). GTVT1 correlated positively with pre IL-6 level. PTVLD correlated negatively with pre TNFb level and PTVHD with CD14 alteration. High alteration in Albumin and a2-HS glycoprotein, lower pre HLA-G and pre IL-6, high pre IgE, pre PD-1 and pre TNF-b and lower altered TNF-b were all associated with longer OS (p<0.05). Accounting for age, tumor volumes and RT volumes, fibrinogen was the most prevalent signal associated with outcomes, the pre CRT level associated with OS (HR: 0.66, p: 0.04) and pre, post, and alteration significant for PFS (pre (HR : 0.60, p : 0.01), post (HR: 1.6, p: 0.01), alt (HR : 1.52 , p < 0.005). SAA pre CRT level was associated with OS (HR : 1.46, p: 0.02) and its alteration with PFS (HR : 1.62, p : 0.02 ). Additional IM alterations associated with OS CRP (HR: 0.57, p: 0.01), PD-1 (HR : 3.52, p , 0.005) and PFS, post CRT IL-10 level (HR : 0.04 , p : 0.02). GTVT1/PTVHD, GTVT2/PTVLD have distinct IM correlates in serum. Serum IM are associated with OS ad PFS and tumor volumes. Potential associations of previously literature-described inflammatory markers including Fibrinogen, SAA, IL-6, TNF-b and PD-1, were identified and are undergoing further analysis. Citation Format: Sarisha V. Jagasia, Thomas Joyce, Shreya Chappidi, Erdal Tasci, Theresa Cooley Zgela, Megan Mackey, Mary Sproull, Kevin Camphausen, Andra V. Krauze. Baseline and alteration in pre vs post standard of care management serum-derived inflammatory markers are associated with radiation treatment volumes and patient outcomes in patients with GBM in a large-scale proteomic panel [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 4992.

Unusual aggressive central nervous system involvement in CLIPPERS syndrome

Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids known as CLIPPERS syndrome is a rare and recently described inflammatory disorder of the central nervous system. Ataxia and cognitive dysfunction are usual symptoms and are dramatically responsive to steroid treatment. We present a case of a 58-year-old female patient, clinically diagnosed CLIPPERS syndrome with unusual aggressive involvement of supratentorial white matter and spinal cord that showed complete recovery with significant atrophy after steroid therapy.

Exposure to Low-Frequency Radiation Changes the Expression of Nestin, VEGF, BCRP and Apoptosis Markers During Glioma Treatment Strategy: An In Vitro Study

Background: Exposure to physical contamination during chemotherapy, including non-ionizing electromagnetic fields, raises concerns about the widespread sources of exposure to this type of radiation. Glioblastoma multiforme (GBM) is an aggressive central nervous system tumor that is hard to treat due to resistance to drugs such as temozolomide (TMZ). Objective: Electromagnetic fields (EMF) and haloperidol (HLP) may have anticancer effects. In this study, we investigated the effects of TMZ, HLP, and EMF on GBM cell lines and analyzed the association between non-ionizing radiation and the risk of change in drug performance. Methods: Cell viability and reactive oxygen species (ROS) generation were measured by MTT and NBT assay, respectively. Then, the expression levels of breast cancer-resistant protein (BCRP), Bax, Bcl2, Nestin, vascular endothelial growth factor (VEGF) genes, and P53, Bax, and Bcl2 Proteins were evaluated by real-time PCR and western blot. Results: Co-treatment of GBM cells by HLP and TMZ enhanced apoptosis in T-98G and A172 cells by increasing the expression of P53 and Bax and decreasing Bcl-2. Interestingly, exposure of GBM cells to EMF decreased apoptosis in the TMZ+HLP group. Conclusion: In conclusion, EMF reduced the synergistic effect of TMZ and HLP. This hypothesis that patients who are treated for brain tumors and suffer from depression should not be exposed to EMF is proposed in the present study. There appears to be an urgent need to reconsider exposure limits for low-frequency magnetic fields, based on experimental and epidemiological research, the relationship between exposure to non-ionizing radiation and adverse human health effects.

Differential H2O2 Metabolism among Glioblastoma Subtypes Confers Variable Responses to Pharmacological Ascorbate Therapy Combined with Chemoradiation.

Glioblastoma (GBM), a highly lethal and aggressive central nervous system malignancy, presents a critical need for targeted therapeutic approaches to improve patient outcomes in conjunction with standard-of-care (SOC) treatment. Molecular subtyping based on genetic profiles and metabolic characteristics has advanced our understanding of GBM to better predict its evolution, mechanisms, and treatment regimens. Pharmacological ascorbate (P-AscH-) has emerged as a promising supplementary cancer therapy, leveraging its pro-oxidant properties to selectively kill malignant cells when combined with SOC. Given the clinical challenges posed by the heterogeneity and resistance of various GBM subtypes to conventional SOC, our study assessed the response of classical, mesenchymal, and proneural GBM to P-AscH-. P-AscH- (20 pmol/cell) combined with SOC (5 µM temozolomide and 4 Gy of radiation) enhanced clonogenic cell killing in classical and mesenchymal GBM subtypes, with limited effects in the proneural subtype. Similarly, following exposure to P-AscH- (20 pmol/cell), single-strand DNA damage significantly increased in classical and mesenchymal but not proneural GBM. Moreover, proneural GBM exhibited increased hydrogen peroxide removal rates, along with increased catalase and glutathione peroxidase activities compared to mesenchymal and classical GBM, demonstrating an altered H2O2 metabolism that potentially drives differential P-AscH- toxicity. Taken together, these data suggest that P-AscH- may hold promise as an approach to improve SOC responsiveness in mesenchymal GBMs that are known for their resistance to SOC.

The role of BCL2L13 in glioblastoma: turning a need into a target.

Glioblastoma (GBM) is the most common aggressive central nervous system cancer. GBM has a high mortality rate, with a median survival time of 12-15 months after diagnosis. A poor prognosis and a shorter life expectancy may result from resistance to standard treatments such as radiation and chemotherapy. Temozolomide has been the mainstay treatment for GBM, but unfortunately, there are high rates of resistance with GBM bypassing apoptosis. A proposed mechanism for bypassing apoptosis is decreased ceramide levels, and previous research has shown that within GBM cells, B cell lymphoma 2-like 13 (BCL2L13) can inhibit ceramide synthase. This review aims to discuss the causes of resistance in GBM cells, followed by a brief description of BCL2L13 and an explanation of its mechanism of action. Further, lipids, specifically ceramide, will be discussed concerning cancer and GBM cells, focusing on ceramide synthase and its role in developing GBM. By gathering all current information on BCL2L13 and ceramide synthase, this review seeks to enable an understanding of these pieces of GBM in the hope of finding an effective treatment for this disease.

MiRNA-660-3p inhibits malignancy in glioblastoma via negative regulation of APOC1-TGFβ2 signaling pathway

ABSTRACT Glioblastoma as the most common and aggressive central nervous system tumor in adults. Its prognosis and therapeutic outcome are poor due to the limited understanding of its molecular mechanism. Apolipoprotein C-1 (APOC1) as a member of the apolipoprotein family that acts as a tumor promoter in various cancers. MicroRNA (miRNA) can silence gene expression and suppress tumor progression. However, the role of APOC1 and its upstream miRNA has not been explored in glioblastoma. Two glioblastoma cell lines (U87 and U251) were used to explore the role of APOC1 and its upstream miRNA-660-3p in glioblastoma tumorigenesis in vitro. Cells with APOC1/miRNA-660-3p overexpression or knockdown were assessed for their proliferation, migration, and invasion in vitro, and tumorigenesis in vivo. Gene and protein expression was assessed by qRT-PCR and western blot, respectively. Cell proliferation was assessed by the MTT assay and the EdU and Ki67 staining. Cell migration and invasion were assessed by the transwell assay. Tumorigenesis in vivo was assessed in U87 cells with a xenograft mouse model. APOC1 was overexpressed in glioblastoma compared with normal peritumoral tissue and was inversely related to patient prognosis. APOC1 overexpression promotes cell proliferation, migration, and invasion in vitro. APOC1 inhibition reduced tumor growth in vivo. miRNA-660-3p inhibits tumorigenesis by directly targeting APOC1. Mechanistically, APOC1 drives the malignancy of glioblastoma by activating the TGFβ2 signaling pathway. miRNA-660-3p suppresses tumorigenesis by targeting APOC1. Therefore, miRNA-660-3p/APOC1 axis can serve as potential intervention targets in managing glioblastoma progression.

INNV-08. LONG-TERM GLOBAL POST-MARKETING SAFETY SURVEILLANCE DATA FROM PEDIATRIC, ADULT AND ELDERLY PATIENTS WITH CENTRAL NERVOUS SYSTEM MALIGNANCIES TREATED WITH TUMOR TREATING FIELDS (TTFIELDS) THERAPY

Abstract BACKGROUND Glioblastoma (GBM) is an aggressive central nervous system (CNS) malignancy with poor prognosis. TTFields are electric fields that exert physical forces to disrupt cellular processes critical for cancer cell viability. TTFields therapy is approved for recurrent and newly diagnosed GBM, and pleural mesothelioma. We report long-term safety data from pediatric, adult and elderly patients with CNS malignancies receiving TTFields, from a global post-marketing surveillance (PMS) dataset. METHODS Unsolicited PMS data were collected from patients receiving TTFields (October 2011–October 2022). AEs were categorized using MedDRA version 25.1, and data stratified by age group (< 18, 18–65, and > 65 years). RESULTS Overall, 25,898 patients from the US, Europe, Israel, and Japan were included. Of these, 93 (0.4%) were < 18 years (pediatric), 17,817 (69%) were 18–65 years (adult), and 7,808 (30%) were > 65 years (elderly). Two-thirds (66%) of all patients were male. Demographic characteristics were therefore consistent with a typical GBM population. Of pediatric patients, 62% experienced ≥ 1 AE, with 53% related to TTFields. This was comparable in adults (72% and 56%, respectively), and elderly patients (75% and 57%, respectively). The most common TTFields-related AEs were skin reaction (pediatric: 39%; adult: 42%; elderly: 45%), heat (warmth) sensation (pediatric: 14%; adult: 12%; elderly: 12%), and electric (tingling) sensation (pediatric: 10%; adult: 15%; elderly: 10%). All-cause serious AEs occurred in 14%, 21% and 25% of pediatric, adult and elderly patients, respectively. No systemic toxicities were reported, regardless of age. CONCLUSIONS These long-term, real-world PMS data demonstrate that TTFields has a tolerable safety profile in pediatric, adult and elderly patients with CNS malignancies, with no new safety signals in any age group. Most AEs were localized skin reactions which are manageable. These data provide supportive evidence of the safety and broad applicability of TTFields, regardless of patient age.

Sellar atypical teratoid/rhabdoid tumor in adults: survival analysis of treatment strategies. Illustrative case.

Atypical teratoid/rhabdoid tumor (ATRT) is a rare, highly aggressive central nervous system tumor predominantly found in children. Limited information exists on ATRT in adults, posing challenges in diagnosis and treatment. This study presents the case of an adult patient with ATRT in the sellar region and explores the impact of different treatment regimens on patient survival. A 60-year-old female with an ATRT underwent resection of the tumor, followed by adjuvant chemoradiotherapy. Molecular genetic analysis revealed compound heterozygous SMARCB1 point mutations. Survival analysis was performed on previously published adult ATRT cases, comparing treatment approaches. The cohort's overall median survival was 6 months, with patients receiving combined chemoradiotherapy showing the longest median survival of 23.5 months. Statistical analysis demonstrated a significant difference in survival between patients treated with surgery alone and those receiving surgery followed by chemoradiotherapy (p < 0.001). However, no significant difference was observed between patients treated with surgery alone and those with postoperative radiotherapy (p = 0.105). Early initiation of adjuvant chemoradiotherapy following surgery improves survival outcomes in adult patients with ATRT. Because of limited data on standardized treatment protocols for adults with ATRT, further research and larger-scale studies are needed to establish effective treatment guidelines for this population.

Hospital Readmission Rates in Patients With Neuromyelitis Optica Spectrum Disorder.

Neuromyelitis optica spectrum disorder (NMOSD) is an aggressive central nervous system astrocytopathy often resulting in rapid neurologic decline. Patients have recurrent flares that require immunomodulatory therapy for relapse prevention. These patients are usually hospitalized and may need rehospitalization after decline. Hospital readmission rates are important indicators that can be used to gauge health care quality and have direct implications on hospital compensation. This study aims to identify high-risk characteristics of patients with NMOSD that can be used to predict hospital readmissions. The 2017 Nationwide Readmissions Database was searched for hospital admissions for NMOSD in the United States. All patients with hospital readmission within 30 days of discharge from the index hospitalization were included. The 30-day all-cause readmission rate for NMOSD was 11.9% (95% CI, 10.6%-13.3%). Patients aged 65 to 74 years had higher odds of readmission; those with private insurance had decreased odds. Sex did not affect readmission. Several comorbidities, such as respiratory failure, peripheral vascular disease, neurocognitive disorders, and neurologic blindness, were predictive of readmissions. Plasma exchange increased the odds of readmission, whereas intravenous immunoglobulin and immunomodulatory infusions, such as chemotherapies and monoclonal antibodies, did not affect readmission. The most common etiologies for 30-day read-mission were neurologic, infectious, and respiratory. Treatment targeted toward these etiologies may result in reduced overall readmission, thereby decreasing overall disease burden.

Survival Benefit from Multimodal Treatment for Patients with Atypical Teratoid Rhabdoid Tumor in a Surveillance, Epidemiology, and End Results Database Analysis

Introduction: Atypical teratoid rhabdoid tumor (ATRT) is among the most aggressive central nervous system malignancies. Although rare, this tumor typically afflicts young children and results in mortality within months. Here, we aim to determine key clinical features and treatment options that impact the survival of patients with ATRT. Methods: From the year 2000 to 2019, 363 patients with ATRT were identified from the Surveillance, Epidemiology, and End Results database. Univariate analysis was used to identify variables that had a significant impact on the primary endpoint of overall survival (OS). Multivariable analysis was then used to identify independent predictors of survival. Results: The median OS of the entire cohort was 13 months. Univariate analysis identified ages between 1 and 3 years, ages between 4 and 17 years, years of diagnosis between 2010 and 2019, and the receipt of treatment to have a significant impact on survival. In multivariable analysis, ages between 1 and 3 years and receipt of treatment were the only significant independent predictors of survival. The median OS was significantly greater in patients who received surgical treatment, chemotherapy, or radiation when compared to those who did not receive any treatment. In general, the receipt of any combination of therapies improved the median OS significantly. The receipt of triple therapy had the greatest impact on survival. Discussion: This study highlights the survival benefit of a multimodal approach in the treatment of ATRT. The use of triple therapy, including surgery, radiation, and chemotherapy, was found to have the greatest survival benefit for patients. Overall, these findings may guide future care for patients with ATRT.

SDPS-29 SERUM-DERIVED CD47 AS A MARKER OF TUMOR BURDENAND OUTCOME IN GBM PATIENTS – CORRELATIVE ANALYSISOF TUMOR LOCATION, RADIATION THERAPY VOLUMES,AND SURVIVAL

Abstract Glioblastomas (GBM) are the most aggressive central nervous system tumors exhibiting near universal recurrence following resection and chemoradiation (CRT). CD47 is an integrin-associated transmembrane protein associated with immunomodulation, invasion, and stemness that is highly expressed in GBM. We tested the hypothesis patient serum-derived CD47 measured pre vs. post-CRT may be related to tumor burden by exploring its association with tumor dissemination in the brain, RT volumes, and outcomes. CD47 was analyzed using an aptamer-based SOMAscan proteomic assay on serum collected pre and post CRT for 82 individuals with a pathologic diagnosis of GBM. Clinical features (tumor location (cortical/periventricular), gross tumor volumes (GTVT1, GTVT2), and outcome (overall survival (OS), progression-free survival (PFS)) were analyzed in conjunction with alteration in CD47 levels. Alteration in CD47 level was associated with OS (HR = 32.34 CI: 3.520 - 288.3, p = 0.0004053) and PFS (HR =8.5, p = .0008 CI: 0.2291-4.011). Expression of CD47 increased after CRT (p = .022). Patients with periventricular tumors had higher expression of CD47 pre vs. post CRT (p = 0.0188) and worse OS (median 13 vs. 25 months) and PFS (median 5 vs. 10 months) as compared to patients with strictly cortical tumor presence. A positive correlation was identified between GTVT1 and GTVT2 and CD47 expression levels (p = .0006). Lower CD47 expression values were associated with higher survival probability (p = .013). The stratification of CD47 expression levels yielded increasingly significant results with the separation of discrete survival groups (p = .00013), indicating clinically distinct subtypes of GBM. Tumor location (cortical vs. periventricular) and GTVT1 correlated with OS and PFS (p&amp;lt;0.05), unlike GTVT2 in this cohort in the absence of CD47 expression level. CD47 expression levels correlate with tumor location, RT volumes, OS, and PFS with distinct GBM subtypes potentially stratified via serum CD47 expression levels.

Nanoparticles Mediated the Diagnosis and Therapy of Glioblastoma: Bypass or Cross the Blood-Brain Barrier.

Glioblastoma is one of the most aggressive central nervous system malignancies with high morbidity and mortality. Current clinical approaches, including surgical resection, radiotherapy, and chemotherapy, are limited by the difficulty of targeting brain lesions accurately, leading to disease recurrence and fatal outcomes. The lack of effective treatments has prompted researchers to continuously explore novel therapeutic strategies. In recent years, nanomedicine has made remarkable progress and expanded its application in brain drug delivery, providing a new treatment for brain tumors. Against this background, this article reviews the application and progress of nanomedicine delivery systems in brain tumors. In this paper, the mechanism of nanomaterials crossing the blood-brain barrier is summarized. Furthermore, the specific application of nanotechnology in glioblastoma is discussed in depth.

CDH1 hypermethylation: a potential molecular pathway for invasiveness in glioblastoma.

Glioblastoma is the most aggressive central nervous system primary tumor. Prognosis is poor, mainly due to the malignant characteristics of the tumor, such as high cell proliferation and invasiveness. CDH1 hypermethylation is linked to the invasive potential in various cancer types, but its importance is still unknown in glioblastoma. In this context, the methylation status of CDH1 was analyzed using MSP-PCR (Methylation-specific Polymerase Chain Reaction) in glioblastoma (n = 34) and normal glial tissue samples (n = 11). CDH1 hypermethylation was found in 39.4% (13/34) of the tumor samples and none of the normal glial tissue, suggesting a relation between CDH1 hypermethylation and glioblastoma ( P = 0.0195). Finally, this study showed unprecedented information that could contribute to clarifying the molecular pathways involved in the invasiveness and aggressiveness of this type of cancer.

The safety and utility of low-intensity pulsed ultrasound for effective blood–brain barrier penetration in the treatment of glioblastoma: a scoping review protocol

Abstract Glioblastoma (GBM) is one of the most aggressive central nervous system tumours with suboptimal treatment options and associated poor prognosis. A major impediment to systemic treatment is the limitation of drug delivery to the tumour by the blood-brain barrier (BBB). Several novel techniques to permeate the BBB have been described, however of significant promise is the disruption of the blood brain barrier with low-intensity pulsed ultrasound (LIPU) to facilitate the delivery of varying therapeutic agents. This emerging technique has been demonstrated in clinical studies to enhance delivery of chemotherapeutic agents to the tumour. This study protocol seeks to guide the comprehensive review of literature concerning the safety and utility of LIPU for effective BBB penetration in the treatment of GBM. This protocol follows the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Extension for Scoping Reviews (PRISMA ScR) guideline 2020. The search strategy was performed on four databases: PubMed, EMBASE, SCOPUS, and Cochrane Central Register of Controlled Trials. All observational and human randomised controlled studies describing the use of LIPU in the treatment of GBM will be included. Excluded studies include non-human randomized control trials, abstract only articles, letters to the editor, conference proceedings. Our outcomes include frequency of LIPU used, duration of intervention, clinical outcomes, complications, and challenges associated with the use of LIPU. This study aims to assess the safety and feasibility of this technique in the management of the GBM and proscribe its use if found effective to improve the outcomes in these patients.

Novel USP9X Mutation in A Lebanese Patient with Delay and Microcephaly: Case Report and Review of Literature

Introduction: USP9X gene is located on the X-chromosome and encodes for an enzyme that regulates important substrates involved in neuronal growth and development. Thus, rare USP9X mutations were identified as directly causative of neurodevelopmental disorders (NDDs) and Intellectual Disability (ID) in homozygous males and more rarely in heterozygous females. In males, USP9X variants have been linked to an X-linked mental retardation syndrome that includes; central nervous system (CNS) abnormalities (white matter disturbances, thin corpus callosum, widened ventricles, and cerebellar defects), global delay with significant alteration of speech, language and behavior, hypotonia, joint hypermobility, digital abnormalities, gastro-intestinal symptoms, visual system defects and dysmorphic facial features. Patient Data: We report the rare case of a 3 years old and 8 months male patient presenting with NDD, ID, speech delay, progressive aggressive behavioral changes and CNS abnormalities (microcephaly, left periventricular lesion). He was found to have a USP9X variant carrying a missense mutation: USP9X, c.1870A&gt;T p.(Met624Leu) on Whole-Exome Sequencing (WES). Discussion: Our patient had most of the important features of the previously described X-linked mental retardation syndrome but some were absent such as dysmorphic features, digital or visual abnormalities and hypotonia. Microcephaly rather than macrocephaly was noted, which could be an additional potential CNS malformation, expanding the spectrum of phenotypic characteristics of the USP9X variants. No associated congenital anomalies were noted that are usually more common in female subjects. Conclusion: This is to our knowledge the first reported case of a USP9X variant in Lebanon. The clinical characteristics matched most of the previously described features in the literature. Microcephaly was a new clinical feature not previously described and could be a new possible phenotypic characteristic of the disease.

Differences in survival prognosticators between children and adults with H3K27M-mutant diffuse midline glioma.

H3K27M-mutant diffuse midline glioma (DMG) is a rare and aggressive central nervous system tumor. The biological behavior, clinicopathological characteristics, and prognostic factors of DMG have not yet been completely uncovered, especially in adult patients. This study aims to investigate the clinicopathological characteristics and identify prognostic factors of H3K27M-mutant DMG in pediatric and adult patients, respectively. A total of 171 patients with H3K27M-mutant DMG were included in the study. The clinicopathological characteristics of the patients were analyzed and stratified based on age. The Cox proportional hazard model was used to determine the independent prognostic factors in pediatric and adult subgroups. The median overall survival (OS) for the entire cohort was 9.0 months. Significant differences were found in some clinicopathological characteristics between children and adults. The median OS was also significantly different between the pediatric and adult subgroups, with 7.1 months for children and 12.3 months for adults (p < 0.001). In the overall population, the multivariate analysis identified adult patients, single lesion, concurrent chemoradiotherapy/radiotherapy, and intact ATRX expression as independent favorable prognostic factors. In the age-stratified subgroups, the prognostic factors varied between children and adults, with intact ATRX expression and single lesion being independent favorable prognostic factors in adults, while infratentorial localization was significantly associated with worse prognosis in children. The differences in clinicopathological features and prognostic factors between pediatric and adult patients with H3K27M-mutant DMG suggest the need for further clinical and molecular stratification based on age.

A demographic and socioeconomic analysis of risk factors in meningeal melanomatosis.

e14019 Background: Meningeal melanomatosis (MM) is a rare and aggressive central nervous system neoplasm that normally occurs in the leptomeningeal melanocytes. Meningeal melanomatosis represents only 0.06% to 0.1% of all primary brain tumors, but it is accompanied with a very poor prognosis with data showing a mean survival of 10 weeks after diagnosis. Despite intrathecal chemotherapy treatment, only a modest positive effect on survival was observed. Limited research has been done. In this study, demographic factors in patients diagnosed with MM from the National Cancer Database (NCDB) were analyzed to elucidate potentially valuable insights regarding its epidemiology. Methods: A retrospective cohort study using data collected between 2004–2020 from the NCDB included 137 patients with a histologically confirmed diagnosis of MN. The descriptive analysis included an examination of demographic factors such as sex, age, race, Hispanic status, insurance coverage, type of medical facility, and Charleson-Deyo score. Primary site was also analyzed. Results: A total of 137 patients were identified with a diagnosis of MM between 2004 – 2020. The most common primary sites of MM were the meninges, not otherwise specified (NOS) (43.8%), spinal meninges (29.2%) and cerebral meninges (19.0%). In the dataset, 50.4% of diagnosed patients were male. The average age of diagnosis was 51.4 years (SD = 21.5, range = 0 – 90 years). The majority of the individuals (73.7%) had a Charlson-Deyo comorbidity score of 0. Most of the individuals diagnosed with MM were non-Hispanic (83.9%) and 87.6% of patients with diagnosed MM were White. Among the 115 patients with available data for median household income, 37.4% were in the top income quartile. A greater proportion of patients, 54.7%, had private insurance compared to those without insurance or those insured through Medicare or Medicaid. The majority of patients resided in metropolitan counties with a population exceeding 250,000 (71.8%) For patients with documented treatment facility type (N = 99), 56.6% of patients were treated in an academic/research program. Conclusions: This first NCDB analysis fills a crucial void in the existing knowledge on MM. MM affected males and females equally, contrary to published literature which suggested a slight predominance in males. The most common primary sites of diagnosis were the meninges NOS, spinal meninges and cerebral meninges, which supports findings in the literature. This is a novel description of the socioeconomic factors of MM patients in the literature, showing that these patients tend to have higher incomes and reside in densely populated metropolitan areas, and are more likely to receive treatment in an academic medical facility. Additional research is imperative to elucidate the influence of demographic and socioeconomic factors on the diagnosis, treatment options, and overall survival outcomes for patients with MM.

Novel Strategy Involving High-Dose Chemotherapy with Stem Cell Rescue Followed by Intrathecal Topotecan Maintenance Therapy without Whole-Brain Irradiation for Atypical Teratoid/Rhabdoid Tumors

Atypical teratoid/rhabdoid tumor (AT/RT) is a rare aggressive central nervous system tumor that typically affects children under three years old and has poor survival with a high risk for neurologic deficits. The primary purpose of this study was to successfully treat the disease and delay or avoid whole-brain radiotherapy for children with AT/RT. A retrospective analysis was performed for six children diagnosed with AT/RT and treated with multimodal treatment at a single institute between 2014 and 2020. Furthermore, germline SMARCB1 aberrations and MGMT methylation status of the tumors were analyzed. One patient who did not receive a modified IRS-III regimen replaced with ifosphamide, carboplatin, and etoposide (ICE) in induction chemotherapy was excluded from this analysis. Five patients who received ICE therapy were under three years old. After a surgical approach, they received intensive chemotherapy and high-dose chemotherapy with autologous peripheral blood stem cell transplantation (HDCT/autoPBSCT) followed by intrathecal topotecan maintenance therapy. Three patients underwent single HDCT/autoPBSCT, and the other two received sequential treatment. Two patients with germline SMARCB1 aberrations and metastases died of progressive AT/RT or therapy-related malignancy, while 3 with localized tumors without germline SMARCB1 aberrations remained alive. One survivor received local radiotherapy only, while the other two did not undergo radiotherapy. All three surviving patients were able to avoid whole-brain radiotherapy. Our results suggest that AT/RT patients with localized tumors without germline SMARCB1 aberrations can be rescued with multimodal therapy, including induction therapy containing ICE followed by HDCT/autoPBSCT and intrathecal topotecan maintenance therapy without radiotherapy. Further large-scale studies are necessary to confirm this hypothesis.

Updates in Glioblastoma Immunotherapy: An Overview of the Current Clinical and Translational Scenario.

Glioblastoma (GBM) is the most common and aggressive central nervous system tumor, requiring multimodal management. Due to its malignant behavior and infiltrative growth pattern, GBM is one of the most difficult tumors to treat and gross total resection is still considered to be the first crucial step. The deep understanding of GBM microenvironment and the possibility of manipulating the patient's innate and adaptive immune system to fight the neoplasm represent the base of immunotherapeutic strategies that currently express the future for the fight against GBM. Despite the immunotherapeutic approach having been successfully adopted in several solid and haematologic neoplasms, immune resistance and the immunosuppressive environment make the use of these strategies challenging in GBM treatment. We describe the most recent updates regarding new therapeutic strategies that target the immune system, immune checkpoint inhibitors, chimeric antigen receptor T cell therapy, peptide and oncolytic vaccines, and the relevant mechanism of immune resistance. However, no significant results have yet been obtained in studies targeting single molecules/pathways. The future direction of GBM therapy will include a combined approach that, in contrast to the inescapable current treatment modality of maximal resection followed by chemo- and radiotherapy, may combine a multifaceted immunotherapy treatment with the dual goals of directly killing tumor cells and activating the innate and adaptive immune response.

The dark side of mRNA translation and the translation machinery in glioblastoma.

Among the different types of cancer affecting the central nervous system (CNS), glioblastoma (GB) is classified by the World Health Organization (WHO) as the most common and aggressive CNS cancer in adults. GB incidence is more frequent among persons aged 45-55years old. GB treatments are based on tumor resection, radiation, and chemotherapies. The current development of novel molecular biomarkers (MB) has led to a more accurate prediction of GB progression. Moreover, clinical, epidemiological, and experimental studies have established genetic variants consistently associated with the risk of suffering GB. However, despite the advances in these fields, the survival expectancy of GB patients is still shorter than 2years. Thus, fundamental processes inducing tumor onset and progression remain to be elucidated. In recent years, mRNA translation has been in the spotlight, as its dysregulation is emerging as a key cause of GB. In particular, the initiation phase of translation is most involved in this process. Among the crucial events, the machinery performing this phase undergoes a reconfiguration under the hypoxic conditions in the tumor microenvironment. In addition, ribosomal proteins (RPs) have been reported to play translation-independent roles in GB development. This review focuses on the research elucidating the tight relationship between translation initiation, the translation machinery, and GB. We also summarize the state-of-the-art drugs targeting the translation machinery to improve patients' survival. Overall, the recent advances in this field are shedding new light on the dark side of translation in GB.