Central Nervous System Malignancies Research Articles

Fatostatin induces ferroptosis through inhibition of the AKT/mTORC1/GPX4 signaling pathway in glioblastoma

Glioblastoma multiforme (GBM) is the most common and fatal primary malignant central nervous system tumor in adults. Although there are multiple treatments, the median survival of GBM patients is unsatisfactory, which has prompted us to continuously investigate new therapeutic strategies, including new drugs and drug delivery approaches. Ferroptosis, a kind of regulated cell death (RCD), has been shown to be dysregulated in various tumors, including GBM. Fatostatin, a specific inhibitor of sterol regulatory element binding proteins (SREBPs), is involved in lipid and cholesterol synthesis and has antitumor effects in a variety of tumors. However, the effect of fatostatin has not been explored in the field of ferroptosis or GBM. In our study, through transcriptome sequencing, in vivo experiments, and in vitro experiments, we found that fatostatin induces ferroptosis by inhibiting the AKT/mTORC1/GPX4 signaling pathway in glioblastoma. In addition, fatostatin inhibits cell proliferation and the EMT process through the AKT/mTORC1 signaling pathway. We also designed a p28-functionalized PLGA nanoparticle loaded with fatostatin, which could better cross the blood-brain barrier (BBB) and be targeted to GBM. Our research identified the unprecedented effects of fatostatin in GBM and presented a novel drug-targeted delivery vehicle capable of penetrating the BBB in GBM.

Time interval from diagnosis to treatment of brain metastases with stereotactic radiosurgery is not associated with radionecrosis or local failure.

Brain metastases are the most common intracranial tumor diagnosed in adults. In patients treated with stereotactic radiosurgery, the incidence of post-treatment radionecrosis appears to be rising, which has been attributed to improved patient survival as well as novel systemic treatments. The impacts of concomitant immunotherapy and the interval between diagnosis and treatment on patient outcomes are unclear. This single institution, retrospective study consisted of patients who received single or multi-fraction stereotactic radiosurgery for intact brain metastases. Exclusion criteria included neurosurgical resection prior to treatment and treatment of non-malignant histologies or primary central nervous system malignancies. A univariate screen was implemented to determine which factors were associated with radionecrosis. The chi-square test or Fisher's exact test was used to compare the two groups for categorical variables, and the two-sample t-test or Mann-Whitney test was used for continuous data. Those factors that appeared to be associated with radionecrosis on univariate analyses were included in a multivariable model. Univariable and multivariable Cox proportional hazards models were used to assess potential predictors of time to local failure and time to regional failure. A total of 107 evaluable patients with a total of 256 individual brain metastases were identified. The majority of metastases were non-small cell lung cancer (58.98%), followed by breast cancer (16.02%). Multivariable analyses demonstrated increased risk of radionecrosis with increasing MRI maximum axial dimension (OR 1.10, p=0.0123) and a history of previous whole brain radiation therapy (OR 3.48, p=0.0243). Receipt of stereotactic radiosurgery with concurrent immunotherapy was associated with a decreased risk of local failure (HR 0.31, p=0.0159). Time interval between diagnostic MRI and first treatment, time interval between CT simulation and first treatment, and concurrent immunotherapy had no impact on incidence of radionecrosis or regional failure. An optimal time interval between diagnosis and treatment for intact brain metastases that minimizes radionecrosis and maximizes local and regional control could not be identified. Concurrent immunotherapy does not appear to increase the risk of radionecrosis and may improve local control. These data further support the safety and synergistic efficacy of stereotactic radiosurgery with concurrent immunotherapy.

Early diagnosis of brain metastases using cerebrospinal fluid cell‐free DNA‐based breakpoint motif and mutational features in lung cancer

Early diagnosis of brain metastases using cerebrospinal fluid cell‐free DNA‐based breakpoint motif and mutational features in lung cancer

Mortality trends in primary malignant brain and central nervous system tumors vary by histopathology, age, race, and sex

PurposePrimary malignant brain and other central nervous system tumors are rare cancers that have shown rising mortality rates in recent years. To elucidate potential factors involved in this rising death rate, we examined mortality trends for primary malignant BT in the United States stratified by histopathology groupings, age, race, and sex.MethodsMortality rates for demographic factors within primary malignant BT were generated using the National Center for Health Statistics' National Vital Statistics Systems data from 2004 to 2018. Additionally, histopathology-specific incidence-based mortality rates were calculated using the National Cancer Institute’s Surveillance, Epidemiology, and End-Results (SEER) 18 data from 2004 to 2018. Joinpoint modeling was used to estimate mortality trends and annual percent changes with corresponding 95% confidence intervals.ResultsOverall, there was a very small increase in mortality from 2004 to 2018. Individuals > 65 years saw a small increase in mortality, while changes in individuals of other ages were non-significant. Asian/Pacific Islander or American Indian/Alaskan Native had the largest increase in mortality. Among histopathology groupings, there was a small mortality increase in adults ages > 65 years with glioblastoma, while the mortality rate of other malignant gliomas declined in the same age group. CNS lymphoma mortality rates in patients ages 15–39 and 40–64 years declined significantly while rising significantly in the > 65 age group. In pediatric patients, embryonal tumor mortality had a non-significant increase between 2004 and 2007 but declined significantly between 2007 and 2018.ConclusionExamining age, race, sex, and histopathology-specific mortality trends at the population level can provide important information for clinicians, researchers, and aid in public health planning.

Rhythmic calcium ion activity related to glioma growth reveals the mechanism of ion transmission

Rhythmic calcium ion activity related to glioma growth reveals the mechanism of ion transmission

Glioblastoma Multiforme: Molecular Biology and Updated Systematic Review on Natural Extract and Phytochemical Efficacy In-vitro

Glioblastoma multiforme (GBM) is the most prevalent primary malignant central nervous system tumours (CNST). Current treatment consists of surgical resection and adjuvant chemoradiotherapy, the gold-standard agent being Temozolomide (TMZ). Despite optimal treatment, GBM has an abysmal associated prognosis of approximately 15 months. The disproportionately high morbidity and mortality necessitate studies which strive to increase knowledge on putative therapeutic agents to confirm or deny their possible use against GBM Therefore, there is an urgent need to develop a deep understanding of GBM molecular biology upon which more effective therapeutic strategies may be developed.
 Natural extracts and phytochemicals have shown promise as potential therapeutic agents against GBM. In this review, the molecular biology of GBM and molecular factors which contribute to therapeutic resistance are discussed in depth. The mechanisms by which phytochemicals and natural extracts exhibit can inhibit GBM growth and proliferation are discussed. Moreover, statistical analysis demonstrated that natural extracts and phytochemicals may be superior to TMZ in-vitro.
 This review demonstrates that phytochemicals have great potential as novel therapeutic agents against GBM. Further preclinical and clinical studies are needed to determine the optimal doses, routes of administration, and potential toxicities of these agents, but their unique molecular targets and low toxicity profiles make them attractive candidates for further investigation.

Clinical, histological, and molecular features of gliomas in adults with neurofibromatosis type 1.

People with NF1 have an increased prevalence of central nervous system malignancy. However, little is known about the clinical course or pathologic features of NF1-associated gliomas in adults, limiting clinical care and research. Adults (≥18 years) with NF1 and histologically confirmed non-optic pathway gliomas (non-OPGs) at Johns Hopkins Hospital, Memorial Sloan Kettering Cancer Center, and Washington University presenting between 1990 and 2020 were identified. Retrospective data were collated, and pathology was reviewed centrally. Forty-five patients, comprising 23 females (51%), met eligibility criteria, with a median of age 37 (18-68 years) and performance status of 80% (30%-100%). Tissue was available for 35 patients. Diagnoses included infiltrating (low-grade) astrocytoma (9), glioblastoma (7), high-grade astrocytoma with piloid features (4), pilocytic astrocytoma (4), high-grade astrocytoma (3), WHO diagnosis not reached (4) and one each of gliosarcoma, ganglioglioma, embryonal tumor, and diffuse midline glioma. Seventy-one percent of tumors were midline and underwent biopsy only. All 27 tumors evaluated were IDH1-wild-type, independent of histology. In the 10 cases with molecular testing, the most common genetic variants were NF1, EGFR, ATRX, CDKN2A/B, TP53, TERT, and MSH2/3 mutation. While the treatments provided varied, the median overall survival was 24 months [2-267 months] across all ages, and 38.5 [18-109] months in individuals with grade 1-2 gliomas. Non-OPGs in adults with NF1, including low-grade tumors, often have an aggressive clinical course, indicating a need to better understand the pathobiology of these NF1-associated gliomas.

Current Status and Challenges of Vaccination Therapy for Glioblastoma.

Glioblastoma (GBM), also known as grade IV astrocytoma, is the most common and deadly type of central nervous system malignancy in adults. Despite significant breakthroughs in current GBM treatments such as surgery, radiotherapy, and chemotherapy, the prognosis for late-stage glioblastoma remains bleak due to tumor recurrence following surgical resection. The poor prognosis highlights the evident and pressing need for more efficient and targeted treatment. Vaccination has successfully treated patients with advanced colorectal and lung cancer. Therefore, the potential value of using tumor vaccines in treating glioblastoma is increasingly discussed as a monotherapy or in combination with other cellular immunotherapies. Cancer vaccination includes both passive administration of monoclonal antibodies and active vaccination procedures to activate, boost, or bias antitumor immunity against cancer cells. This article focuses on active immunotherapy with peptide, genetic (DNA, mRNA), and cell-based vaccines in treating GBM and reviews the various treatment approaches currently being tested. Although the ease of synthesis, relative safety, and ability to elicit tumor-specific immune responses have made these vaccines an invaluable tool for cancer treatment, more extensive cohort studies and better guidelines are needed to improve the efficacy of these vaccines in anti-GBM therapy.

Recent progress and novel approaches to treating atypical teratoid rhabdoid tumor

Atypical teratoid rhabdoid tumors (AT/RT) are malignant central nervous system (CNS) tumors that occur mostly in young children and have historically carried a very poor prognosis. While recent clinical trial results show that this tumor is curable, outcomes are still poor compared to other central nervous system embryonal tumors. We here review prior AT/RT clinical trials and highlight promising pre-clinical results that may inform novel clinical approaches to this aggressive cancer.

A critical analysis of neuro-oncology clinical trials.

Limitations in trial design, accrual, and data reporting impact efficient and reliable drug evaluation in cancer clinical trials. These concerns have been recognized in neuro-oncology but have not been comprehensively evaluated. We conducted a semi-automated survey of adult interventional neuro-oncology trials, examining design, interventions, outcomes, and data availability trends. Trials were selected programmatically from ClinicalTrials.gov using primary malignant central nervous system tumor classification terms. Regression analyses assessed design and accrual trends; effect size analysis utilized survival rates among trials investigating survival. Of 3038 reviewed trials, most trials reporting relevant information were nonblinded (92%), single group (65%), nonrandomized (51%), and studied glioblastomas (47%) or other gliomas. Basic design elements were reported by most trials, with reporting increasing over time (OR = 1.24, P < .00001). Trials assessing survival outcomes were estimated to assume large effect sizes of interventions when powering their designs. Forty-two percent of trials were completed; of these, 38% failed to meet their enrollment target, with worse accrual over time (R = -0.94, P < .00001) and for US versus non-US based trials (OR = 0.5, P < .00001). Twenty-eight percent of completed trials reported partial results, with greater reporting for US (34.6%) versus non-US based trials (9.3%, P < .00001). Efficacy signals were detected by 15%-23% of completed trials reporting survival outcomes. Low randomization rates, underutilization of controls, and overestimation of effect size, particularly pronounced in early-phase trials, impede generalizability of results. Suboptimal designs may be driven by accrual challenges, underscoring the need for cooperative efforts and novel designs. The limited results reporting highlights the need to incentivize data reporting and harmonization.

Proton beam therapy in pediatric patients with central nervous system tumors: method features, clinical data analysis

Introduction. Central nervous system (CNS) tumors are the most common pediatric solid tumor, that need multimodality treatment approach including surgery, intensive chemotherapy (CT) and radiotherapy (RT). Due to toxicity, mostly late, RT has limited use in children, especially those under 3 years of age. The physical characteristics of proton beam therapy (PBT) minimize the risk and types of toxicity compared to photons, making it the preferred choice for pediatric use. Aim – to analyze the experience of PBT in patients under 18 years of age with various types of CNS malignancies, the assessment of risk factors for acute and late toxicity and its clinical manifestations. Materials and methods. A retrospective analysis of 63 courses of PBT performed in 58 patients with CNS malignancies for the period from 2018 to 2022 was carried out on Proton Center of the Sergey Beresin Medical Institute. The manifestations of local and systemic toxicity (predominantly acute) were analyzed, with an assessment of the influence of age, the volume of RT, the use of previous and concomitant CT on the severity of adverse events (AE). Results. In the study cohort, patients with embryonal CNS malignancies predominated (72.3 %). Median age was 5 years 2 months, median follow-up was 15 months. In 36 % of cases, a complete response was achieved by the start of PBT. Patients with craniospinal irradiation (CSI) prevailed (60 %). Among the manifestations of toxicity, AE grade I–II predominated. The most common AE were local reactions (dermatitis (84 %), focal alopecia (96 %)). Among systemic AE, hematological complications (84 %) were the most often occurred. A more pronounced toxicity profile was registered in the group with CSI, while concomitant CT, the patient’s age, previous CT did not significantly affect the severity of most of the assessed AE parameters (p &gt; 0.05). The analysis of late toxic effects was difficult due to the short follow-up period, the cumulative effect of other treatment modalities on the AE’s development. The reported complications included persistent focal alopecia (14 % of cases), endocrinopathies (7 %), neurological manifestations (6 %). One (2 %) child had a severe neurological deficit, secondary epilepsy with psychomotor regression, which can also be associated with the potentiating effect of previous CT and high-dose CT. Conclusion. The analysis of our data and literature review allows to conclude that PBT has relatively low toxicity profile, which is the determining factor for choosing this method of RT in pediatric patients. The main risk factor of AE’s was CSI. The acceptable acute toxicity of repeat PBT makes it possible to be used in pts with disease progression or relapse in case of absence of alternative therapeutic options.

Immunotherapy reverses glioma-driven dysfunction of immune system homeostasis

BackgroundGlioma-induced immune dysregulation of the hematopoietic system has been described in a limited number of studies. In this study, our group further demonstrates that gliomas interrupt the cellular differentiation programming...

ONC201 for Glioma Treatment: Adding an Important Weapon to Our Arsenal

Glioma, specifically gliobastoma, represents the commonest central nervous system malignancy and is notoriously challenging to treat, with only a minimal number of patients surviving beyond a year after diagnosis. The available treatment options include surgical resection, radiotherapy, and chemotherapy, mainly with temozolomide. However, gliomas can be particularly treatment resistant and novel options are currently being researched. One such agent is ONC201, the first member of the imipridone class and a TNF-related apoptosis inducing ligand (TRAIL)-inducing compound, which has shown positive results in the first preliminary clinical reports about its application in glioma patients, while also being safe and well-tolerated. Particular promise has been shown for the H3K27M mutated glioblastomas, with more trials focusing on this patient subset. It is likely that this compound will be added in the treatment algorithms of glioma in the future, although more research is still needed.

Temporal trends in the incidence of malignant and nonmalignant primary brain and central nervous system tumors by the method of diagnosis in England, 1993-2017.

Several studies report increases in the incidences of primary central nervous system (CNS) tumors. The reasons for this are unclear. Data on all 188 340 individuals diagnosed with a primary CNS tumor in England (1993-2017) were obtained from the National Cancer Registration and Analysis Service. Data on all computerized tomography (CT) head and magnetic resonance imaging (MRI) brain scans in England (2013-2017) were obtained from the National Health Service Digital. Age-sex-standardized annual incidence rates per 100 000 population (ASR) were calculated by calendar year, tumor behavior, tumor location, and method of diagnosis. Temporal trends were quantified using average annual percent change (AAPC). The ASR for all CNS tumors increased from 13.0 in 1993 to 18.6 in 2017 (AAPC: +1.5%, 95% CI: 1.3, 1.7). The ASR for malignant tumors (52% overall) remained stable (AAPC: +0.5%, 95% CI: -0.2, 1.3), while benign tumors (37% overall) increased (AAPC: +2.6%, 95% CI: 1.2, 4.0). Among the 66% of benign tumors that were microscopically confirmed, the ASR increased modestly (AAPC: +1.3%, 95% CI: 0.5, 2.1). However, among the 25% of benign tumors that were radiographically confirmed, the ASR increased substantially (AAPC: 10.2%, 95% CI: 7.9, 12.5), principally driven by large increases in those who are aged 65+ years. The rate of CT head scans in Accident & Emergency (A&E) increased during 2013-2017, with especially large increases in 65-84 and 85+-year-olds (AAPCs: +18.4% and +22.5%). Increases in CNS tumor incidence in England are largely attributable to the greater detection of benign tumors. This could be the result of the increasing use of neuroimaging, particularly CT head scans in A&E in people who are aged 65+ years.

The Epidemiology of Brain and Spinal Cord Tumors.

CNS tumors are a diverse group of neoplasms that emerge from a variety of different CNS cell types. These tumors may be benign, malignant, or borderline in nature. The majority of high grade glial tumors are fatal, with the exception of pilocytic astrocytoma. Primary malignant CNS tumors occur at a global annual rate of 2.1 to 5.8 per 100,000 persons. Males are more likely to develop malignant brain tumors than females, whereas benign meningiomas are more common in adultfemales. Additionally, gender inequalities in non-malignant tumors peak between the ages of 25 and 29years. Only a small number of genetic variants have been associated with survival and prognosis. Notably, central nervous system (CNS) tumors exhibit significant age, gender, and race variation. Race is another factor that affects the incidence of brain and spinal cord tumors. Different races exhibit variation in terms of the prevalence of brain and CNS malignancies. This chapter discusses ongoing research on brain and spinal cord tumor epidemiology, as well as the associated risks and accompanied disorders.

A deep dive into neurofibromatosis type 1: Expert experiences and perspectives from SNO 2023

The Society for NeuroOncology (SNO) is an international organization that brings together clinicians and researchers with an interest in central nervous system malignancies. Although a large part of its focus is on diagnosis and management of malignant brain tumours, this year’s SNO conference provided valuable educational and scientific sessions on other malignant and non-malignant tumours affecting nerves and supporting cells throughout the body. Of note, SNO 2023 gave attendees in-depth opportunities to hear from world-renowned experts about the clinical impact and best practices for diagnosis and management of neurofibromatosis type 1 (NF1), a single-gene tumour predisposition syndrome with a diverse clinical presentation. This report will focus on the insights and data presented at SNO 2023 into the current state of the art in understanding and managing two key types of NF1-associated tumours: plexiform neurofibromas and cutaneous neurofibromas.

Facility patient volume and survival among individuals diagnosed with malignant central nervous system tumors

Prior research indicates that the volume of central nervous system (CNS) tumor patients seen by a facility is associated with outcomes. However, most studies have focused on short-term survival and specific CNS tumor subtypes. Our objective was to examine whether facility CNS tumor patient volume is associated with longer-term CNS tumor survival overall and by subtype. We obtained National Cancer Database (NCDB) data including individuals diagnosed with CNS tumors from 2004 to 2016. Analyses were stratified by age group (0-14, 15-39, 40-64, and ≥ 65years) and tumor type. We used Cox Proportional Hazards (PH) regression and restricted mean survival time (RMST) analyses to examine associations between survival and facility patient volume percentile category adjusting for potential confounding factors. Our analytic dataset included data from 130,830 individuals diagnosed with malignant first primary CNS tumors. We found a consistently reduced hazard rate of death across age groups for individuals reported by higher vs. lower (> 95th vs. ≤ 70th percentile) volume facilities (hazard ratio (HR)0-14 = 0.78, 95% confidence interval (CI) 0.64-0.95; HR15-39 = 0.87, 95% CI 0.78-0.96; HR40-64 = 0.82, 95% CI 0.76-0.88; HR≥65 = 0.80, 95% CI 0.75-0.86). Significantly longer survival times within 5 years for higher vs. lower volume facilities were observed ranging from 1.20months (15-39) to 3.08months (40-64) higher. Associations varied by CNS tumor subtype for all age groups. These results suggest facility factors influence CNS tumor survival with longer survival for patients reported by higher volume facilities. Understanding these factors will be critical to developing strategies that eliminate modifiable differences in survival times.

Epigenetically regulated lncRNAs dissect the intratumoural heterogeneity and facilitate immune evasion of glioblastomas.

Background: Glioblastomas are the most common and malignant central nervous system (CNS) tumors that occupied a highly heterogeneous tumor microenvironment (TIME). Long noncoding RNAs (lncRNAs), whose expression can be modified by DNA methylation, are emerging as critical regulators in the immune system. However, knowledge about the epigenetic changes in lncRNAs and their contribution to the immune heterogeneity of glioma is still lacking. Methods: In this study, we integrated paired methylome and transcriptome datasets of glioblastomas and identified 2 robust immune subtypes based on lncRNA methylation features. The immune characteristics of glioma subtypes were compared. Furthermore, immune-related lncRNAs were identified and their relationships with immune evasion were evaluated. Results: Glioma immunophenotypes exhibited distinct immune-related characteristics as well as clinical and epigenetic features. 149 epigenetically regulated (ER) lncRNAs were recognized that possessed inverse variation in epigenetic and transcriptional levels between glioma subtypes. Immune-related lncRNAs were further identified through the investigation of their correlation with immune cell infiltrations and immune-related pathways. In particular, the 'Hot' glioma subtype with higher immunoactivity while a worse survival outcome was found to character immune evasion features. We finally prioritized candidate ER lncRNAs associated with immune evasion markers and response to glioma immunotherapy. Among them, CD109-AS1 and LINC02447 were validated as novel immunoevasive biomarkers for glioma through in vitro experiments. Conclusion: In summary, our study systematically reveals the crosstalk among DNA methylation, lncRNA, and immune regulation in glioblastomas, and will facilitate the development of epigenetic immunotherapy approaches.

Exogenous Ceramide Treatment Induce Death and Cytotoxicity in Glioma Cells.

To evaluate the cytotoxic and proapoptotic effects of C6 ceramide on the C6 rat glioma cell line. The C6 rat glioma cell line was evaluated. Using a confocal microscope and the appropriate software, the cytotoxic effects of C6 ceramide were identified using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H tetrazolium bromide (MTT) colorimetric experiments. Transmission electron microscopy (TEM) was utilized to examine the ultrastructural changes following treatment with IC50 concentrations of C6 ceramide. Condensation and fragmentation of nuclei and DNA laddering was observed, indicating apoptotic cell death. C6 ceramide induced apoptosis and effectively caused cytotoxicity in the C6 glioblastoma cells. MTT assay demonstrated > 90% cell death after short-term application of C6 ceramide, confirming its apoptosis-triggering effect. Apoptosis was also confirmed via confocal microscopy and TEM. Glioblastoma cells undergo apoptosis when exposed to C6 ceramide, which makes it a potential chemotherapeutic agent for the treatment of this aggressive brain cancer.

Combination of Caffeic Acid Phenethyl Ester and Crocin Realign Potential Molecular Markers in U87-MG Glioma Cells

Glial tumors are the most common primary malignant central nervous system tumors. They are hard to treat, not only because of the deregulation in multiple pathways but also because they are not contained in a well-defined mass with clear borders. The use of a single therapeutic agent to target gliomas has yielded unsatisfactory results. A combination of molecules targeting multiple pathways may prove to be a better alternative. The effect of caffeic acid phenethyl ester and crocin on the proliferation and death of U87-MG cells over a concentration range was analyzed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and lactate dehydrogenase assays. A colony formation assay was used to measure the effect of caffeic acid phenethyl ester and crocin on contact inhibition and anchorage independence ability of U87-MG cells. Furthermore, apoptosis in U87-MG cells was analyzed by propidium iodide assay. Real-time polymerase chain reaction and Western blotting were performed to determine the expression level of p53, epidermal growth factor receptor, and proliferating cell nuclear antigen. Caffeic acid phenethyl ester and crocin when used in combination present an anticancer potential for glioma. These molecules, in combination, inhibit proliferation and induce apoptosis in U87-MG glioma cells. Our results provide evidence that combination treatment realigns the expression paradigm of p53, epidermal growth factor receptor, and proliferating cell nuclear antigen in cotreated U87-MG cells. The combination of caffeic acid phenethyl ester and crocin led to inhibition in glioma cell proliferation and might prove to be an effective adjunct to the therapies in vogue.