Central Nervous System Malignancies Research Articles

Phase 1 clinical trial of durvalumab in children with solid and central nervous system tumors.

10029 Background: Immune checkpoint inhibitors targeting PDL-1 have shown clinical benefit in adults with cancer. We conducted a first in pediatrics, phase 1 clinical trial to assess safety, pharmacokinetics (PK), and pharmacodynamics of durvalumab in children with solid and central nervous system malignancies. Methods: This single center investigator-initiated trial enrolled eligible patients considered incurable with measurable/evaluable disease (exception: osteosarcoma in 3rd remission), no prior exposure to checkpoint inhibitors and adequate organ function on 2 dose levels: 10 mg/kg (DL1) and 15 mg/kg (DL2), utilizing a standard 3+3 design. The primary objectives were to assess safety and PK of durvalumab. Durvalumab was administered intravenously (IV) Q2 weeks for a maximum of 24 doses (12 cycles) on study or until disease progression/unacceptable toxicity. Patients were assessed for dose-limiting toxicity (DLT) in the first 28 days. The tolerable dose level was expanded to obtain PK on at most 6 patients age ≥12 years (yrs) and 6 patients < 12 yrs weighing < 35 kg). Soluble PDL-1 (sPDL1) and anti-drug antibody (ADA) levels were also assessed. Results: Fifteen patients (8M/7F) were enrolled (3 DL1, 12 DL2) with median age of 12.7 (2.9-16.6) yrs. Diagnoses included 5 osteosarcoma, 4 ependymoma and 1 each of glioblastoma, astrocytoma, rhabdomyosarcoma, synovial sarcoma, hepatoblastoma and adrenocortical carcinoma. Of the 14 patients evaluable for DLT, 3 were on DL1 and 11 on DL2. Only 1 DLT was observed, Grade (Gr) 3 intracranial hemorrhage (ICH). Median number of cycles administered was 3 (1-12). There were no treatment related deaths. There were 72 treatment-related adverse events (TRAEs) observed in 11 patients in a total of 73 cycles administered on the trial. The most common TRAE was AST elevation (7 instances in 4 patients). All TRAEs were < Gr 3 except for 1 instance each of Gr 3 AST elevation, anemia, and ICH. All 15 patients had PK, sPDL1 and ADA samples analyzed. PK for DL2 in patients ≥35 Kg and < 35 Kg were comparable to PK in adults dosed with durvalumab 10 mg/kg IV Q2W. Mean (SD) DL2 Cmax 292 (102) mg/mL, Ctrough 85.1 (27.7) mg/mL, AUC 2220 (986) day*mg/mL in pts ≥35 Kg and Cmax 442 (338), Ctrough 120 (123), AUC 2470 (1870) in pts < 12 yrs weighing < 35 kg. sPDL1 was completely suppressed in all patients 2 weeks after a single dose of durvalumab. No ADA were detected in any patients. Five patients (2 osteosarcoma, 3 ependymoma) completed > 6 cycles and 3 (1 osteosarcoma, 2 ependymoma) completed all 12 cycles of treatment. One objective response (PR) was seen in a patient with anaplastic ependymoma by RECIST1.1. Four patients were alive at the time of data cut-off with a median follow up of 30.5 (8.8-58.1) months. Conclusions: Durvalumab at 15 mg/kg IV Q2W was well tolerated in children with drug exposures comparable to adults receiving10 mg/kg IV Q2W. A signal for activity was noted in ependymoma where 3 of 5 children benefitted clinically. Clinical trial information: NCT02793466.

A bioequivalence study of a novel liquid and ready-to-use temozolomide oral suspension and temozolomide capsules in patients with primary tumors central nervous system malignancies.

e22008 Background: Oral temozolomide capsule is approved for the treatment of glioma and malignant glioblastoma in adults and in Europe in children over 3-years. As recommended by international pediatric medical associations, temozolomide is also used for the treatment of high-risk relapsed or refractory neuroblastoma, a solid tumor affecting young children. Nevertheless, capsules are not adapted to the pediatric population leading caregivers to handle temozolomide capsules, which bears major risks (i.e. dose inaccuracy, temozolomide instability and exposure to cytotoxic drug). To overcome this situation, a temozolomide oral suspension (Kimozo) was developed. The aim of this phase I study was to demonstrate bioequivalence between the temozolomide oral suspension and the temozolomide capsules (Temodal) and to assess the general and local safety in adult patients. Methods: A randomized, open-label, two-way crossover, single-dose bioequivalence study was performed in 8 centers. Adult patients with primary malignancies and treated with temozolomide 200 mg/m² as monotherapy received a single oral administration of the oral suspension (test) or capsule (reference) on days 1 and 2 of a 5-day cycle, depending on the randomization, and under fasting conditions. Fourteen blood samples were collected over 10-hr in each period for pharmacokinetic purpose. General and buccal safety was assessed along the study. The assessment of bioequivalence was based upon 90% confidence intervals (CI) for the ratio of the population geometric means (test/reference) for maximum plasma concentration (Cmax) and area under the curve (AUC0-t). Results: Among the thirty-six patients enrolled in the study, thirty were assessable for pharmacokinetic primary endpoint. The point estimate and the 90% CI of the ratios of Cmax and AUC0-t were 107.62 (98.07-118.09) and 97.18 (95.05-99.35), respectively. The results obtained satisfy the bioequivalence criteria of the Bioequivalence Guidelines (90% CI between 80.00% and 125.00%). Neither serious adverse events nor adverse events of special interest (i.e. mucositis) were reported. Conclusions: The oral suspension of temozolomide (Kimozo) and capsule of temozolomide (Temodal) are bioequivalent under fasting conditions in patients with CNS primary malignancies, supporting that they are therapeutic equivalent. Clinical trial information: NCT04467346.

The impact of clinical trial enrollment on specialty palliative care utilization in pediatric patients with high-grade gliomas.

10057 Background: In pediatric oncology patients, palliative care has been shown to provide numerous benefits, including less intense clinical care in the last month of life, improved symptom management, and dedicated family communication. Pediatric patients with high grade glioma (HGG) represent a patient population particularly well suited for early involvement of palliative care given their high symptom burden and relatively poor prognosis. However, a recent study revealed that pediatric patients with primary malignant central nervous system (CNS) tumors missed multiple opportunities for appropriate palliative care involvement throughout their disease courses. We hypothesize that clinical trial enrollment may lead to a lack of or delay in involvement of palliative care in children and young adults with HGG. Methods: We identified a cohort of 43 deceased pediatric patients with HGG who received care at our institution. IRB exemption was obtained. For each patient, the electronic medical record was reviewed to collect patient demographics, cancer diagnoses and outcomes, clinical trial enrollment, non-clinical trial treatments, and palliative care involvement. Statistical analysis was performed comparing patients enrolled in trials to those not enrolled, employing Fisher’s exact tests for categorical data and t tests for numerical data. Results: Overall, 72% (31/43) of patients had at least one visit with a specialty palliative care provider. 56% (24/43) of patients enrolled in a clinical trial with HGG-directed therapy. 71% (17/24) of patients who enrolled in a clinical trial received specialty palliative care compared to 74% (14/19) of non-trial participants (p = 1.000). Similarly, among patients who received palliative care there was no statistically significant difference in the timing of palliative care involvement, measured from the date of first palliative care contact to date of death, for patients who enrolled in a clinical trial (mean = 177 days) compared to those who did not (mean = 113 days, p = 0.180). Of the 24 patients enrolled in clinical trials, only 7 (29%) had palliative care involvement prior to initiation of study treatment. Conclusions: As our understanding of the genomic landscape of pediatric brain tumors increases, it can be expected that patients electing to enroll in targeted therapy clinical trials will also increase. As such, it is reassuring that our data suggest that trial participation does not interfere with the receipt of specialty palliative care in children with HGG. While not statistically significant, initial palliative care involvement trends toward occurring in closer proximity to death in the patients who are not enrolled on a clinical trial. Overall, it is encouraging that in our pediatric HGG patient cohort, enrollment in clinical trials does not appear to have an adverse impact on specialty palliative care involvement.

Effects of Dimethyl Fumarate on the Karnofsky Performance Status and Serum S100β Level in Newly Glioblastoma Patients: A Randomized, Phase-II, Placebo, Triple Blinded, Controlled Trial: Effect of DMF On the Serum S100β Level and KPS Score of GBM Patients.

Background: Glioblastoma (GBM) is the most common primary central nervous system malignancy with a low survival without extra logistics. Currently, there is no definitive chemotherapy among the studied options. This study aims to evaluate the neuroprotective effects of dimethyl fumarate (DMF) on surgical brain injuries in patients treated for GBM. Materials and Methods: This randomized, phase II, placebo, triple-blinded, controlled trial was performed on 36 patients with a diagnosis of GBM. All the patients received DMF (240 mg, three-times per day) or placebo (with the same shape and administration route) one week before surgery. Also, patients in both groups after the operation received standard treatments (radiotherapy plus chemotherapy). In addition, Kanofsky's performance status (KPS) score was evaluated at baseline and one month later. Also, serum S100β was measured 48 hours before and after surgery. Results: There was no significant difference among DMF and control groups with regard to age, gender, and the extent of resections (P˃0.05). The most adverse event in both groups was a headache. Although the serum S100β level was not markedly changed after surgery, the mean KPS in the DMF group was higher than in the control group after surgery. Conclusion: The DMF could be a possible good regime for the treatment of GBM; however, questions are raised regarding its efficacy and application for the addition to standard treatment.

Modifiers of and Disparities in Palliative and Supportive Care Timing and Utilization among Neurosurgical Patients with Malignant Central Nervous System Tumors.

Patients with primary or secondary central nervous system (CNS) malignancies benefit from utilization of palliative care (PC) in addition to other supportive services, such as home health and social work. Guidelines propose early initiation of PC for patients with advanced cancers. We analyzed a cohort of privately insured patients with malignant brain or spinal tumors derived from the Optum Clinformatics Datamart Database to investigate health disparities in access to and utilization of supportive services. We introduce a novel construct, "provider patient racial diversity index" (provider pRDI), which is a measure of the proportion of non-white minority patients a provider encounters to approximate a provider's patient demographics and suggest a provider's cultural sensitivity and exposure to diversity. Our analysis demonstrates low rates of PC, home health, and social work services among racial minority patients. Notably, Hispanic patients had low likelihood of engaging with all three categories of supportive services. However, patients who saw providers categorized into high provider pRDI (categories II and III) were increasingly more likely to interface with supportive care services and at an earlier point in their disease courses. This study suggests that prospective studies that examine potential interventions at the provider level, including diversity training, are needed.

Germline MUTYH mutations and high-grade gliomas: Novel evidence for a potential association.

There is growing body of evidence supporting the role of germline mutations in the pathogenesis of pediatric central nervous system (CNS) tumors, and the widespread use of next‐generation sequencing (NGS) panels facilitates their detection. Variants of the MUTYH gene are increasingly recognized as suspected germline background of various extraintestinal malignancies, besides their well‐characterized role in the polyposis syndrome associated with biallelic mutations. Using a multigene NGS panel (Illumina TruSight Oncology 500), we detected one H3 G34V‐ and one H3 K27M‐mutant pediatric high‐grade diffuse glioma, in association with c.1178G>A (p.G393D) and c.916C>T (p.R306C) MUTYH variants, respectively. Both MUTYH mutations were germline, heterozygous and inherited, according to the subsequent genetic testing of the patients and their first‐degree relatives. In the H3 K27M‐mutant glioma, amplifications affecting the 4q12 region were also detected, in association with KDR‐PDGFRA, KIT‐PDGFRA, and KDR‐CHIC2 fusions, previously unreported in this entity. Among 47 other CNS tumors of various histological types tested with the same NGS panel in our institution, only one adult glioblastoma harbored MUTYH mutation. Together with a single previous report, our data raises the possibility of an association between germline MUTYH mutations and CNS malignancies, particularly in pediatric histone H3‐mutant gliomas.

Epidemiology of Glioblastoma Multiforme-Literature Review.

Simple SummaryGlioblastoma multiforme (GBM) is one of the most aggressive malignancies, accounting for 14.5% of all central nervous system tumors and 48.6% of malignant central nervous system tumors. The median overall survival (OS) of GBM patients is only 15 months. The aim of this review was to provide an overview of the epidemiology of GBM and factors that may have a significant impact on the risk of GBM.Glioblastoma multiforme (GBM) is one of the most aggressive malignancies, with a median overall survival of approximately 15 months. In this review, we analyze the pathogenesis of GBM, as well as epidemiological data, by age, gender, and tumor location. The data indicate that GBM is the higher-grade primary brain tumor and is significantly more common in men. The risk of being diagnosed with glioma increases with age, and median survival remains low, despite medical advances. In addition, it is difficult to determine clearly how GBM is influenced by stimulants, certain medications (e.g., NSAIDs), cell phone use, and exposure to heavy metals.

Alarm Signal S100-Related Signature Is Correlated with Tumor Microenvironment and Predicts Prognosis in Glioma.

Glioma are the most common malignant central nervous system tumor and are characterized by uncontrolled proliferation and resistance to therapy. Dysregulation of S100 proteins may augment tumor initiation, proliferation, and metastasis by modulating immune response. However, the comprehensive function and prognostic value of S100 proteins in glioma remain unclear. Here, we explored the expression profiles of 17 S100 family genes and constructed a high-efficient prediction model for glioma based on CGGA and TCGA datasets. Immune landscape analysis displayed that the distribution of immune scores, ESTIMATE scores, and stromal scores, as well as infiltrating immune cells (macrophages M0/M1/M2, T cell CD4+ naïve, Tregs, monocyte, neutrophil, and NK activated), were significant different between risk-score subgroups. Overall, we demonstrated the value of S100 protein-related signature in the prediction of glioma patients' prognosis and determined its relationship with the tumor microenvironment (TME) in glioma.

Neurological complications in adult allogeneic hematopoietic stem cell transplant patients: Incidence, characteristics and long-term follow-up in a multicenter series.

Neurological complications (NCs) represent a diagnostic and clinical challenge in allogeneic hematopoietic stem cell transplant (alloHSCT) patients. We retrospectively analyzed NC incidence, etiology, timing, characteristics, outcome, and long-term effects in 2384 adult patients transplanted in seven Italian institutions between January 2007 and December 2019. Ninety-three (3.9%) patients were affected by 96 NCs that were infectious (29.2%), immune/inflammatory (26%), drug-related (12.5%), cerebrovascular (5.2%), metabolic (3.1%), related to central nervous system disease relapse (11.5%) and malignancy (3.1%), or undefined (9.4%). Six patients (6.4%) had neurological manifestations of chronic graft-versus-host disease (GVHD). NCs occurred on average at day +128 (from -5 to +4063). Early (< day +120) and late NCs had similar frequencies (46.9% vs 53.1%, p = 0.39). Thirty-one patients (33.3%) were affected by acute or chronic GVHD at the NC onset. With a median follow-up of 25.4 (0.4-163) months, the overall mortality due to NCs was 22.6%. The median time between NC onset and death was 36 (1-269) days. Infectious NCs were the main cause (61.9%) of NC-related mortality. A persistent neurological impairment occurred in 20.4% patients, 57.9% of whom being affected by immune/inflammatory NCs. This study highlights the rare, yet severe impact of alloHSCT-associated NCs on patient survival and long-term functional ability.

An Integrated Immune-Related Bioinformatics Analysis in Glioma: Prognostic Signature's Identification and Multi-Omics Mechanisms' Exploration.

As the traditional treatment for glioma, the most common central nervous system malignancy with poor prognosis, the efficacy of high-intensity surgery combined with radiotherapy and chemotherapy is not satisfactory. The development of individualized scientific treatment strategy urgently requires the guidance of signature with clinical predictive value. In this study, five prognosis-related differentially expressed immune-related genes (PR-DE-IRGs) (CCNA2, HMGB2, CASP3, APOBEC3C, and BMP2) highly associated with glioma were identified for a prognostic model through weighted gene co-expression network analysis, univariate Cox and lasso regression. Kaplan-Meier survival curves, receiver operating characteristic curves and other methods have shown that the model has good performance in predicting the glioma patients’ prognosis. Further combined nomogram provided better predictive performance. The signature’s guiding value in clinical treatment has also been verified by multiple analysis results. We also constructed a comprehensive competing endogenous RNA (ceRNA) regulatory network based on the protective factor BMP2 to further explore its potential role in glioma progression. Numerous immune-related biological functions and pathways were enriched in a high-risk population. Further multi-omics integrative analysis revealed a strong correlation between tumor immunosuppressive environment/IDH1 mutation and signature, suggesting that their cooperation plays an important role in glioma progression.

Ultrasmall Nanoparticle Delivery of Doxorubicin Improves Therapeutic Index for High-Grade Glioma.

Despite dramatic growth in the number of small-molecule drugs developed to treat solid tumors, durable therapeutic options to control primary central nervous system malignancies are relatively scarce. Chemotherapeutic agents that appear biologically potent in model systems have often been found to be marginally effective at best when given systemically in clinical trials. This work presents for the first time an ultrasmall (<8 nm) multimodal core-shell silica nanoparticle, Cornell prime dots (or C' dots), for the efficacious treatment of high-grade gliomas. This work presents first-in-kind renally clearable ultrasmall (<8 nm) multimodal C' dots with surface-conjugated doxorubicin (DOX) via pH-sensitive linkers for the efficacious treatment in two different clinically relevant high-grade glioma models. Optimal drug-per-particle ratios of as-developed nanoparticle-drug conjugates were established and used to obtain favorable pharmacokinetic profiles. The in vivo efficacy results showed significantly improved biological, therapeutic, and toxicological properties over the native drug after intravenous administration in platelet-derived growth factor-driven genetically engineered mouse model, and an EGF-expressing patient-derived xenograft (EGFR PDX) model. Ultrasmall C' dot-drug conjugates showed great translational potential over DOX for improving the therapeutic outcome of patients with high-grade gliomas, even without a cancer-targeting moiety.

Liquid biopsy in CNS tumors: Current status & future perspectives.

Precise classification of central nervous system (CNS) malignancies is vital for the treatment and prognostication. Identification of noninvasive markers can be of importance to guide treatment decisions and in monitoring treatment response. CNS tumors are classified based on morphology with an essential complement of molecular changes, including mutations, amplifications, and methylation. Neuroimaging is the mainstay for initial diagnosis and monitoring tumor response with obvious limitations of imprecise tumor typing and no information on diagnostic, predictive and prognostic markers. Liquid biopsy has evolved as a diagnostic tool in body fluids and is being investigated as a surrogate for tissue biopsy in managing primary and metastatic brain tumors. Liquid biopsy refers to analyzing biological fluids such as peripheral blood, urine, pleural effusion, ascites, and cerebrospinal fluid (CSF); however, peripheral blood remains the primary source of fluid biopsy. The analytes include cell-free DNA (cfDNA) circulating tumor cells (CTCs), circulating micro RNAs (miRNAs), circulating proteins and extracellular vesicles (EVs). Analysis of these components is actively used for early cancer detection, auxiliary staging, prognosis assessment, detection of minimal residual disease (MRD), and monitoring drug resistance in various solid tumors. In recent years, liquid biopsy has been studied in CNS tumors, and analysis of CTCs and cfDNA have become relevant research topics. In the current review, we have explained the clinical potential of liquid biopsy in CNS tumors to assist in diagnosing and predicting prognosis and response to treatment.

Multi-omics analysis predicts fibronectin 1 as a prognostic biomarker in glioblastoma multiforme

Glioblastoma (GBM) is one of the most malignant and intractable central nervous system tumors with high recurrence, low survival rate, and poor prognosis. Despite the advances of aggressive, multimodal treatment, a successful treatment strategy is still elusive, often leading to therapeutic resistance and fatality. Thus, it is imperative to search for and identify novel markers critically associated with GBM pathogenesis to improve the existing trend of diagnosis, prognosis, and treatment. Seven publicly available GEO microarray datasets containing 409 GBM samples were integrated and further data mining was conducted using several bioinformatics tools. A total of 209 differentially expressed genes (DEGs) were identified in the GBM tissue samples compared to the normal brains. Gene Ontology (GO) enrichment analysis of the DEGs revealed association of the upregulates genes with extracellular matrix (ECM), conceivably contributing to the invasive nature of GBM while downregulated DEGs were found to be predominantly related to neuronal processes and structures. Alongside, Kyoto Encyclopedia of Genes and Genomes (KEGG) and Reactome pathway analyses described the involvement of the DEGs with various crucial contributing pathways (PI3K-Akt signaling pathway, p53 signaling pathway, insulin secretion, etc.) in GBM progression and pathogenesis. Protein-protein interaction (PPI) network containing 879 nodes and 1237 edges revealed 3 significant modules and consecutive KEGG pathway analysis of these modules showed a significant connection to gliomagenesis. Later, 10 hub genes were screened out based on degree and their expressions were externally validated. Surprisingly, only fibronectin 1 (FN1) high expression appeared to be related to poor prognosis. Subsequently, 109 transcription factors and 211 miRNAs were detected to be involved with the hub genes where FN1 demonstrated the highest number of interactions. Considering its high connectivity and potential prognostic value FN1 could be a novel biomarker providing new insights into the prognosis and treatment for GBM, although experimental validation is required.

Glioblastoma: Changing concepts in the WHO CNS5 classification.

Glioblastoma is the most common malignant central nervous system (CNS) tumor in adults. Acute common clinical symptoms include headache, seizure, behavior changes, focal neurological deficits, and signs of increased intracranial pressure. The classic MRI finding of glioblastoma is an irregularly shaped, rim-enhancing or ring-enhancing lesion with a central dark area of necrosis. This constellation of features correlates with microscopic findings of tumor necrosis and microvascular proliferation. Besides these common features, several well-recognized histological subtypes include giant cell glioblastoma, granular cell glioblastoma, gliosarcoma, glioblastoma with a primitive neuronal component, small cell glioblastoma, and epithelioid glioblastoma. While glioblastoma was historically classified as isocitrate dehydrogenase (IDH)-wildtype and IDH-mutant groups, the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT-NOW) and the fifth edition of the WHO Classification of Tumors of the Central Nervous System clearly updated the nomenclature to reflect glioblastoma to be compatible with wildtype IDH status only. Therefore, glioblastoma is now defined as "a diffuse, astrocytic glioma that is IDH-wildtype and H3-wildtype and has one or more of the following histological or genetic features: microvascular proliferation, necrosis, Telomerase reverse transcriptase promoter mutation, Epidermal growth factor receptor gene amplification, +7/-10 chromosome copy-number changes (CNS WHO grade 4)."

Potential of Polyphenolic Nutraceuticals in the Management of Glioblastoma Multiforme

Abstract: Glioblastoma Multiforme (GBM) is a malignant central nervous system tumor. GBM is produced by aggressive proliferation of cells and invasion of normal brain tissue. The current conventional therapies for GBM include surgery, chemotherapy, and radiation therapies which are challenging and produce adverse effects. Thus, polyphenolic nutraceuticals are effective natural compounds for preventing and treating GBM due to their chemoprotective activity. Polyphenols are bioactive, non-nutrient plant chemicals structurally sub-divided into 5 groups; among these groups, phenolics and flavonoids are widely studied as they have lesser side effects and a more significant potential to pass the Blood-Brain Barrier (BBB). These polyphenolic nutraceuticals have the potential to advance current GBM treatment options. This review throws light on the anti-cancer efficacy of major polyphenol classes (Phenolic acid, Flavonoids, Stilbenes, Lignans) and discusses their prospective mechanisms of action in GBM.

LncRNA PRADX is a Mesenchymal Glioblastoma Biomarker for Cellular Metabolism Targeted Therapy.

Glioblastoma (GBM) is the most common and lethal type of primary malignant central nervous system (CNS) tumor with an extremely poor prognosis, and the mesenchymal subtype of GBM has the worst prognosis. Here, we found that lncRNA PRADX was overexpressed in the mesenchymal GBM and was transcriptionally regulated by RUNX1-CBFβ complex, overexpressed PRADX suppressed BLCAP expression via interacting with EZH2 and catalyzing trimethylation of lysine 27 on histone H3 (H3K27me3). Moreover, we showed that BLCAP interacted with STAT3 and reduced STAT3 phosphorylation, overexpressed PRADX activated STAT3 phosphorylation, and promoted ACSL1 expression via suppressing BLCAP expression, accelerating tumor metabolism. Finally, we determined that combined of ACSL1 and CPT1 inhibitors could reverse the accelerated cellular metabolism and tumor growth induced by PRADX overexpression in vivo and in vitro. Collectively, PRADX/PRC2 complex activated the STAT3 pathway and energy metabolism in relation to mesenchymal GBM progression. Furthermore, our findings provided a novel therapeutic strategy targeting the energy metabolism activity of GBM.

Proline Metabolism in Malignant Gliomas: A Systematic Literature Review.

Simple SummaryStudies of various types of cancers have found proline metabolism to be a key player in tumor development, involved in basic metabolic pathways, regulating cell proliferation, survival, and signaling. Here, we systematically searched the literature to find data on proline metabolism in malignant glial tumors. Despite limited availability, existing studies have found several ways in which proline metabolism may affect the development of gliomas, involving the maintenance of redox balance, providing essential glutamate, and affecting major signaling pathways. Metabolomic profiling has revealed the importance of proline as a link to basic cell metabolic cycles and shown it to be correlated with overall survival. Emerging knowledge on the role of proline in general oncology encourages further studies on malignant gliomas.Background: Proline has attracted growing interest because of its diverse influence on tumor metabolism and the discovery of the regulatory mechanisms that appear to be involved. In contrast to general oncology, data on proline metabolism in central nervous system malignancies are limited. Materials and Methods: We performed a systematic literature review of the MEDLINE and EMBASE databases according to PRISMA guidelines, searching for articles concerning proline metabolism in malignant glial tumors. From 815 search results, we identified 14 studies pertaining to this topic. Results: The role of the proline cycle in maintaining redox balance in IDH-mutated gliomas has been convincingly demonstrated. Proline is involved in restoring levels of glutamate, the main glial excitatory neurotransmitter. Proline oxidase influences two major signaling pathways: p53 and NF- κB. In metabolomics studies, the metabolism of proline and its link to the urea cycle was found to be a prognostic factor for survival and a marker of malignancy. Data on the prolidase concentration in the serum of glioblastoma patients are contradictory. Conclusions: Despite a paucity of studies in the literature, the available data are interesting enough to encourage further research, especially in terms of extrapolating what we have learned of proline functions from other neoplasms to malignant gliomas.

Regional Development of Glioblastoma: The Anatomical Conundrum of Cancer Biology and Its Surgical Implication.

Glioblastoma (GBM) are among the most common malignant central nervous system (CNS) cancers, they are relatively rare. This evidence suggests that the CNS microenvironment is naturally equipped to control proliferative cells, although, rarely, failure of this system can lead to cancer development. Moreover, the adult CNS is innately non-permissive to glioma cell invasion. Thus, glioma etiology remains largely unknown. In this review, we analyze the anatomical and biological basis of gliomagenesis considering neural stem cells, the spatiotemporal diversity of astrocytes, microglia, neurons and glutamate transporters, extracellular matrix and the peritumoral environment. The precise understanding of subpopulations constituting GBM, particularly astrocytes, is not limited to glioma stem cells (GSC) and could help in the understanding of tumor pathophysiology. The anatomical fingerprint is essential for non-invasive assessment of patients’ prognosis and correct surgical/radiotherapy planning.

Efficacy of Cytokine-Induced Killer Cell Immunotherapy for Patients With Pathologically Pure Glioblastoma.

The most common malignant central nervous system tumor is glioblastoma multiforme (GBM). Cytokine-induced killer (CIK) cell therapy is a promising type of adoptive cell immunotherapy for various cancers. We previously conducted a randomized clinical trial on CIK cell therapy in patients with GBM. The aim of this study was to evaluate the efficacy of CIK immunotherapy for patients with pathologically pure GBM, using data from our previous randomized clinical trial. The difference between overall survival (OS) and progression-free survival (PFS) according to CIK immunotherapy was analyzed using the Kaplan–Meier method. Hazard ratios were calculated using univariate and multivariate Cox regression analyses to determine whether CIK cell immunotherapy was independently associated with higher OS and PFS in patients with pure GBM. A total of 156 eligible patients were included in the modified intention-to-treat (mITT) population. We confirmed that 125 (80.1%) GBM samples were pure GBM tumors without the presence of other types of tumors. For patients with pure GBM, Kaplan-Meier analysis showed no significant difference in OS between the CIK cell treatment and control groups. However, multivariate Cox regression demonstrated CIK cell immunotherapy as an independent predictor of greater OS (hazard ratio, 0.59; 95% CI, 0.36–0.97; p = 0.038) and PFS (hazard ratio, 0.55; 95% CI, 0.36–0.84; p = 0.001) in patients with pathologically pure GBM in the mITT population. This study showed that CIK cell immunotherapy combined with conventional temozolomide chemoradiotherapy could prolong OS and PFS in patients with newly diagnosed pathologically pure GBM, with no significant adverse events related to treatment. However, unlike the results of multivariate Cox analysis, no statistical significance of CIK cell immunotherapy in OS in Kaplan-Meier analysis raises a question. Further studies are required to validate these results.

A Toolkit for Profiling the Immune Landscape of Pediatric Central Nervous System Malignancies.

The prognosis of pediatric central nervous system (CNS) malignancies remains dismal due to limited treatment options, resulting in high mortality rates and long-term morbidities. Immunotherapies, including checkpoint inhibition, cancer vaccines, engineered T cell therapies, and oncolytic viruses, have promising results in some hematological and solid malignancies, and are being investigated in clinical trials for various high-grade CNS malignancies. However, the role of the tumor immune microenvironment (TIME) in CNS malignancies is mostly unknown for pediatric cases. In order to successfully implement immunotherapies and to eventually predict which patients would benefit from such treatments, in-depth characterization of the TIME at diagnosis and throughout treatment is essential. In this review, we provide an overview of techniques for immune profiling of CNS malignancies, and detail how they can be utilized for different tissue types and studies. These techniques include immunohistochemistry and flow cytometry for quantifying and phenotyping the infiltrating immune cells, bulk and single-cell transcriptomics for describing the implicated immunological pathways, as well as functional assays. Finally, we aim to describe the potential benefits of evaluating other compartments of the immune system implicated by cancer therapies, such as cerebrospinal fluid and blood, and how such liquid biopsies are informative when designing immune monitoring studies. Understanding and uniformly evaluating the TIME and immune landscape of pediatric CNS malignancies will be essential to eventually integrate immunotherapy into clinical practice.