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Although primary studies have reported the safety and efficacy of LITT as a primary treatment in glioma, they are limited by sample sizes and institutional variation in stereotactic parameters such as temperature and laser power. The current literature has yet to provide pooled statistics on outcomes solely for primary brain tumors according to the 2021 WHO Classification of Tumors of the Central Nervous System (WHO CNS5). In the present study, we identify recent articles on primary CNS neoplasms treated with LITT without prior intervention, focusing on relationships with molecular profile, PFS, and OS. This meta-analysis includes the extraction of data from primary sources across four databases using the Covidence systematic review manager. The pooled data suggest LITT may be a safe primary management option with tumor ablation rates of 94.8% and 84.6% in IDH-wildtype glioblastoma multiforme (GBM) and IDH-mutant astrocytoma, respectively. For IDH-wildtype GBM, the pooled PFS and OS were 5.0 and 9.0 months, respectively. Similar to rates reported in the prior literature, the neurologic and non-neurologic complication rates for IDH-wildtype GBM were 10.3% and 4.8%, respectively. The neurologic and non-neurologic complication rates were somewhat higher in the IDH-mutant astrocytoma cohort at 33% and 8.3%, likely due to a smaller cohort size.

Simple Summary: In the present study, the intraoperative fluorescence of brain metastases after the administration of 5-aminolevulinic acid (5-ALA) is investigated in 80 cases. Brain metastases fluoresced in 57.5% of cases, with no significant correlation between fluorescence and primary tumor or histological subtype. Complete resection of brain metastases was detected in 82.5%, of which 56.1% were fluorescence positive, compared to 43.9% which were non-fluorescent. Thus, prior administration of 5-ALA tended to improve the resectability rate by 12.1%. Fluorescence-positive and -negative metastases showed significantly different overall survival in this study. Therefore, administration of 5-ALA as a surgical adjuvant may be beneficial in resecting brain metastases and may potentially optimize the surgical procedure. (1) Background: In this study, the intraoperative fluorescence behavior of brain metastases after the administration of 5-aminolevulinic acid (5-ALA) was analyzed. The aim was to investigate whether the resection of brain metastases using 5-ALA fluorescence also leads to a more complete resections and thus to a prolongation of survival; (2) Methods: The following variables have been considered: age, sex, number of metastases, localization, involvement of eloquent area, correlation between fluorescence and primary tumor/subtype, resection, and survival time. The influence on the degree of resection was determined with a control MRI within the first three postoperative days; (3) Results: Brain metastases fluoresced in 57.5% of cases. The highest fluorescence rates of 73.3% were found in breast carcinoma metastases and the histologic subtype adenocarcinoma (68.1%). No correlation between fluorescence behavior and localization, primary tumor, or histological subtype was found. Complete resection was detected in 82.5%, of which 56.1% were fluorescence positive. There was a trend towards improved resectability (increase of 12.1%) and a significantly longer survival time (p = 0.009) in the fluorescence-positive group; (4) Conclusions: 5-ALA-assisted extirpation leads to a more complete resection and longer survival and can therefore represent a low-risk addition to modern surgery for brain metastases. [ABSTRACT FROM AUTHOR]

Annotation: Malignant gliomas are the most common primary brain tumor. Despite the variety of modern treatments, it is still a fatal disease with an extremely poor prognosis. The use of immunotherapy as a technique for the treatment of malignant tumors has great promise, retraining and exploiting the patient's immune response against tumors. Objective: Evaluation of the effectiveness of dendritic cell vaccine in patients with malignant brain gliomas in the structure of complex treatment in comparison with the control group of patients without immunotherapy in the structure of treatment. Materials and methods: In a single-center, prospective, cohort study, taking place on the basis of the RNSI named after prof. A.L. Polenov, 91 patients with morphologically established malignant glial tumor (glioblastoma) took part. The main group of 41 patients who, in addition to standard treatment (surgical, radiation and chemotherapy), underwent specific antitumor immunotherapy. 50 patients received only standard treatment, without immunotherapy. Results: Median survival was 21.7 months in the immunotherapy group (95% CI 4–37 months) and 15.8 months (95% CI 3–22 months) in the non-immunotherapy group (p = 0.002). The median relapse-free period in the group with immunotherapy was 13.8 months (95% CI 1–20 months), and in the group without immunotherapy 7.9 months (95% CI 1–12 months) (p = 0.003). Conclusion: In general, the use of immunotherapy in the structure of complex treatment of patients with malignant gliomas demonstrates a clear positive trend in terms of overall survival and median relapse-free period. But nevertheless, immunotherapy requires further development as a therapeutic tool, study and improvement, which will take into account immunosuppression in malignant gliomas and means of overcoming it, optimization in terms of target antigen selection, cell preparation and integration of dendritic vaccines into other treatment regimens. [ABSTRACT FROM AUTHOR]

Introduction: Malignant gliomas are the most prevalent and fatal types of primary malignant brain tumors with poor prognosis. Protein phosphatase 3 catalytic subunit beta (PPP3CB) is a pivotal constituent of the Ca2+/calmodulin-dependent serine/threonine protein phosphatases and widely expressed in brain. We aimed at identifying whether PPP3CB has potential in being a novel biomarker of malignant gliomas, bringing new insights to clinical management and therapy. Methods: Transcriptomes and clinical data of Glioblastoma (GBM) and low-grade glioma (LGG) samples were downloaded from TCGA and CGGA. We first explored the expressional and survival features of tumor tissues. Then, PPP3CB-associated genes were identified and their functional pathways were explored through GSEA analyses. Western blotting was conducted to modify PPP3CB expression. Samples of glioma patients and healthy controls were collected and immunohistochemistry (IHC) staining was performed to detect protein level. Further, we carried out an immune infiltration analysis, explored the correlation between PPP3CB and immune checkpoint genes, as well as to assessed the tumor mutation burden (TMB) and tumor microenvironment score (TMEscore) of PPP3CB. Results: PPP3CB expression in malignant glioma tissues was significantly downregulated and was considered an independent prognostic factor. Several functional pathways were observed through functional pathway analyses. PPP3CB's expression was strongly related to the infiltration of various immune cells and expression of key immune checkpoint genes. PPP3CB expression in high-grade gliomas was significantly lower, affecting glioma cells' proliferation and apoptosis in vitro. Conclusion: PPP3CB was a potential biomarker for the diagnosis and prognosis of malignant gliomas.

Malignant gliomas are known to be one of the most difficult diseases to diagnose and treat because of the infiltrative growth pattern, rapid progression, and poor prognosis. Many antitumor drugs are not ideal for the treatment of gliomas due to the blood-brain barrier. Temozolomide (TMZ) is a DNA alkylating agent that can cross the blood-brain barrier. As the only first-line chemotherapeutic drug for malignant gliomas at present, TMZ is widely utilized to provide a survival benefit; however, some patients are inherently insensitive to TMZ. In addition, patients could develop acquired resistance during TMZ treatment, which limits antitumor efficacy. To clarify the mechanism underlying TMZ resistance, numerous studies have provided multilevel solutions, such as improving the effective concentration of TMZ in tumors and developing novel small molecule drugs. This review discusses the in-depth mechanisms underlying TMZ drug resistance, thus aiming to provide possibilities for the establishment of personalized therapeutic strategies against malignant gliomas and the accelerated development and transformation of new targeted drugs.

Objectives: Angiogenesis is one of the main characteristic features of malignant gliomas. Phosphorylated signal transducer and activator of transcription factor 3 (pSTAT3) is not only involved in glioma cell proliferation, anti-apoptosis, and immunosuppression but also plays a key role in cell migration and invasion. Constitutively, activated pSTAT3 induces expression of vascular endothelial growth factor (VEGF) and its receptor VEGFR, leading to endothelial cell proliferation and abnormal microvascular formation causing peritumoral edema (PTE). PTE is one of the significant contributors to mortality in malignant gliomas. Therefore, understanding the molecular mechanism involved in the evolution of gliomas is necessary. This study was to assess the level of expression of pSTAT3, VEGF, and VEGFR in malignant gliomas and analyze the extent of PTE and the extent of expression of one or more of these markers. Materials and Methods: This study included 84 patients categorized as per the World Health Organization classification of central nervous system tumors into grade IV, III, and II gliomas to investigate the expression of pSTAT3, VEGF, and VEGFR by immunohistochemistry. Furthermore, the presence or absence of PTE was determined using magnetic resonance imaging/computed tomography scans in these patients. Results: The association between the markers (pSTAT3, VEGFR, and VEGF) and the extent of PTE in these patients was statistically significant (P < 0.05). Conclusion: The pSTAT3, VEGF-R, and VEGF signaling pathways could contribute to peritumoral edema and might be a regulatory mechanism during PTE formation during tumorigenesis and progression. [ABSTRACT FROM AUTHOR]

Introduction: The primary objective of neurosurgical management of malignant gliomas is maximal safe resection of the tumour. One of the main obstacles in achieving this is the ability to accurately discriminate between tumour edges and the surrounding healthy brain tissue. The use of fluorescence-guided surgery utilising 5-aminolevulinic acid (5-ALA), first introduced more than 20 years ago, has become an invaluable adjunct in high-grade glioma surgery in adults. However, as 5-ALA is not licensed for use in paediatric patients, the safety profile for such use remains undetermined. Case report: We describe the case of a 4-year-old boy who underwent 5-ALA-guided resection of a fourth ventricle anaplastic ependymoma. Although complete resection was achieved and the patient awoke from surgery well with no neurological deficits, the patient developed acute transaminitis, anaemia, thrombocytopaenia and coagulopathy postoperatively. The patient had a sudden neurological deterioration on postoperative day 2; imaging revealed that he had suffered a spontaneous right frontal intracerebral haemorrhage. The patient returned to theatre for surgical decompression and evacuation of the haematoma, and ultimately went on to make a full recovery. Conclusion: The use of 5-ALA in paediatric patients can be helpful in maximising surgical resection, but the associated safety profile remains undefined. Further research is urgently warranted in order to characterise the efficacy and risk of the use of 5-ALA in the paediatric population. [ABSTRACT FROM AUTHOR]

One of the biggest challenges in neuro-oncology is understanding the complexity of central nervous system tumors, such as gliomas, in order to develop suitable therapeutics. Conventional therapies in malignant gliomas reconcile surgery and radiotherapy with the use of chemotherapeutic options such as temozolomide, chloroethyl nitrosoureas and the combination therapy of procarbazine, lomustine and vincristine. With the unraveling of deregulated cancer cell signaling pathways, targeted therapies have been developed. The most affected signaling pathways in glioma cells involve tyrosine kinase receptors and their downstream pathways, such as the phosphatidylinositol 3-kinases (PI3K/AKT/mTOR) and mitogen-activated protein kinase pathways (MAPK). MAPK pathway inhibitors include farnesyl transferase inhibitors, Ras kinase inhibitors and mitogen-activated protein extracellular regulated kinase (MEK) inhibitors, while PI3K/AKT/mTOR pathway inhibitors are divided into pan-inhibitors, PI3K/mTOR dual inhibitors and AKT inhibitors. The relevance of the immune system in carcinogenesis has led to the development of immunotherapy, through vaccination, blocking of immune checkpoints, oncolytic viruses, and adoptive immunotherapy using chimeric antigen receptor T cells. In this article we provide a comprehensive review of the signaling pathways underlying malignant transformation, the therapies currently used in the treatment of malignant gliomas and further explore therapies under development, including several ongoing clinical trials. [ABSTRACT FROM AUTHOR]

In recent years, photodynamic therapy (PDT) has been increasingly introduced into the surgical practice of treating malignant neoplasms. In this publication, the authors show the appearance of therapeutic pathomorphosis in vivo in human malignant glioma cells after intraoperative photodynamic therapy. Tissue samples obtained 10–14 days after PDT revealed nuclear and cytoplasmic signs indicating apoptosis, necrosis, and autophagy. A decrease in the proliferative activity of glial tumor cells and their higher death count were detected.. Immunohistochemical analysis shows decreases expression of Ki-67 cell proliferation marker and decreased amount of transcription factor protein p53.

Background. The analytic findings concerning 3-year cumulative survival of patients with malignant brain gliomas are presented, depending on IDH1 gene mutation status, tumor grade (Grade II) and patient’s age. Purpose. To study cumulative survival of patients with malignant brain gliomas depending on IDH1 gene mutation status, tumor grade (Grade II) and patient’s age for prediction of the disease course. Material and methods. The disease specific 3-year cumulative survival of 95 patients with malignant brain glioma treated at N.N. Alexandrov National cancer Centre in 2009–2014 was evaluated with the Kaplan-Meier method calculating standard error (Se). The ageelated survival was assessed using univariate Cox proportional hazards regression. The data were processed in statistical R package, version 3.4.2 using Survival Library. Results: According to the analytic findings, the favourable prognostic factors in patients with malignant brain glioma are patient’s age younger than 45 years, low tumor grade (Grade II) and the presence of mutation in IDH1 gene. Conclusions. The factors influencing the survival of patients with malignant brain gliomas are the tumor grade (Grade), the mutational status of IDH1 gene, the patient’s age.

BackgroundWorld Health Organization (WHO) grade IV glioma remains one of the most lethal tumors with a dismal prognosis and inevitable recurrence. We evaluated the safety and efficacy of immunotherapy with radiotherapy in this population of patients.MethodsThis study was a single-arm, open-label, phase I trial based on patients with recurrent WHO grade IV glioma. Patients were treated with intracranial and systemic immunoadjuvants in combination with low-dose reirradiation. The primary endpoint of the present trial was safety. Secondary endpoints were overall survival (OS) and progression-free survival (PFS). This trial is registered at ClinicalTrials.gov, NCT03392545.ResultsThirty patients were enrolled. The most common adverse events (AEs) were fever (66.7%), vomiting (33.3%), headache (30.0%), and fatigue (23.3%). Only a single patient experienced grade 3 fever, and no grade 4 AEs or deaths related to treatment were observed. Of the 30 patients, 1 (3.3%) had a complete response, 5 (16.7%) had a partial response, 9 (30.0%) had stable disease, and 15 (50.0%) had progressive disease, resulting in an objective response rate of 20.0%. The median PFS of the entire cohort was 88.0 (61.0-254.0) days, and the median OS was 362.0 (197.0-601.0) days. Patients could be divided into responders and non-responders, and these groups exhibited a significant difference in terms of survival time, T lymphocyte subsets, frequency of cell division cycle 27 (CDC27) mutation status, and CD15 and CD68 expression (P

Background: World Health Organization (WHO) grade IV glioma remains one of the most lethal tumors with a dismal prognosis and inevitable recurrence. We evaluated the safety and efficacy of immunotherapy with radiotherapy in this population of patients. Methods: This study was a single-arm, open-label, phase I trial based on patients with recurrent WHO grade IV glioma. Patients were treated with intracranial and systemic immunoadjuvants in combination with low-dose reirradiation. The primary endpoint of the present trial was safety. Secondary endpoints were overall survival (OS) and progression-free survival (PFS). This trial is registered at ClinicalTrials.gov, NCT03392545. Results: Thirty patients were enrolled. The most common adverse events (AEs) were fever (66.7%), vomiting (33.3%), headache (30.0%), and fatigue (23.3%). Only a single patient experienced grade 3 fever, and no grade 4 AEs or deaths related to treatment were observed. Of the 30 patients, 1 (3.3%) had a complete response, 5 (16.7%) had a partial response, 9 (30.0%) had stable disease, and 15 (50.0%) had progressive disease, resulting in an objective response rate of 20.0%. The median PFS of the entire cohort was 88.0 (61.0-254.0) days, and the median OS was 362.0 (197.0-601.0) days. Patients could be divided into responders and non-responders, and these groups exhibited a significant difference in terms of survival time, T lymphocyte subsets, frequency of cell division cycle 27 (CDC27) mutation status, and CD15 and CD68 expression (P <0.05). Conclusion: The combination of immunotherapy and radiotherapy is well tolerated and may provide clinical benefit for patients with recurrent WHO grade IV glioma. A prospective phase II study is needed to further validate the efficacy of our therapeutic regimen. [ABSTRACT FROM AUTHOR]

Abstract Background D2C7-IT is a novel immunotoxin (IT) targeting wild-type epidermal growth factor receptor (EGFRwt) and mutant EGFR variant III (EGFRvIII) proteins in glioblastoma. In addition to inherent tumoricidal activity, immunotoxins induce secondary immune responses through the activation of T cells. However, glioblastoma-induced immune suppression is a major obstacle to an effective and durable immunotoxin-mediated antitumor response. We hypothesized that D2C7-IT-induced immune response could be effectively augmented in combination with αCTLA-4/αPD-1/αPD-L1 therapies in murine models of glioma. Methods To study this, we overexpressed the D2C7-IT antigen, murine EGFRvIII (dmEGFRvIII), in established glioma lines, CT-2A and SMA560. The reactivity and therapeutic efficacy of D2C7-IT against CT-2A-dmEGFRvIII and SMA560-dmEGFRvIII cells was determined by flow cytometry and in vitro cytotoxicity assays, respectively. Antitumor efficacy of D2C7-IT was examined in immunocompetent, intracranial murine glioma models and the role of T cells was assessed by CD4+ and CD8+ T cell depletion. In vivo efficacy of D2C7-IT/αCTLA-4/αPD-1 monotherapy or D2C7-IT+αCTLA-4/αPD-1 combination therapy was evaluated in subcutaneous unilateral and bilateral CT-2A-dmEGFRvIII glioma-bearing immunocompetent mice. Further, antitumor efficacy of D2C7-IT+αCTLA-4/αPD-1/αPD-L1/αTim-3/αLag-3/αCD73 combination therapy was evaluated in intracranial CT-2A-dmEGFRvIII and SMA560-dmEGFRvIII glioma-bearing mice. Pairwise differences in survival curves were assessed using the generalized Wilcoxon test. Results D2C7-IT effectively killed CT-2A-dmEGFRvIII (IC50 = 0.47 ng/mL) and SMA560-dmEGFRvIII (IC50 = 1.05 ng/mL) cells in vitro. Treatment of intracranial CT-2A-dmEGFRvIII and SMA560-dmEGFRvIII tumors with D2C7-IT prolonged survival (P = 0.0188 and P = 0.0057, respectively), which was significantly reduced by the depletion of CD4+ and CD8+ T cells. To augment antitumor immune responses, we combined D2C7-IT with αCTLA-4/αPD-1 in an in vivo subcutaneous CT-2A-dmEGFRvIII model. Tumor-bearing mice exhibited complete tumor regressions (4/10 in D2C7-IT+αCTLA-4 and 5/10 in D2C7-IT+αPD-1 treatment groups), and combination therapy-induced systemic antitumor response was effective against both dmEGFRvIII-positive and dmEGFRvIII-negative CT-2A tumors. In a subcutaneous bilateral CT-2A-dmEGFRvIII model, D2C7-IT+αCTLA-4/αPD-1 combination therapies showed dramatic regression of the treated tumors and measurable regression of untreated tumors. Notably, in CT-2A-dmEGFRvIII and SMA560-dmEGFRvIII intracranial glioma models, D2C7-IT+αPD-1/αPD-L1 combinations improved survival, and in selected cases generated cures and protection against tumor re-challenge. Conclusions These data support the development of D2C7-IT and immune checkpoint blockade combinations for patients with malignant glioma.

One of the biggest challenges in neuro-oncology is understanding the complexity of central nervous system tumors, such as gliomas, in order to develop suitable therapeutics. Conventional therapies in malignant gliomas reconcile surgery and radiotherapy with the use of chemotherapeutic options such as temozolomide, chloroethyl nitrosoureas and the combination therapy of procarbazine, lomustine and vincristine. With the unraveling of deregulated cancer cell signaling pathways, targeted therapies have been developed. The most affected signaling pathways in glioma cells involve tyrosine kinase receptors and their downstream pathways, such as the phosphatidylinositol 3-kinases (PI3K/AKT/mTOR) and mitogen-activated protein kinase pathways (MAPK). MAPK pathway inhibitors include farnesyl transferase inhibitors, Ras kinase inhibitors and mitogen-activated protein extracellular regulated kinase (MEK) inhibitors, while PI3K/AKT/mTOR pathway inhibitors are divided into pan-inhibitors, PI3K/mTOR dual inhibitors and AKT inhibitors. The relevance of the immune system in carcinogenesis has led to the development of immunotherapy, through vaccination, blocking of immune checkpoints, oncolytic viruses, and adoptive immunotherapy using chimeric antigen receptor T cells. In this article we provide a comprehensive review of the signaling pathways underlying malignant transformation, the therapies currently used in the treatment of malignant gliomas and further explore therapies under development, including several ongoing clinical trials.

Background and ObjectivePossible treatment strategies for recurrent malignant gliomas include surgery, chemotherapy, radiotherapy, and combined treatments. Among different reirradiation modalities, the CyberKnife System has shown promising results. We conducted a systematic review of the literature and a meta-analysis to establish the efficacy and safety of CyberKnife treatment for recurrent malignant gliomas.MethodsWe searched PubMed, MEDLINE, and EMBASE from 2000 to 2021 for studies evaluating the safety and efficacy of CyberKnife treatment for recurrent WHO grade III and grade IV gliomas of the brain. Two independent reviewers selected studies and abstracted data. Missing information was requested from the authors via email correspondence. The primary outcomes were median Overall Survival, median Time To Progression, and median Progression-Free Survival. We performed subgroup analyses regarding WHO grade and chemotherapy. Besides, we analyzed the relationship between median Time To Recurrence and median Overall Survival from CyberKnife treatment. The secondary outcomes were complications, local response, and recurrence. Data were analyzed using random-effects meta-analysis.ResultsThirteen studies reporting on 398 patients were included. Median Overall Survival from initial diagnosis and CyberKnife treatment was 22.6 months and 8.6 months. Median Time To Progression and median Progression-Free Survival from CyberKnife treatment were 6.7 months and 7.1 months. Median Overall Survival from CyberKnife treatment was 8.4 months for WHO grade IV gliomas, compared to 11 months for WHO grade III gliomas. Median Overall Survival from CyberKnife treatment was 4.4 months for patients who underwent CyberKnife treatment alone, compared to 9.5 months for patients who underwent CyberKnife treatment plus chemotherapy. We did not observe a correlation between median Time To Recurrence and median Overall Survival from CyberKnife. Rates of acute neurological and acute non-neurological side effects were 3.6% and 13%. Rates of corticosteroid dependency and radiation necrosis were 18.8% and 4.3%.ConclusionsReirradiation of recurrent malignant gliomas with the CyberKnife System provides encouraging survival rates. There is a better survival trend for WHO grade III gliomas and for patients who undergo combined treatment with CyberKnife plus chemotherapy. Rates of complications are low. Larger prospective studies are warranted to provide more accurate results.

Background and Objective: Possible treatment strategies for recurrent malignant gliomas include surgery, chemotherapy, radiotherapy, and combined treatments. Among different reirradiation modalities, the CyberKnife System has shown promising results. We conducted a systematic review of the literature and a meta-analysis to establish the efficacy and safety of CyberKnife treatment for recurrent malignant gliomas. Methods: We searched PubMed, MEDLINE, and EMBASE from 2000 to 2021 for studies evaluating the safety and efficacy of CyberKnife treatment for recurrent WHO grade III and grade IV gliomas of the brain. Two independent reviewers selected studies and abstracted data. Missing information was requested from the authors via email correspondence. The primary outcomes were median Overall Survival, median Time To Progression, and median Progression-Free Survival. We performed subgroup analyses regarding WHO grade and chemotherapy. Besides, we analyzed the relationship between median Time To Recurrence and median Overall Survival from CyberKnife treatment. The secondary outcomes were complications, local response, and recurrence. Data were analyzed using random-effects meta-analysis. Results: Thirteen studies reporting on 398 patients were included. Median Overall Survival from initial diagnosis and CyberKnife treatment was 22.6 months and 8.6 months. Median Time To Progression and median Progression-Free Survival from CyberKnife treatment were 6.7 months and 7.1 months. Median Overall Survival from CyberKnife treatment was 8.4 months for WHO grade IV gliomas, compared to 11 months for WHO grade III gliomas. Median Overall Survival from CyberKnife treatment was 4.4 months for patients who underwent CyberKnife treatment alone, compared to 9.5 months for patients who underwent CyberKnife treatment plus chemotherapy. We did not observe a correlation between median Time To Recurrence and median Overall Survival from CyberKnife. Rates of acute neurological and acute non-neurological side effects were 3.6% and 13%. Rates of corticosteroid dependency and radiation necrosis were 18.8% and 4.3%. Conclusions: Reirradiation of recurrent malignant gliomas with the CyberKnife System provides encouraging survival rates. There is a better survival trend for WHO grade III gliomas and for patients who undergo combined treatment with CyberKnife plus chemotherapy. Rates of complications are low. Larger prospective studies are warranted to provide more accurate results. [ABSTRACT FROM AUTHOR]

Objective: Several studies have compared the immune microenvironment of isocitrate dehydrogenase (IDH)-wildtype glioma versus IDH-mutant glioma. The authors sought to determine whether histological tumor progression in a subset of IDH-mutant glioma was associated with concomitant alterations in the intratumoral immune microenvironment., Methods: The authors performed bulk RNA sequencing on paired and unpaired samples from patients with IDH-mutant glioma who underwent surgery for tumor progression across multiple timepoints. They compared patterns of differential gene expression, overall inflammatory signatures, and transcriptomic measures of relative immune cell proportions., Results: A total of 55 unique IDH-mutant glioma samples were included in the analysis. The authors identified multiple genes associated with progression and higher grade across IDH-mutant oligodendrogliomas and astrocytomas. Compared with lower-grade paired samples, grade 4 IDH-mutant astrocytomas uniquely demonstrated upregulation of VEGFA in addition to counterproductive alterations in inflammatory score reflective of a more hostile immune microenvironment., Conclusions: Here, the authors have provided a transcriptomic analysis of a progression cohort for IDH-mutant glioma. Compared with lower-grade tumors, grade 4 astrocytomas displayed alterations that may inform the timing of antiangiogenic and immune-based therapy as these tumors progress.

There is a great effort to connect the accumulation of 2-hydroxyglutarate (2-HG) oncometabolite with cellular oncoepigenetic status and subsequently predict the prognoses of glioma patients. In this observational study, the concentrations of D- and L- 2-HG were determined in 57 tumor tissue samples of glioma patients (n=57) WHO grade I through IV (astrocytoma, oligodendroglioma, secondary glioblastoma, and glioblastoma multiforme) in vitro. Also, genetic mutation status on isocitrate dehydrogenase 1 and 2 (IDH 1/2) was determined from these samples. The objective of this study was to confirm or to reject the hypothesis of the direct correlation of 2-HG concentration in tumor tissue and the results from IDH 1/IDH 2 point mutation analyses. The concentrations of 2-HG were quantified using high sensitive HPLC and Q-TOF HRMS spectrometer setup. Concurrently, the genetic mutation analyses of both IDH 1 (cytosolic) and IDH 2 (mitochondrial) were performed by the isolation of tumor tissue DNA, PCR amplification, and subsequent Sanger forward sequencing. Our results indicate that there is no definite correlation between the two as we identified cases of glioma tumors with significantly increased concentration of one or both L- and D- 2-HG but no IDH 1/2 mutations (44% 2-HG positive cases). [ABSTRACT FROM AUTHOR]

The aim of this study was assess acute and early delayed radiation-induced changes in normal-appearing brain tissue perfusion as measured with perfusion magnetic resonance imaging (MRI) and the dependence of these changes on the fractionated radiotherapy (FRT) dose level.

Context: The most common type of brain tumors are gliomas, among which glioblastoma multiforme is the most life-threatening. In spite of the existing treatments, malignant gliomas often do not respond to treatment. Objectives: The aim of this study was to investigate the antitumor activity of vitamin D3 in malignant gliomas through the study of in vitro and in vivo articles. Data Sources: The electronic databases, including PubMed, ScienceDirect, Webof Science, Google Scholar, and the Cochrane Central Register of Clinical Trials (last updated April 12th, 2019) were searched, using medical subject headings (MeSH) keywords "vitamin D AND brain malignancy". Data Extraction: There was no limitation on the date and language of the articles. A review of all the found articles at the level of titles and abstracts was made to find eligible articles. Our work is in accordance with the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. The quality of the articles was judged in accordance with the GRADE tool for in vitro studies and CIRCLEs RoB tool for in vivo studies. Results: Totally, 88 articles were identified and after careful examination, 16 eligible articles meeting the inclusion criteria were selected. These studies showed that vitamin D3 and its analogs suppress self-renewal ability, cell viability and/or cell growth, migration rate, and invasive capacity; in addition, they induce autophagy and cell death. They also reduce tumor size in animal models. Evidence was mainly of moderate to high quality. Conclusions: Based on the in vitro and in vivo evidence of this systematic review, vitamin D3, compared to the control group, induced cell death and reduced cell growth, invasion, and migratory capacity in gliomas cell culture. As well as, vitamin D analogs were able to show the same effects without the hypercalcemic effect in vivo. We suggest performing future high-quality studies with the aim of shedding light on the relevant mechanisms and the effects of vitamin D3 derivatives and its analogs on health status and clinical outcomes in patients with malignant gliomas. [ABSTRACT FROM AUTHOR]

Background: D2C7-IT is a novel immunotoxin (IT) targeting wild-type epidermal growth factor receptor (EGFRwt) and mutant EGFR variant III (EGFRvIII) proteins in glioblastoma. In addition to inherent tumoricidal activity, immunotoxins induce secondary immune responses through the activation of T cells. However, glioblastoma-induced immune suppression is a major obstacle to an effective and durable immunotoxin-mediated antitumor response. We hypothesized that D2C7-IT-induced immune response could be effectively augmented in combination with αCTLA-4/αPD-1/αPD-L1 therapies in murine models of glioma. Methods: To study this, we overexpressed the D2C7-IT antigen, murine EGFRvIII (dmEGFRvIII), in established glioma lines, CT-2A and SMA560. The reactivity and therapeutic efficacy of D2C7-IT against CT-2A-dmEGFRvIII and SMA560- dmEGFRvIII cells was determined by flow cytometry and in vitro cytotoxicity assays, respectively. Antitumor efficacy of D2C7-IT was examined in immunocompetent, intracranial murine glioma models and the role of T cells was assessed by CD4+ and CD8+ T cell depletion. In vivo efficacy of D2C7-IT/αCTLA-4/αPD-1 monotherapy or D2C7-IT+αCTLA-4/ αPD-1 combination therapy was evaluated in subcutaneous unilateral and bilateral CT-2A-dmEGFRvIII glioma-bearing immunocompetent mice. Further, antitumor efficacy of D2C7-IT+αCTLA-4/αPD-1/αPD-L1/αTim-3/αLag-3/αCD73 combination therapy was evaluated in intracranial CT-2A-dmEGFRvIII and SMA560-dmEGFRvIII glioma-bearing mice. Pairwise differences in survival curves were assessed using the generalized Wilcoxon test. Results: D2C7-IT effectively killed CT-2A-dmEGFRvIII (IC50 = 0.47 ng/mL) and SMA560-dmEGFRvIII (IC50 = 1.05 ng/mL) cells in vitro. Treatment of intracranial CT-2A-dmEGFRvIII and SMA560-dmEGFRvIII tumors with D2C7-IT prolonged survival (P = 0.0188 and P = 0.0057, respectively), which was significantly reduced by the depletion of CD4+ and CD8+ T cells. To augment antitumor immune responses, we combined D2C7-IT with αCTLA-4/αPD-1 in an in vivo subcutaneous CT-2A-dmEGFRvIII model. Tumor-bearing mice exhibited complete tumor regressions (4/10 in D2C7-IT+αCTLA-4 and 5/10 in D2C7-IT+αPD-1 treatment groups), and combination therapy-induced systemic antitumor response was effective against both dmEGFRvIII-positive and dmEGFRvIII-negative CT-2A tumors. In a subcutaneous bilateral CT-2A-dmEGFRvIII model, D2C7-IT+αCTLA-4/αPD-1 combination therapies showed dramatic regression of the treated tumors and measurable regression of untreated tumors. Notably, in CT-2A-dmEGFRvIII and SMA560-dmEGFRvIII intracranial glioma models, D2C7-IT+αPD-1/αPD-L1 combinations improved survival, and in selected cases generated cures and protection against tumor re-challenge. Conclusions: These data support the development of D2C7-IT and immune checkpoint blockade combinations for patients with malignant glioma. [ABSTRACT FROM AUTHOR]

Malignant gliomas represent the majority of primary brain tumors, and the prognosis of the patients afflicted with these tumors has been historically dismal, with almost uniform progressive neurologic impairment and rapid death. Even with multimodal treatment using surgery, focal radiation, and chemotherapy, no major strides were made until recently. The development of interstitial BCNU wafers (carmustine wafers, Gliadel((R))) has led to promising results in the treatment of a selected patients with malignant gliomas, as well as with other intracranial malignancies.BCNU is one of the first systemic chemotherapies which had obtained United States Food and Drug Administration (FDA) approval for the treatment of brain tumors. However, systemic use has been hampered by the modest prolongation of survival and by the prolonged myelosuppression and potentially fatal pulmonary toxicity. The development of interstitial therapies with BCNU represented a great step forward, allowing direct delivery to the tumor bed, with virtually no systemic toxicities. Clinical studies of BCNU wafers have showed good efficacy in both newly diagnosed and recurrent gliomas, as well as a possible therapeutic role in other primary or secondary intracranial malignancies. New studies are currently underway trying to improve the efficacy of the BCNU wafers (Gliadel((R))) by combining them with different systemic chemotherapies. An overview of the current knowledge ranging from the preclinical developments, to the efficacy and safety seen in the clinical trials and in clinical practice following the drug approval to the future avenues of research is therefore timely.

Single-cell technologies allow precise identification of tumor composition at the single-cell level, providing high-resolution insights into the intratumoral heterogeneity and transcriptional activity of cells in the tumor microenvironment (TME) that previous approaches failed to capture. Malignant gliomas, the most common primary brain tumors in adults, are genetically heterogeneous and their TME consists of various stromal and immune cells playing an important role in tumor progression and responses to therapies. Previous gene expression or immunocytochemical studies of immune cells infiltrating TME of malignant gliomas failed to dissect their functional phenotypes. Single-cell RNA sequencing (scRNA-seq) and cytometry by time-of-flight (CyTOF) are powerful techniques allowing quantification of whole transcriptomes or >30 protein targets in individual cells. Both methods provide unprecedented resolution of TME. We summarize the findings from these studies and the current state of knowledge of a functional diversity of immune infiltrates in malignant gliomas with different genetic alterations. A precise definition of functional phenotypes of myeloid and lymphoid cells might be essential for designing effective immunotherapies. Single-cell omics studies have identified crucial cell subpopulations and signaling pathways that promote tumor progression, influence patient survival or make tumors vulnerable to immunotherapy. We anticipate that the widespread usage of single-cell omics would allow rational design of oncoimmunotherapeutics.

Fluorescence-guided resections have become standard of care for malignant gliomas. Strong fluorescence has been shown to correlate with solid enhancing tumor. However, with experience it has also been shown that visualized fluorescence may not identify the entire extent of the tumor. Knowing that malignant gliomas extend beyond the contrast-enhancing tumor seen on magnetic resonance imaging (MRI), reliance only on the fluorescence intraoperatively may not be enough. Intraoperative ultrasound is a readily available tool for real-time assessment of resection status, irrespective of the tumor type. We describe one such case in which after resecting all the visible fluorescing tumor component, we identified a significant component of nonfluorescing tumor, using intraoperative ultrasound that was further resected completely. This illustrates the need for multimodal intraoperative guidance for achieving optimal tumor resection in malignant gliomas.

Introduction: Glioblastoma Multiforme (GBM) has a variegated outcome due to several prognostic factors, radiotherapy dose being one of them. Aim: To find whether short course hypofractionated Radiotherapy (RT) in poor prognosis GBM is equivalent to standard 6 weeks of RT, in terms of survival and Quality of Life (QOL). Materials and Methods: Patients of GBM belonging to Radiotherapy Oncology Group Recursive Partitioning Analysis (RTOG RPA) class IV, V and VI were prospectively randomised into study arm (35Gy in 7 fractions over 15 days) and control arm (60Gy in 30 fractions over 6 weeks). A sample size of 40 with 20 patients in each arm was decided. The changes in Karnofsky Performance Status (KPS), Clinical Performance Status (CPS) and Neurological Performance Status (NPS) were noted as an assessment of QOL. Kaplan Meier method was used to analyse the overall survival and progression free survival. Log rank test was used to test the difference between the survival curves. Results: The two arms had similar demographic profile. The survival outcomes were identical for patients in the study arm (median survival 7.2 months) and the control arm (median survival 10.4 months) with log rank p=0.09. Freedom from progression was also identical at a median value of 5.5 months vs. 3.8 months, log rank p=0.34. The two arms had no difference in terms of QOL i.e., KPS, CPS and NPS. Conclusion: Hypofractionated short course RT is equivalent to standard 6 weeks RT for poor prognosis GBM patients both in terms of survival and QOL.

Objective: Analysis of long-lived patients from the group of patients with glioblastomas after using photodynamic therapy in the structure of their complex treatment in order to assess the influence of various factors on their life expectancy., Material and Methods: In total, a single-center, retrospective categorical study analyzed the long-term results of treatment of 63 patients with glioblastoma in the structure of complex treatment including photodynamic therapy. Clinical factors (age, sex, number of cases, preoperative Karnofsky index, location and size of the tumor, radicality of the operation), histological (nuclear polymorphism, mitosis, vascular proliferation, necrosis), immunohistochemical (Ki-67, p53 index) molecular-genetic factors (expression of VEGF, MGMT, IDH, CD34 ), amount of radiation and chemotherapy were analyzed., Results: In the entire group of patients, there was a direct correlation of life expectancy with MGMT status, IDH status, the number of courses of chemotherapy, the age of the patient, and the severity of the first surgical intervention., Conclusion: Clinical features such as age at diagnosis and extent of surgical resection and amount of chemotherapy have predictive value in assessing their effect on life expectancy. Mutations in IDH and MGMT promoter methylation were the most important molecular factors determining long-term patient survival.

Introduction: Malignant gliomas are the most prevalent and fatal types of primary malignant brain tumors with poor prognosis. Protein phosphatase 3 catalytic subunit beta (PPP3CB) is a pivotal constituent of the Ca 2+ /calmodulin-dependent serine/threonine protein phosphatases and widely expressed in brain. We aimed at identifying whether PPP3CB has potential in being a novel biomarker of malignant gliomas, bringing new insights to clinical management and therapy., Methods: Transcriptomes and clinical data of Glioblastoma (GBM) and low-grade glioma (LGG) samples were downloaded from TCGA and CGGA. We first explored the expressional and survival features of tumor tissues. Then, PPP3CB-associated genes were identified and their functional pathways were explored through GSEA analyses. Western blotting was conducted to modify PPP3CB expression. Samples of glioma patients and healthy controls were collected and immunohistochemistry (IHC) staining was performed to detect protein level. Further, we carried out an immune infiltration analysis, explored the correlation between PPP3CB and immune checkpoint genes, as well as to assessed the tumor mutation burden (TMB) and tumor microenvironment score (TMEscore) of PPP3CB., Results: PPP3CB expression in malignant glioma tissues was significantly downregulated and was considered an independent prognostic factor. Several functional pathways were observed through functional pathway analyses. PPP3CB's expression was strongly related to the infiltration of various immune cells and expression of key immune checkpoint genes. PPP3CB expression in high-grade gliomas was significantly lower, affecting glioma cells' proliferation and apoptosis in vitro., Conclusion: PPP3CB was a potential biomarker for the diagnosis and prognosis of malignant gliomas., Competing Interests: The authors declare that they have no competing interests., (© 2023 The Authors.)

Microglia are the resident immune cells of the central nervous system (CNS) that have distinct ontogeny from other tissue macrophages and play a pivotal role in health and disease. Microglia rapidly react to the changes in their microenvironment. This plasticity is attributed to the ability of microglia to adapt a context-specific phenotype. Numerous gene expression profiling studies of immunosorted CNS immune cells did not permit a clear dissection of their phenotypes, particularly in diseases when peripheral cells of the immune system come to play. Only recent advances in single-cell technologies allowed studying microglia at high resolution and revealed a spectrum of discrete states both under homeostatic and pathological conditions. Single-cell technologies such as single-cell RNA sequencing (scRNA-seq) and mass cytometry (Cytometry by Time-Of-Flight, CyTOF) enabled determining entire transcriptomes or the simultaneous quantification of >30 cellular parameters of thousands of individual cells. Single-cell omics studies demonstrated the unforeseen heterogeneity of microglia and immune infiltrates in brain pathologies: neurodegenerative disorders, stroke, depression, and brain tumors. We summarize the findings from those studies and the current state of knowledge of functional diversity of microglia under physiological and pathological conditions. A precise definition of microglia functions and phenotypes may be essential to design future immune-modulating therapies.

Management of malignant gliomas is challenging and has evolved significantly. In the last decade, a solid body of evidence integrated molecular markers to the histological findings, severely changing the landscape of high-grade gliomas classification, helping carve more detailed subgroups with different prognosis and potential responsiveness to therapy. Moreover, technical development of surgery and radiotherapy and emergency of new systemic approaches have modified clinical practice both in the initial and recurrent setting. All these aspects are integrated and revised in this updating article. [ABSTRACT FROM AUTHOR]

The lack of effective glioma therapeutics mandates the development of novel treatment strategies. Hepatoma-derived growth factor (HDGF) has been considered as a potential glioma therapeutic target, and its expression level in gliomas is positively related to the malignant grade. Although there are no effective and specific inhibitors against this target, small interfering RNA targeting HDGF (siHDGF)-mediated RNA interference (RNAi) can inhibit the target protein function by knockdown of HDGF expression. However, the application of siHDGF in glioma research and therapy is hampered by the challenge to safe and effective in vivo systemic delivery of siHDGF to gliomas. To address this question, we develop the peptide H 7 K(R 2) 2 -modified pH-sensitive self-assembled hybrid nanoparticles encapsulating siHDGF (H 7 K(R 2) 2 -PSNPs (siHDGF)). The acidic glioma microenvironment is beneficial to the membrane penetration of H 7 K(R 2) 2 -PSNPs and the encapsulated siHDGF. Following systemic administration, H 7 K(R 2) 2 -PSNPs (siHDGF) can effectively deliver siHDGF into the brain and malignant glioma cells, and therefore can significantly downregulate HDGF expression, inhibit malignant phenotypes of glioma cells, result in reduced tumor volumes and prolonged survival times in nude mice bearing U251 human glioblastoma. Thus, systemic administration of H 7 K(R 2) 2 -PSNPs (siHDGF) offers an effective way for the targeted delivery of siHDGF and may serve as a practical malignant glioma therapy. Unlabelled Image • H 7 K(R 2) 2 -PSNPs were developed to deliver siHDGF for malignant glioma treatment. • Acidic microenvironment attenuates the interaction of PLGA core and polyhistidine. • The pH responsiveness confers the tumor targeting to H 7 K(R 2) 2 -PSNPs. • Intravenously administrated H 7 K(R 2) 2 -PSNPs deliver siHDGF into malignant gliomas. • H 7 K(R 2) 2 -PSNPs (siHDGF) have potent anti-glioma effects in vitro and vivo. [ABSTRACT FROM AUTHOR]

• Malignant glioma cells highly expressed layilin, compared to astrocytes. • Layilin was mainly localized in the cytoplasm of A172 and T98G cells. • Layilin up-regulated SNAI1 to increase expression of MMP2, MMP9 and COL1A1. • Transcription of SNAI1 was up-regulated via down-regulation of MTA3 by layilin. • Layilin enhanced the invasive ability of malignant glioma cells. Malignant gliomas are characterized by high invasive ability. In this study, we investigated roles of layilin, a C-type lectin-homologous protein, in the invasive ability of malignant glioma cells. Expression of layilin was investigated by western blotting in the malignant glioma cell lines of U251-MG, A172, and T98G and in astrocytes. The effects of layilin-knockdown on the expression and protein levels of snail family transcriptional repressor 1 (SNAI1), a transcriptional factor involved in the acquisition and enhancement of invasive ability in malignant gliomas, and on the expression of its target genes, matrix metalloproteinase 2 (MMP2), MMP9 , and collagen type I alpha 1 chain (COL1A1), were investigated by qPCR and/or western blotting. Furthermore, the effects of layilin-knockdown on the expression and protein levels of metastasis associated 1 family member 3 (MTA3), a transcriptional repressor of SNAI1 , were also investigated by qPCR and western blotting. Finally, the effects of layilin-knockdown on the invasive ability of the cells were investigated by a wound healing assay. All the tested malignant glioma cells highly expressed layilin, compared to astrocytes, one of representative glial cell types. Layilin-knockdown reduced SNAI1 both at the mRNA and protein levels in A172 cells, and consequently mRNA levels of MMP2, MMP9, and COL1A1 were also reduced. Furthermore, layilin-knockdown increased nuclear protein levels of MTA3 in A172 cells. Notably, layilin-knockdown suppressed the invasive ability of the cells. Layilin up-regulates the expression of SNAI1 via down-regulation of MTA3. This process enhances the invasive ability of malignant glioma cells. [ABSTRACT FROM AUTHOR]

Gene therapy of malignant gliomas has shown a lack of clinical success to date due in part to inability of conventional gene vectors to achieve widespread gene transfer throughout highly disseminated tumor areas within the brain. Here, we demonstrate that newly engineered polymer-based DNA-loaded nanoparticles (DNA-NP) possessing small particle diameters (~50 nm) and non-adhesive surface polyethylene glycol (PEG) coatings efficiently penetrate brain tumor tissue as well as healthy brain parenchyma. Specifically, this brain-penetrating nanoparticle (BPN), following intracranial administration via convection enhanced delivery (CED), provides widespread transgene expression in heathy rodent striatum and an aggressive brain tumor tissue established orthotopically in rats. The ability of BPN to efficiently traverse both tissues is of great importance as the highly invasive glioma cells infiltrated into normal brain tissue are responsible for tumor recurrence. Of note, the transgene expression within the orthotopic tumor tissue occurred preferentially in glioma cells over microglial cells. We also show that three-dimensional (3D) multicellular spheroids established with malignant glioma cells, unlike conventional two-dimensional (2D) cell cultures, serve as an excellent in vitro model reliably predicting gene vector behaviors in vivo. Briefly, DNA-NP possessing greater surface PEG coverage exhibited more uniform and higher-level transgene expression both in the 3D model and in vivo , whereas the trend was opposite in 2D culture. The finding here alerts that gene transfer studies based primarily on 2D cultures should be interpreted with caution and underscores the relevance of 3D models for screening newly engineered gene vectors prior to their in vivo evaluation. Unlabelled Image [ABSTRACT FROM AUTHOR]

There is a distinct need for new and second-line therapies to delay or prevent local tumor regrowth after current standard of care therapy. Intracavitary radioimmunotherapy, in combination with radiotherapy, is discussed in the present review as a therapeutic strategy of high potential. We performed a systematic literature search following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA). The available body of literature on intracavitary radioimmunotherapy (iRIT) in glioblastoma and anaplastic astrocytomas is presented. Several past and current phase I and II clinical trials, using mostly an anti-tenascin monoclonal antibody labeled with I-131, have shown median overall survival of 19–25 months in glioblastoma, while adverse events remain low. Tenascin, followed by EGFR and variants, or smaller peptides have been used as targets, and most clinical studies were performed with I-131 or Y-90 as radionuclides while only recently Re-188, I-125, and Bi-213 were applied. The pharmacokinetics of iRIT, as well as the challenges encountered with this therapy, is comprehensively discussed. This promising approach deserves further exploration in future studies by incorporating several innovative modifications. [ABSTRACT FROM AUTHOR]

We investigate a mathematical model using a system of coupled ordinary differential equations, which describes the interplay of malignant glioma cells, macrophages, glioma specific CD8+T cells and the immunotherapeutic drug Adoptive Cellular Immunotherapy (ACI). To better understand under what circumstances the glioma cells can be eliminated, we employ the theory of optimal control. We investigate the dynamics of the system by observing biologically feasible equilibrium points and their stability analysis before administration of the external therapy ACI. We solve an optimal control problem with an objective functional which minimizes the glioma cell burden as well as the side effects of the treatment. We characterize our optimal control in terms of the solutions to the optimality system, in which the state system coupled with the adjoint system. Our model simulation demonstrates that the strength of treatment u 1 (t) $u_{1}(t)$ plays an important role to eliminate the glioma cells. Finally, we derive an optimal treatment strategy and then solve it numerically. [ABSTRACT FROM AUTHOR]

Introduction: Glioblastoma Multiforme (GBM) has a variegated outcome due to several prognostic factors, radiotherapy dose being one of them. Aim: To find whether short course hypofractionated Radiotherapy (RT) in poor prognosis GBM is equivalent to standard 6 weeks of RT, in terms of survival and Quality of Life (QOL). Materials and Methods: Patients of GBM belonging to Radiotherapy Oncology Group Recursive Partitioning Analysis (RTOG RPA) class IV, V and VI were prospectively randomised into study arm (35Gy in 7 fractions over 15 days) and control arm (60Gy in 30 fractions over 6 weeks). A sample size of 40 with 20 patients in each arm was decided. The changes in Karnofsky Performance Status (KPS), Clinical Performance Status (CPS) and Neurological Performance Status (NPS) were noted as an assessment of QOL. Kaplan Meier method was used to analyse the overall survival and progression free survival. Log rank test was used to test the difference between the survival curves. Results: The two arms had similar demographic profile. The survival outcomes were identical for patients in the study arm (median survival 7.2 months) and the control arm (median survival 10.4 months) with log rank p=0.09. Freedom from progression was also identical at a median value of 5.5 months vs. 3.8 months, log rank p=0.34. The two arms had no difference in terms of QOL i.e., KPS, CPS and NPS. Conclusion: Hypofractionated short course RT is equivalent to standard 6 weeks RT for poor prognosis GBM patients both in terms of survival and QOL. [ABSTRACT FROM AUTHOR]

Current standard-of-care treatment for glioblastoma, the most common malignant primary central nervous system (CNS) tumor, consists of surgical resection followed by adjuvant chemotherapy and radiation (Stupp protocol), providing an overall median survival of 15 months. With additional treatment using tumor-treating fields (Optune® therapy, Novocure Ltd., Haifa, Israel), survival can be extended up to 20 months. In spite of significant progress in our understanding of the molecular pathogenesis, the prognosis for patients with malignant gliomas remains poor and additional treatment modalities are critically needed. Curcumin is a bright yellow pigment found in the rhizome of the widely utilized spice, turmeric (Curcuma longa). It has long been used in South Asian traditional medicines and has been demonstrated to have in vitro antioxidant, anti-inflammatory, and antiproliferative effects. Curcumin has been demonstrated to induce multiple cytotoxic effects in tumor cells including cell cycle arrest, apoptosis, autophagy, changes in gene expression, and disruption of molecular signaling. Additionally, curcumin has been shown to potentiate the effect of radiation on cancer cells, while exhibiting a protective effect on normal tissue. Curcumin’s positive safety profile and widespread availability make it a promising compound for future clinical trials for high-grade gliomas.