Treatment Of Malignant Gliomas Research Articles

Effects of the Ketogenic Diet in the Treatment of Gliomas: A Systematic Review.

The ketogenic diet (KD) is a restrictive therapeutic diet, distinguished by being hyperlipidic, normoproteic, and hypoglucidic. This diet simulates biochemical changes related to fasting periods to achieve systemic ketosis. The metabolic particularities of glioma tumors motivated the rise in investigations and nutritional strategies, such as KD, to modulate the glycemic response as a treatment. This systematic review followed the PRISMA recommendations and was published in PROSPERO, with the identification CRD42021264173. The databases used were EMBASE, PubMed/Medline, Scopus, and Web of Science, and the studies were analyzed using the web-based application Rayyan. To analyze the risk of bias, Cochrane RevMan 5 software was used. For the analysis and treatment of statistical data, Microsoft® Excel® was used. A total of nine original articles were included. Data on survival, symptomology, and quality of life were collected. Mean overall survival was 15.9 months. Constipation and fatigue were the most reported symptoms. In 44.4% of the studies, an improvement in the quality of life was found. The KD is supported by most published studies as an effective therapy in the treatment of malignant gliomas due to its positive effects on patient survival. It was not possible to conclude the effectiveness of KD on quality of life.

Gallic Acid Enhances the Anti-Cancer Effect of Temozolomide in Human Glioma Cell Line via Inhibition of Akt and p38-MAPK Pathway

(1) Background: Temozolomide (TMZ), an oral alkylating agent, is used to treat malignant gliomas and other difficult-to-treat tumors. TMZ can enter the cerebrospinal fluid p.o. (per os) and does not need hepatic metabolism for activation of its use as a standard chemotherapeutic regimen after surgical resection of malignant glioma of the brain. However, the prognosis remains poor for most patients, and the survival rate is still unsatisfactory. Gallic acid (Ga) is a secondary metabolite existent in numerous plants. Ga shows various bioactivities, including antioxidant, anti-inflammatory, anticancer and antimicrobial effects. In this study, the latent enhanced anti-cancer efficacy of Ga in TMZ-treated U87MG cells (a human glioma line) was evaluated. (2) Methods: The U87MG cell line was cultured for 24 h. The cells were incubated with Ga alone, TMZ alone, or their combination for various time points. Cell viability and the drug combination index were evaluated by an XTT-based analysis and isobologram analysis, respectively. DNA destruction and intracellular reactive oxygen species (ROS) generation were analyzed by flow cytometer. The expression of various proteins was assessed via Western blotting. (3) Results: Compared with the action of TMZ alone or Ga alone, TMZ/Ga combination augmented the inhibition of cellular viability and apoptotic level in the U87MG glioma cell line. This enhanced anti-cancer effect correlated with the decreased expression of Bcl-2 and p-Akt, and corresponded with the activation of the p38 mitogen-activated protein kinase (MAPK) pathway. In addition, Ga suppressed the TMZ-promoted ROS generation. (4) Conclusions: Ga can augment the anti-cancer effect of TMZ via the repression of Bcl-2 expression and Akt activation and the enhancement of the p38 MAPK pathway. Our results offer a novel probable approach for the medical treatment of malignant glioma.

Survival after stereotactic radiosurgery of recurrent glioblastomas in patients with radical resection of primary tumor

glioblastoma (GBM) is an aggressive tumor with high rate of recurrence and estimated survival of 15-18 months after diagnosis. Factors associated with longer survival of GBM patients are age < 50 years, high performance status and radical resection of the primary tumor. The optimal treatment for recurrence/ progression of GBM has not yet been determined and remains a challenging issue. Stereotactic radiosurgery (SRS) is considered today as a therapeutic option for effective treatment of recurrent malignant gliomas. The aim of this retrospective study was to analyze the survival after SRS of the recurrent GBM in a cohort of 59 patients, which had a radical resection of the primary tumor. The cohort consisted of 59 patients (28 / 47.5% of women and 31 / 52.5% of men); the average age was 51 years (interval 24 - 81). SRS was performed by means of linear accelerator "Trilogy" (USA) (6 MeV) from 2014 to 2020 at the State Institution "Romodanov Neurosurgery Institute". In all cases, the diagnosis of grade 4 GBM according to the WHO classification was confirmed after neurosurgical procedures of the primary tumor. All 59 patients underwent the maximal safe removal of the primary tumor: in the vast majority of cases (54 / 91.5%) - in the perifocal area; in 5 / 8.5% of cases - subtotal. In all 59 cases, patients received adjuvant radiation therapy (total dose 60 Gy in 30 fractions); in 33 / 55.9% of cases radiotherapy was combined with concomitant alkylating chemotherapy (CHT) (Temozolomide 75 mg / m2). In 31 / 52.5% of patients, maintenance alkylating CHT was continued (Temozolomide 150-200 mg / m2). In most cases (51 / 86.4%) recurrent GBM (RGBM) was diagnosed by clinical and radiological signs; in 8 / 13.6% of patients - after repeated surgery. Overall survival (OS), recurrence/progression free survival (RFS) and survival after recurrence (SAR) represented the end-points of the study. The effect of the following quantitative and categorical factors (covariates) on the survival was studied: sex, age, performance status, combination of adjuvant RT with alkylating chemotherapy, neurosurgical procedures of RGBM, type of GBM recurrence, total dose of irradiation (BED11) and SRS dose (BED11), number of SRS fractions, volume of target in SRS, duration of RFS. The effect of RFS was studied in three independent groups: group I – RFS < 10 months; group II – RFS from 10 to 20 months; group III – RFS > 20 months. The survival was analyzed by Kaplan-Meier (KM) method. Log-rank test was used for analysis of the survival according to the binary predictors. The effect of several categorical factors on survival was analyzed by Pearson Chi-square test. The effect of the quantitative covariates on survival was studied by regression analysis in Cox proportional risk model. Hazard ratio was calculated with 95 % confidential intervals (CI). The analysis revealed the following. Median OS following SRS RGBM was 26.3 months (95 % CІ 17 – 45.5), median RFS was 12.9 months (95 % CІ 8.4 – 25.6), median SAR – 9.8 months (95 % CІ 6.7 – 24.4). Two-year OS in our study was 56 %. 6-month survival after SRS –77 %; one-year survival after SRS – 39 %, and two-year survival after SRS – 28 %. The significant impact of performance status (p = 0.00159), duration of recurrence-free period (p = 0.02711) and surgical resection of RGBM (р = 0.009391) on the OS was demonstrated. The best OS was shown for the patients with Karnofsky score 90, recurrence occurring after more than 20 months and previous surgical resection of RGBM. The effects of other factors on OS were not demonstrated. Such factors as age, sex, performance status, adjuvant RT with сoncomitant alkylating CHT, surgical resection of RGBM, type of recurrence, number of SRS fractions, BED11 in SRS RGBM, BED11 for overall courses of irradiation, SRS target volume demonstrated no effect on SAR. SRS is non-invasive method for RGBM treatment that allows for improving the survival without significant radiation toxicity. Primary biological properties of the tumor seem to be of priority in determining the survival of RGBM patients. Although irradiation of GBM is advantageous regarding the improvement of the survival, one could also speculate that re-irradiation of the recurrent malignant glioma triggers some changes in its biology neutralizing the potential effect of the survival factors that had predictive value before re-irradiation.

Efficacy and Safety of Temozolomide Combined with Radiotherapy in the Treatment of Malignant Glioma.

MG is a clinical common intracranial tumor, with the characteristics of strong invasion. In our study, we aim to explore the efficacy and safety of temozolomide combined with radiotherapy in the treatment of malignant glioma (MG) and its influence on postoperative complications and survival rate of patients. 120 MG patients admitted to our hospital (January 2019–January 2020) were chosen as the research objects and were randomly divided into group A (n = 60) and group B (n = 60). All patients were treated with radiotherapy, and patients in group A were additionally treated with temozolomide. The clinical efficacy, quality of life, incidence of adverse reactions, incidence of postoperative complications, survival rates, and average survival time of the two groups were compared. The objective remission rate (ORR), disease control rate (DCR), survival rates after one year and two years of follow-up, and the number of patients with improved quality of life in group A were markedly higher compared with group B (P < 0.05). The incidence of postoperative complications in group A was remarkably lower compared with group B (P < 0.05). The average survival time of group A was dramatically longer compared with group B (P < 0.001). There was no significant difference in the incidence of adverse reactions between the two groups (P > 0.05), and no new adverse reactions occurred in the patients. Temozolomide combined with radiotherapy can effectively improve the quality of life, treatment effect, and survival rate of MG patients, with a lower incidence of postoperative complications and better tolerance. Our finding indicates that temozolomide combined with radiotherapy has a high clinical application value. In addition, it indicates that this treatment method should be promoted in practice.

High-grade gliomas: a literature review. Part 2. Radiosurgical treatment

Malignant brain tumors remain one of the most complex problem in modern oncology, being among the most dangerous types of cancer not only because of their poor prognosis, but also due to the immediate consequences for quality of life and cognitive functions. It is expected that the number of such patients will increase as the life expectancy of the population increases.The mortality rate of patients with malignant gliomas remains the highest among all cancer patients. The median survival rate in this population does not exceed 24.5 months. Despite serious progress in the study of the molecular biology of this type of tumor, the question of effective application of this knowledge in the treatment process remains open.The review highlights the most advanced diagnostic methods and analyzes the effectiveness of a multidisciplinary therapeutic strategy. Special attention is given to the search for new approaches to radiosurgical treatment of high-grade gliomas in order to increase the duration and improve the quality of life of patients. The literature review is divided into 2 parts. Part 1 covers the epidemiology, clinic, and diagnosis of high-grade gliomas, as well as a combined approach to the treatment of the disease. In the 2nd part, the issues of stereotactic radiosurgery of high-grade gliomas, the features of the practical application of the “gamma knife” device in this pathology are highlighted; the effectiveness of the multimodal approach to the treatment of malignant gliomas is analyzed.

Current Immunotherapeutic Approaches for Malignant Gliomas.

Glioblastoma is the most common malignant central nervous system (CNS) tumor (48.3%), with a median survival of only about 14.6 months. Although the CNS is an immune-privileged site, activated T cells can cross the blood-brain barrier. The recent successes of several immunotherapies for various cancers have drawn interest in immunotherapy for treatment of malignant glioma. There have been extensive attempts to evaluate the efficiency of immunotherapy against malignant glioma. Passive immunotherapy for malignant glioma includes monoclonal antibody-mediated immunotherapy, cytokine-mediated therapy, and adoptive cell transfer, also known as chimeric antigen receptor T cell treatment. On the other hand, active immunotherapy, which stimulates the patient’s adaptive immune system against specific tumor-associated antigens, includes cancer vaccines that are divided into peptide vaccines and cell-based vaccines. In addition, there is immune checkpoint blockade therapy, which increases the efficiency of immunotherapy by reducing the resistance of malignant glioma to immunotherapy. Despite centuries of efforts, immunotherapeutic successes for malignant glioma remain limited. However, many clinical trials of adoptive cell transfer immunotherapy on malignant glioma are ongoing, and the outcomes are eagerly awaited. In addition, although there are still several obstacles, current clinical trials using personalized neoantigen-based dendritic cell vaccines offer new hope to glioblastoma patients. Furthermore, immune checkpoint targeted therapy is expected to decipher the mechanism of immunotherapy resistance in malignant glioma in the near future. More studies are needed to increase the efficacy of immunotherapy in malignant glioma. We hope that immunotherapy will become a new treatment of malignant glioma.

Nicotinic acid induces apoptosis of glioma cells via the calcium-dependent endoplasmic reticulum stress pathway

Malignant glioma is one of the most common and deadly tumors in the central nervous system while developing effective treatments for this devastating disease remains a challenge. Previously, we demonstrated that the vitamin nicotinic acid (NA) inhibits glioma invasion. Here, we show that high-dose NA induces apoptosis of malignant glioma cells in vitro and in vivo. In cultured U251 glioma cells treated with NA, we detected ER stress that was likely caused by elevated intracellular calcium levels. The elevated calcium can be attributed to the activation of TRPV1, a cation channel that has been implicated in cutaneous flushing caused by NA administration. Our data further suggested that NA-induced apoptosis is mediated by the calcium-dependent proteases called calpains, whose activities are drastically upregulated by NA. NA-induced apoptosis of U251 cells can be attenuated by blocking calpain activity or knocking down TRPV1. These results reveal a novel function of NA in regulating glioma cell apoptosis via the calcium-dependent ER stress pathway and imply a potential application of NA for the treatment of malignant glioma.

Targeted disruption of tumor vasculature via polyphenol nanoparticles to improve brain cancer treatment

SUMMARYDespite being effective for many other solid tumors, traditional anti-angiogenic therapy has been shown to be insufficient for the treatment of malignant glioma. Here, we report the development of polyphenol nanoparticles (NPs), which not only inhibit the formation of new vessels but also enable targeted disruption of the existing tumor vasculature. The NPs are synthesized through a combinatory iron-coordination and polymer-stabilization approach, which allows for high drug loading and intrinsic tumor vessel targeting. We study a lead NP consisting of quercetin and find that the NP after intravenous administration preferentially binds to VEGFR2, which is overexpressed in tumor vasculature. We demonstrate that the binding is mediated by quercetin, and the interaction of NPs with VEGFR2 leads to disruption of the existing tumor vasculature and inhibition of new vessel development. As a result, systemic treatment with the NPs effectively inhibits tumor growth and increases drug delivery to tumors.

NI-7 Diffusion-weighted imaging for monitoring acute response and recurrence after photodynamic therapy in malignant gliomas

BackgroundPhotodynamic therapy (PDT) subsequent to surgical tumor removal is a novel light-activated localized treatment for malignant glioma. Although PDT provides effective local control, even PDT cannot completely suppress local recurrence of malignant glioma. We previously reported that the acute response of malignant glioma to PDT could be detected as linear hyperintense signals on diffusion-weighted imaging (DWI) and a decline in apparent diffusion coefficient (ADC) values that were asymptomatic and transient. However, their long-term clinical significance has not yet been examined. This study aimed to clarify the link between the hyperintense signal on DWI as an acute response and recurrence after PDT in malignant glioma. MethodsThirty consecutive patients (16 men, 14 women; median age 60.5 years) underwent PDT for malignant glioma at our institution between 2017 and 2020. We analyzed signal changes on DWI after PDT and the link between these findings and the recurrence pattern. ResultsIn all patients, linear hyperintense signals of 5–7 mm on DWI were detected at the surface of the resected cavity from day 1 after PDT. These changes matched the PDT-irradiated area and disappeared in about 30 days without any neurological deterioration. Of the 30 patients, 19 (63%) exhibited recurrence: local recurrence in 10 (33%), distant recurrence in 1 (3%), and dissemination in 8 (27%). All local recurrences arose from areas that did not show a hyperintense signal on DWI obtained on day 1 after PDT. Patients with distant recurrence or dissemination tended to have uninterrupted hyperintense signal on DWI obtained on day 1 after PDT. ConclusionThe local recurrence in malignant glioma after PDT occurred in the areas without hyperintense signal on DWI as the acute response to PDT. This characteristic finding could aid in the monitoring of not only PDT-irradiated area but also local recurrence site after PDT.

ACT-8 Current status and prospects for the treatment of malignant glioma using cancer gene panel tests

Introduction: The cancer gene panel test was covered by insurance in June 2019. Our institution started the test in May 2020 and has experienced 10 cases, so we will report on the current status and future prospects. Methods: The subjects were 10 patients who underwent the cancer gene panel test using FoundationOne CDx. Results:The cases included 8 glioblastomas, an anaplastic astrocytoma, and an anaplastic oligodendroglioma. The total number of tumor mutational burden (TMB) was judged to be low in all cases, and the microsatellite instability test (MSI) showed no instability in all cases (MSI-Stable). The total number of genetic changes detected was 11 ± 5.0, oncogene mutations were 5.3 ± 2.4, and gene mutations of unknown relevance to cancer were 5.7 ± 2.8. Major oncogene mutations were IDH1 mutation in 4 cases, ATRX mutation in 2 cases, TP53 mutation in 6 cases, and BRAF V600E mutation in 1 case. Based on the test results, a 25-year-old man with BRAF V600E mutation was initiated into the NCCH1901 study (Patient-Proposed Healthcare Services). A case with IDH1 mutation (47-year-old male) entered a phase I clinical trial of a mutant IDH1 inhibitor. It is estimated that the chance of finding an appropriate drug by cancer gene panel test is about 10–20%. However, in cases that are resistant to standard treatment, the benefits can be expected if the drugs associated with the cancer gene panel test can be used. Conclusions: Although Malignant gliomas are often TMB-low and MSI-stable and the response rate to molecular-targeted drugs and other therapies is not high, there are some cases that can be salvaged by performing the cancer gene panel test. It is suggested that the active use of cancer gene panel test may contribute to the development of new drugs with high response rates and the improvement of prognosis.

Boron delivery agents for boron neutron capture therapy

<p indent=0mm>Boron neutron capture therapy (BNCT) is a binary method of radiotherapy, which is based on the nuclear reaction that occurs when boron-10 is irradiated with thermal neutron to yield high linear energy transfer α particles and recoiling lithium-7 nuclei. These particles with high energy and short range can kill cancer cells which absorbed ¹⁰B while little damage to normal tissues. BNCT has experienced nearly <sc>90 years</sc> of development since it was first proposed in 1936, which is one of the most effective methods for the treatment of malignant glioma. One of the key factors for the success of BNCT is to find boron delivery agents with high targeting and high affinity to tumors. Currently, although there are various of boron delivery agents, the best compound recognized for BNCT is still boronophenylalanine (BPA), for it has little side effect and no chemistry toxicity. BPA can penetrate the BBB and cell membrane, so it owns higher relative biological effectiveness. BPA is the most widely used BNCT drug in the world, which was officially approved in Japan last year, and the therapeutic effect on glioma is without question. In the past few decades, in order to improve the efficacy of BNCT, significant effort has been devoted to developing new boron delivery agents that possess better uptake and favorable pharmacokinetic characteristics for clinical use. This review focuses on differents kinds of boron delivery agents developed over the past years, which can be divided into three generations. At present, the first generation of boron delivery agents has been banned for lacking of targeting. The second generation of boron delivery agents is the most mature of the clinical application, but there are some problems need to be solved, such as limited boron loading and individual uptake varies greatly. The third generation of boron delivery agents contains various of agents—The boron-containing amino acids and peptides, the boron-containing compound conjugated with nucleosides, porphyrin derivatives, and different types of nanomaterials, was introduced in detail in this review. The boron loading and targeting of the third generation of boron delivery agents have greatly increased, but most of them are still in the experimental stage, and the safety and effectiveness need to be further verified. The advantages and disadvantages of the three generation boron delivery agents were analyzed and compared. Meanwhile the limitations of the various boron delivery agents were discussed and summarized. Additionally, the prospect and bottleneck of clinical arpplication of these boron delivery agents was critically analyzed from different view of research institutions, pharmaceutical enterprises and government policy. And the corresponding solutions were proposed: (1) Expand the application scope of BPA and BSH; develop new drugs and expand the application fields of BNCT technology; (2) enhance the cooperation of enterprises, university and research institutions, and promote the clinical approval and application of BPA and BSH; (3) multi disciplines jointly overcome technical barriers and establish a perfect evaluation system of safety and effectiveness for BNCT. In summary, with the official approval of the Japanese accelerator BNCT treatment system, the application prospects of BNCT technology will be broad all over the world. The comprehensive research of BNCT technology will be promoted by enhancing the intercrossing and coalescence between subjects relative with BNCT, and new ideas will be inspired, all of which will promote the clinical application of BNCT technology, and that benefit patients.

Preliminary Report: Rapid Intraoperative Detection of Residual Glioma Cell in Resection Cavity Walls Using a Compact Fluorescence Microscope.

Objective: The surgical eradication of malignant glioma cells is theoretically impossible. Therefore, reducing the number of remaining tumor cells around the brain–tumor interface (BTI) is crucial for achieving satisfactory clinical results. The usefulness of fluorescence–guided resection for the treatment of malignant glioma was recently reported, but the detection of infiltrating tumor cells in the BTI using a surgical microscope is not realistic. Therefore, we have developed an intraoperative rapid fluorescence cytology system, and exploratorily evaluated its clinical feasibility for the management of malignant glioma. Materials and methods: A total of 25 selected patients with malignant glioma (newly diagnosed: 17; recurrent: 8) underwent surgical resection under photodiagnosis using photosensitizer Talaporfin sodium and a semiconductor laser. Intraoperatively, a crush smear preparation was made from a tiny amount of tumor tissue, and the fluorescence emitted upon 620/660 nm excitation was evaluated rapidly using a compact fluorescence microscope in the operating theater. Results: Fluorescence intensities of tumor tissues measured using a surgical microscope correlated with the tumor cell densities of tissues evaluated by measuring the red fluorescence emitted from the cytoplasm of tumor cells using a fluorescence microscope. A “weak fluorescence” indicated a reduction in the tumor cell density, whereas “no fluorescence” did not indicate the complete eradication of the tumor cells, but indicated that few tumor cells were emitting fluorescence. Conclusion: The rapid intraoperative detection of fluorescence from glioma cells using a compact fluorescence microscope was probably useful to evaluate the presence of tumor cells in the resection cavity walls, and could provide surgical implications for the more complete resection of malignant gliomas.

IMMU-30. IDENTIFICATION OF COORDINATELY REGULATED IMMUNO-MODULATORY GENES USING SINGLE-CELL RNA SEQUENCING OF DECITABINE TREATED GLIOMA CELLS

Abstract INTRODUCTION The immunotherapeutic targeting of New York-esophageal squamous cell carcinoma (NY-ESO-1) and other cancer/testis antigens (CTA) is an appealing strategy for the treatment of malignant gliomas because CTA are not expressed in most normal adult tissues and their expression can be induced in tumors for targeting by T-cells. Basally, NY-ESO-1 is often poorly expressed in glioblastoma (GBM), presumably through promoter methylation. Our previous data has shown that the hypomethylating agent decitabine (DAC) is a strong sensitizer of GBM to NY-ESO-1 specific adoptive T-cell induced cytotoxicity. However, we hypothesized that DAC alters expression of other immuno-modulatory genes in addition to NY-ESO-1 that may also increase T-cell mediated killing in GBM. The extent of regulation of other immuno-modulatory genes to DAC demethylation has not yet been thoroughly investigated. METHODS We performed single-cell RNA sequencing on DAC and non-DAC treated glioma cells. We confirmed DAC treatment induced NY-ESO-1 expression with quantitative real-time PCR and demethylation using bisulfite sequencing. We analyzed our single-cell RNA sequencing data with Seurat and our customized R-based pipelines to identify coordinate differential expression of immuno-modulatory genes and their tumor subpopulations. RESULTS Using our single-cell data, we identified tumor subpopulations with coordinate differentially expressed immuno-modulatory genes including cancer testes antigens, antigen presentation proteins, and apoptosis regulators. Amongst these candidate genes, we validated their expression with qPCR and promoter demethylation with bisulfite sequencing and TA bisulfite cloning. CONCLUSION Exposure of glioma cells to DAC results in promoter demethylation of NY-ESO-1, with increased expression of CTA and other immunomodulatory genes. DAC treatment may therefore sensitize GBM to the immunotherapeutic targeting of these antigens and reveals a feasible strategy for clinical translation.

Chronic pathophysiological changes in the normal brain parenchyma caused by radiotherapy accelerate glioma progression

Radiation therapy is one of standard treatment for malignant glioma after surgery. The microenvironment after irradiation is considered not to be suitable for the survival of tumor cells (tumor bed effect). This study investigated whether the effect of changes in the microenvironment of parenchymal brain tissue caused by radiotherapy affect the recurrence and progression of glioma. 65-Gy irradiation had been applied to the right hemisphere of Fisher rats. After 3 months from irradiation, we extracted RNA and protein from the irradiated rat brain. To study effects of proteins extracted from the brains, we performed WST-8 assay and tube formation assay in vitro. Cytokine production were investigated for qPCR. Additionally, we transplanted glioma cell into the irradiated and sham animals and the median survival time of F98 transplanted rats was also examined in vivo. Immunohistochemical analyses and invasiveness of implanted tumor were evaluated. X-ray irradiation promoted the secretion of cytokines such as CXCL12, VEGF-A, TGF-β1 and TNFα from the irradiated brain. Proteins extracted from the irradiated brain promoted the proliferation and angiogenic activity of F98 glioma cells. Glioma cells implanted in the irradiated brains showed significantly high proliferation, angiogenesis and invasive ability, and the post-irradiation F98 tumor-implanted rats showed a shorter median survival time compared to the Sham-irradiation group. The current study suggests that the microenvironment around the brain tissue in the chronic phase after exposure to X-ray radiation becomes suitable for glioma cell growth and invasion.

Oncolytic Viro-Immunotherapy: An Emerging Option in the Treatment of Gliomas

The prognosis of malignant gliomas remains poor, with median survival fewer than 20 months and a 5-year survival rate merely 5%. Their primary location in the central nervous system (CNS) and its immunosuppressive environment with little T cell infiltration has rendered cancer therapies mostly ineffective, and breakthrough therapies such as immune checkpoint inhibitors (ICIs) have shown limited benefit. However, tumor immunotherapy is developing rapidly and can help overcome these obstacles. But for now, malignant gliomas remain fatal with short survival and limited therapeutic options. Oncolytic virotherapy (OVT) is a unique antitumor immunotherapy wherein viruses selectively or preferentially kill tumor cells, replicate and spread through tumors while inducing antitumor immune responses. OVTs can also recondition the tumor microenvironment and improve the efficacy of other immunotherapies by escalating the infiltration of immune cells into tumors. Some OVTs can penetrate the blood-brain barrier (BBB) and possess tropism for the CNS, enabling intravenous delivery. Despite the therapeutic potential displayed by oncolytic viruses (OVs), optimizing OVT has proved challenging in clinical development, and marketing approvals for OVTs have been rare. In June 2021 however, as a genetically engineered OV based on herpes simplex virus-1 (G47Δ), teserpaturev got conditional and time-limited approval for the treatment of malignant gliomas in Japan. In this review, we summarize the current state of OVT, the synergistic effect of OVT in combination with other immunotherapies as well as the hurdles to successful clinical use. We also provide some suggestions to overcome the challenges in treating of gliomas.

Accurately Controlled Delivery of Temozolomide by Biocompatible UiO-66-NH2 Through Ultrasound to Enhance the Antitumor Efficacy and Attenuate the Toxicity for Treatment of Malignant Glioma.

BackgroundGlioma is the most common and malignant primary brain tumour in adults and has a dismal prognosis. Temozolomide (TMZ) is the only clinical first-line chemotherapy drug for malignant glioma up to present. Due to poor aqueous solubility and toxic effects, TMZ is still inefficient and limited for clinical glioma treatment.MethodsUiO-66-NH2 nanoparticle is a zirconium-based framework, constructed by Zr and 2-amino-1,4-benzenedicarboxylic acid (BDC-NH2) with octahedral microporous structure, which can be decomposed by the body into an ionic form to discharge. We prepared the nanoscale metal-organic framework (MOF) of UiO-66-NH2 to load TMZ for therapy of malignant glioma, TMZ is released from UiO-66-NH2 through a porous structure. The ultrasound accelerates its porous percolation and promotes the rapid dissolution of TMZ through low-frequency oscillations and cavitation effect. The biological safety and antitumor efficacy were evaluated both in vitro and in vivo.ResultsThe prepared TMZ@MOF exhibited excellent biocompatibility and biosafety due to minimal drug leakage without ultrasound intervention. We further used the flank model of glioblastoma to verify the in vivo therapeutic effect. TMZ@UiO-66-NH2 nanocomposites could be well delivered to the tumour tissue, which led to local enrichment of the TMZ concentration. Furthermore, TMZ@UiO-66-NH2 nanocomposites under ultrasound demonstrated much more efficient inhibition for tumor growth than TMZ@UiO-66-NH2 nanocomposites and TMZ alone. Meanwhile, the bone marrow suppression side effects of TMZ were significantly reduced by TMZ@UiO-66-NH2 nanocomposites.ConclusionIn this work, TMZ@UiO-66-NH2 nanocomposites with ultrasound mediation could effectively improve the killing effect of malignant glioma and decrease TMZ-induced toxicity in normal tissues, demonstrating great potential for the delivery of TMZ in the clinical treatment of malignant gliomas.

Hyperintense signal on diffusion-weighted imaging for monitoring the acute response and local recurrence after photodynamic therapy in malignant gliomas.

Photodynamic therapy (PDT) subsequent to surgical tumor removal is a novel localized treatment for malignant glioma that provides effective local control. The acute response of malignant glioma to PDT can be detected as linear transient hyperintense signal on diffusion-weighted imaging (DWI) and a decline in apparent diffusion coefficient values without symptoms. However, their long-term clinical significance has not yet been examined. The aim of this study was to clarify the link between hyperintense signal on DWI as an acute response and recurrence after PDT in malignant glioma. Thirty patients (16 men; median age, 60.5 years) underwent PDT for malignant glioma at our institution between 2017 and 2020. We analyzed the signal changes on DWI after PDT and the relationship between these findings and the recurrence pattern. All patients showed linear hyperintense signal on DWI at the surface of the resected cavity from day 1 after PDT. These changes disappeared in about 30 days without any neurological deterioration. During a mean post-PDT follow-up of 14.3 months, 19 patients (63%) exhibited recurrence: 10 local, 1 distant, and 8 disseminated. All of the local recurrences arose from areas that did not show hyperintense signal on DWI obtained on day 1 after PDT. The local recurrence in malignant glioma after PDT occurs in an area without hyperintense signal on DWI as an acute response to PDT. This characteristic finding could aid in the monitoring of local recurrence after PDT.

PL03.1.A Surgery for glioblastomas in the elderly: an ANOCEF trial (CSA)

Abstract BACKGROUND The role of surgery for the treatment of malignant gliomas in patients 70 years of age or older is unsettled. We conducted a randomized trial that compared surgical resection of the tumor and biopsy only, both followed by standard therapy, in such patients. MATERIAL AND METHODS Patients aged 70 years and older, with a KPS of at least 50, presenting with a radiological suspicion of an operable glioblastoma (GBM) were randomly assigned between tumor resection and biopsy. Subsequently, they underwent standard radiotherapy during the first years of the trial (2008–2017), with the adjunction of concomitant and adjuvant temozolomide when this regimen became standard (2017–2019). The primary end point was survival; secondary endpoints were progression free survival (PFS), cognitive status (MMS), autonomy (KPS), quality of life (EORTC QLQ C30 and BN20), and perioperative morbidity/ mortality. RESULTS From 2008 to 2019, 107 patients from 9 centers were enrolled in the study, of whom 101 were evaluable for analysis because the diagnosis of GBM was histologically confirmed (50 patients in the “surgery” arm and 51 patients in the “biopsy” arm). There was no statistically significant difference of median survival between the “surgery” arm (9.37 mo) and the “biopsy” arms (8.96 mo, p=0.36). However, the surgery group had increased PFS (5.06 mo vs 4.02 mo; p=0.034; p=0.002 on multivariate analysis) and better QOL (e.g. physical and cognitive functioning, motor dysfunction, fatigue) and KPS score evolution as compared to the “biopsy” group. Surgery was not associated with increased mortality or morbidity. CONCLUSION This study suggests that optimal debulking surgery does not provide a significant survival benefit in elderly patients suffering from newly diagnosed malignant glioma, but resection improves QOL and autonomy with a significant though modest improvement of PFS.

In Vitro and In Vivo Enhancement of Temozolomide Effect in Human Glioblastoma by Non-Invasive Application of Cold Atmospheric Plasma.

Simple SummaryGlioblastoma (GBM) is an aggressive type of brain cancer, with which only 25% of patients survive for more than one year. Treatment of GBM has remained a challenge due to its resistance to chemotherapy. Here, we aimed to assess the potential for a combination therapy of cold atmospheric plasma (CAP) and Temozolomide (TMZ) to treat GBM. We confirmed the effect of co-treatment on different GBM cell lines in vitro and determined the enhancement of the effect of TMZ and the potential sensitization of GBM to CAP + TMZ in murine models in vivo. We found that co-treatment with CAP + TMZ inhibited GBM significantly compared to single treatment with CAP or TMZ alone. We provided further evidence related to the bone penetration of reactive oxygen and nitrogen species, as well as electromagnetic waves generated by CAP. RNA sequencing further indicated an effect of CAP + TMZ on cell cycle pathways. Collectively, these findings point to potential non-invasive translational approaches to target GBM in the future.Glioblastoma (GBM) is one of the most aggressive forms of adult brain cancers and is highly resistant to treatment, with a median survival of 12–18 months after diagnosis. The poor survival is due to its infiltrative pattern of invasion into the normal brain parenchyma, the diffuse nature of its growth, and its ability to quickly grow, spread, and relapse. Temozolomide is a well-known FDA-approved alkylating chemotherapy agent used for the treatment of high-grade malignant gliomas, and it has been shown to improve overall survival. However, in most cases, the tumor relapses. In recent years, CAP has been used as an emerging technology for cancer therapy. The purpose of this study was to implement a combination therapy of CAP and TMZ to enhance the effect of TMZ and apparently sensitize GBMs. In vitro evaluations in TMZ-sensitive and resistant GBM cell lines established a CAP chemotherapy enhancement and potential sensitization effect across various ranges of CAP jet application. This was further supported with in vivo findings demonstrating that a single CAP jet applied non-invasively through the skull potentially sensitizes GBM to subsequent treatment with TMZ. Gene functional enrichment analysis further demonstrated that co-treatment with CAP and TMZ resulted in a downregulation of cell cycle pathway genes. These observations indicate that CAP can be potentially useful in sensitizing GBM to chemotherapy and for the treatment of glioblastoma as a non-invasive translational therapy.

MiRNA-451 regulates the NF-κB signaling pathway by targeting IKKβ to inhibit glioma cell growth

ABSTRACT Glioblastoma multiforme (GBM) is associated with a poor prognosis, and effective treatments are lacking. Our previous studies have shown that miRNA-451 is closely related to the development and progression of glioma. miRNA-451 is a tumor suppressor whose expression is negatively correlated with the WHO grades of gliomas, but its specific mechanism is still unclear. Research shows that NF-κB is highly expressed in early malignant glioma, and thus, the NF-κB signaling pathway has become an important target for the treatment of malignant glioma. Activation of IKK is a critical step in the activation of the classical NF-κB pathway. By performing a bioinformatics analysis, we found that IKKβ is a potential direct target of miRNA-451 in glioma. In this study, we transfected lentivirus expressing miRNA-451 to test the effect of miRNA-451 overexpression on malignant glioma cell lines and confirmed that IKKβ is a target gene of miRNA-451 by luciferase assay. By targeting IKKβ, MTT, cell invasion and wound-healing assays showed that cell proliferation, cell invasion and migration were significantly suppressed in the LV-miRNA-451 group. Western blotting results showed that the expression levels of IKKβ, p-p65, MMP-2, MMP-9, Cyclin D1, p16 and PCNA were significantly decreased in the LV-miRNA-451 group. In vivo, miRNA-451 significantly decreased glioma cell growth, and the survival of BALB/c-A nude mice was significantly prolonged. Immunohistochemistry showed that p-p65, Cyclin D1 and Ki67 expression was significantly reduced in the LV-miRNA-451 group. Taken together, these results suggest that miRNA-451 could regulate the NF-κB signaling pathway by targeting IKKβ, which inhibits glioma cell growth in vitro and in vivo. Therefore, this study may provide novel insight into miRNA-451-targeted therapy for glioma.