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Journal of Experimental & Clinical... Jun 2021Immunotherapy is currently under intensive investigation as a potential breakthrough treatment option for glioblastoma. Given the anatomical and immunological... (Review)
Review
Immunotherapy is currently under intensive investigation as a potential breakthrough treatment option for glioblastoma. Given the anatomical and immunological complexities surrounding glioblastoma, lymphocytes that infiltrate the brain to develop durable immunity with memory will be key. Polyinosinic:polycytidylic acid, or poly(I:C), and its derivative poly-ICLC could serve as a priming or boosting therapy to unleash lymphocytes and other factors in the (immuno)therapeutic armory against glioblastoma. Here, we present a systematic review on the effects and efficacy of poly(I:C)/poly-ICLC for glioblastoma treatment, ranging from preclinical work on cellular and murine glioblastoma models to reported and ongoing clinical studies. MEDLINE was searched until 15 May 2021 to identify preclinical (glioblastoma cells, murine models) and clinical studies that investigated poly(I:C) or poly-ICLC in glioblastoma. A systematic review approach was conducted according to PRISMA guidelines. ClinicalTrials.gov was queried for ongoing clinical studies. Direct pro-tumorigenic effects of poly(I:C) on glioblastoma cells have not been described. On the contrary, poly(I:C) changes the immunological profile of glioblastoma cells and can also kill them directly. In murine glioblastoma models, poly(I:C) has shown therapeutic relevance as an adjuvant therapy to several treatment modalities, including vaccination and immune checkpoint blockade. Clinically, mostly as an adjuvant to dendritic cell or peptide vaccines, poly-ICLC has been demonstrated to be safe and capable of eliciting immunological activity to boost therapeutic responses. Poly-ICLC could be a valuable tool to enhance immunotherapeutic approaches for glioblastoma. We conclude by proposing several promising combination strategies that might advance glioblastoma immunotherapy and discuss key pre-clinical aspects to improve clinical translation.
Topics: Animals; Brain Neoplasms; Cancer Vaccines; Carboxymethylcellulose Sodium; Clinical Trials as Topic; Glioblastoma; Humans; Immune Checkpoint Inhibitors; Immunotherapy; Mice; Poly I-C; Polylysine
PubMed: 34172082
DOI: 10.1186/s13046-021-02017-2 -
Neurology India 2022Different variant of GBM has been reported viz. Epithelioid Glioblastoma (GBM-E), Rhabdoid GBM (GBM-R), Small cell GBM (GBM-SC), Giant cell GBM (GBM-GC), GBM with neuro...
OBJECTIVES
Different variant of GBM has been reported viz. Epithelioid Glioblastoma (GBM-E), Rhabdoid GBM (GBM-R), Small cell GBM (GBM-SC), Giant cell GBM (GBM-GC), GBM with neuro ectodermal differentiation (GBM-PNET) with unknown behavior.
MATERIALS
We conducted a systematic review and individual patient data analysis of these rare GBM variants. We searched PubMed, google search, and Cochrane library for eligible studies till July 1 2016 published in English language and collected data regarding age, sex, subtype and treatment received, Progression Free Survival (PFS), Overall Survival (OS). Statistical Package for social sciences (SPSS) v16 software was used for all statistical analysis.
RESULTS
We retrieved data of 196 patients with rare GBM subtypes. Among these GBM-GC is commonest (51%), followed by GBM-R (19%), GBM-PNET (13%), GBM-SC (9%) and GBM-E (8%). Median age at diagnosis was 38, 40, 43.5, 69.5 and 18 years, respectively. Male: female ratio was 2:1 for GBM-E, and 1:3 for GBM-SC. Maximal safe resection followed by adjuvant local radiation was used for most of the patients. However, 6 patients with GBM-PNET, 3 each of GBM-E, GBM-SC received adjuvant craniospinal radiation. Out of 88 patients who received chemotherapy, 64 received Temozolomide alone or combination chemotherapy containing Temozolomide. Median PFS and OS for the entire cohort were 9 and 16 months. In univariate analysis, patient with a Gross Total Resection had significantly better PFS and OS compared to those with a Sub Total Resection [23 vs. 13 months (p-0.01)]. Median OS for GBM PNET, GBM-GC, GBM-SC, GBM-R and GBM-E were 32, 18.3, 11, 12 and 7.7 months, respectively (P = 0.001). Interestingly, 31.3%, 37.8% of patients with GBM-E, GBM-R had CSF dissemination.
CONCLUSION
Overall cohort of rarer GBM variant has equivalent survival compared to GBM not otherwise specified. However, epithelioid and Rhabdoid GBM has worst survival and one third shows CSF dissemination.
Topics: Humans; Male; Female; Glioblastoma; Temozolomide; Data Analysis; Brain Neoplasms; Retrospective Studies; Neuroectodermal Tumors, Primitive; Antineoplastic Agents, Alkylating
PubMed: 36352613
DOI: 10.4103/0028-3886.359222 -
Chinese Clinical Oncology Aug 2017Tumor treating fields (TTF, Optune®), one of the low-intensity alternating electric fields, have been demonstrated to disrupt mitosis and inhibit tumor growth with... (Review)
Review
BACKGROUND
Tumor treating fields (TTF, Optune®), one of the low-intensity alternating electric fields, have been demonstrated to disrupt mitosis and inhibit tumor growth with antimitotic properties in a variety of tumor types. The Food and Drug Administration (FDA) of the United States approved TTF for recurrent GBM and newly diagnosed GBM in 2011 and 2015, respectively.
METHODS
A systematic review was conducted regarding the relevant studies published between January 1, 2000, and May 31, 2017 in PubMed database. The search term included "Tumor Treating Fields", "Optune", "TTF", "Novocure", and "GBM". This review summarizes the mechanism of action, efficacy, and adverse events based on pre-clinical studies and clinical trials for TTF in GBM.
RESULTS
Pre-clinical studies showed that TTF could inhibit tumor growth in vitro and in vivo by disrupting mitosis, inducing cell cycle arrest and apoptosis. Two randomized phase III trials evaluated the efficacy and safety of TTF in GBM patients. It was revealed that the combination of TTF and standard chemotherapy (temozolomide) prolonged the progression-free survival (PFS) and overall survival (OS) without systemic safety issues in newly diagnosed GBM (EF-14 trial). For recurrent GBM, the efficacy of TTF monotherapy was shown to be equivalent in PFS and OS without systemic adverse events when compared to the control group that received best physicians-chosen chemotherapies (EF-11 trial).
CONCLUSIONS
The advantages of TTF in GBM treatment, including non-invasive antitumor effect, superior therapeutic benefit in combination with chemotherapy, and minimal systematic toxicity, have been demonstrated in pre-clinical data and randomized phased III clinical trials. Future investigations will be needed to explore combinations of chemotherapy, radiation therapy, targeted therapy, as well as immunotherapy with this novel anti-tumor treatment modality to achieve additive or synergistic therapeutic benefit for GBM and other solid tumors.
Topics: Antineoplastic Agents, Alkylating; Brain Neoplasms; Clinical Trials, Phase III as Topic; Combined Modality Therapy; Dacarbazine; Disease-Free Survival; Electric Stimulation Therapy; Glioblastoma; Humans; Randomized Controlled Trials as Topic; Safety; Temozolomide; Treatment Outcome; United States
PubMed: 28841803
DOI: 10.21037/cco.2017.06.29 -
Cureus Feb 2023Subependymal giant cell astrocytoma (SEGA) is the most common intracranial tumor in tuberous sclerosis (TS) patients. The tumor generally localizes in the proximity of...
Subependymal giant cell astrocytoma (SEGA) is the most common intracranial tumor in tuberous sclerosis (TS) patients. The tumor generally localizes in the proximity of Monro's foramen; as it grows, it subsequently causes hydrocephalus and increases intracranial pressure (ICP). However, acute symptoms of increased ICP due to intratumoral bleeding rarely manifest in SEGA patients. We present a 27-year-old male with TS who presented due to hemorrhagic complications of SEGA with intratumoral bleeding and vitreous orbital hemorrhage. We then conducted a systematic review with four databases (PubMed, Web of Science, Google Scholar, and Cochrane) to identify similar cases using the following keywords: "Subependymal giant cell astrocytoma," "Hemorrhage," "Haemorrhage," and "Bleeding." Our review identified 12 articles reporting 14 cases of hemorrhagic complications of SEGA in addition to our case report. The median age of diagnosis was 21 (range 5-79) years with unequal gender distribution (M:F ratio, 11:4). Headache was the most presented symptom, followed by hemiparesis, seizure, altered mental status, visual deterioration, and headache accompanied by seizure. TS was seen in most of the cases (80%). Gross total resection (GTR) was achieved in 53.5% of the patients. Regarding the clinical outcome, 66.7% had a good outcome, 20% died, and 13.3% had no report of their outcomes. No tumor recurrence was seen in the cases with a reported duration of follow-up. Catastrophic presentation of SEGA apoplexy is a rare occurrence. We present a case report with a systematic review and discuss SEGA apoplexy's possible pathophysiology and outcome.
PubMed: 36915840
DOI: 10.7759/cureus.34784 -
Apoptosis : An International Journal on... Dec 2018Autophagy is an evolutionarily conserved catabolic process that plays an essential role in maintaining cellular homeostasis by degrading unneeded cell components. When... (Review)
Review
Autophagy is an evolutionarily conserved catabolic process that plays an essential role in maintaining cellular homeostasis by degrading unneeded cell components. When exposed to hostile environments, such as hypoxia or nutrient starvation, cells hyperactivate autophagy in an effort to maintain their longevity. In densely packed solid tumors, such as glioblastoma, autophagy has been found to run rampant due to a lack of oxygen and nutrients. In recent years, targeting autophagy as a way to strengthen current glioblastoma treatment has shown promising results. However, that protective autophagy inhibition or autophagy overactivation is more beneficial, is still being debated. Protective autophagy inhibition would lower a cell's previously activated defense mechanism, thereby increasing its sensitivity to treatment. Autophagy overactivation would cause cell death through lysosomal overactivation, thus introducing another cell death pathway in addition to apoptosis. Both methods have been proven effective in the treatment of solid tumors. This systematic review article highlights scenarios where both autophagy inhibition and activation have proven effective in combating chemoresistance and radioresistance in glioblastoma, and how autophagy may be best utilized for glioblastoma therapy in clinical settings.
Topics: Antineoplastic Agents; Autophagosomes; Autophagy; Brain Neoplasms; Cell Death; Drug Resistance, Neoplasm; Glioblastoma; Humans; Radiation-Sensitizing Agents; Temozolomide
PubMed: 30171377
DOI: 10.1007/s10495-018-1480-9 -
PloS One 2016Currently, the standard treatment for newly diagnosed glioblastoma multiforme (GBM) is maximal safe surgical resection followed by radiation therapy with concurrent and... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Currently, the standard treatment for newly diagnosed glioblastoma multiforme (GBM) is maximal safe surgical resection followed by radiation therapy with concurrent and adjuvant temozolomide. However, disease recurs in almost all patients, and the optimal salvage treatment for recurrent GBM remains unclear. We conducted a systematic review and meta-analysis of published clinical trials to assess the efficacy and toxicities of angiogenesis inhibitors alone as salvage treatment in these patients.
METHODS
Trials published between 1994 and 2015 were identified by an electronic search of public databases (MEDLINE, EMBASE, Cochrane library). Demographic data, treatment regimens, objective response rate (ORR), median progression-free survival (PFS), median overall survival (OS), 6-months PFS rate, 1-year OS and grade 3/4 toxicities were extracted. We also compared the main outcomes of interest between bevacizumab and other angiogenesis inhibitors. All analyses were performed using Comprehensive Meta Analysis software (Version 2.0).
RESULTS
A total of 842 patients were included for analysis: 343 patients were treated with bevacizumab, 386 with other angiogenesis inhibitors and 81 with thalidomide. The pooled ORR, 6-months PFS, and 1-year OS for recurrent GBM patients receiving angiogenesis inhibitors was 20.1%, 19.5% and 29.3%, respectively. The use of single agent bevacizumab in recurrent GBM significantly improved ORR and 6-months PFS when compared to other angiogenesis inhibitors [relative risk (RR) 2.93, 95% CI 1.38-6.21; p = 0.025; and RR 2.36 95% CI 1.46-3.82; p<0.001, respectively], while no significant difference in 1-year OS was found between the two groups (p = 0.07). when compared to thalidomide, bevacizumab treatment in recurrent GBM significantly improved ORR (RR 6.8, 95%CI: 2.64-17.6, p<0.001), but not for 6-months PFS (p = 0.07) and 1-year OS (p = 0.31). As for grade 3/4 toxicities, the common toxicity was hypertension with pooled incidence of 12.1%, while high-grade thromboembolic events (2.2%), hemorrhage (5.1%) and GI perforation (2.8%) associated with angiogenesis inhibitors were relatively low.
CONCLUSIONS
In comparison with other angiogenesis inhibitors and thalidomide, the use of single agent bevacizumab as salvage treatment for recurrent GBM patients improve ORR and 6-months PFS, but not for 1-year OS.
Topics: Angiogenesis Inhibitors; Bevacizumab; Glioblastoma; Humans; Recurrence; Salvage Therapy; Thalidomide
PubMed: 27007828
DOI: 10.1371/journal.pone.0152170 -
Asian Journal of Neurosurgery 2021Although a critical chemotherapeutic, temozolomide's optimal regimen for 2016 World Health Organization (WHO) Grade II gliomas remains elusive, hence there is utility in... (Review)
Review
OBJECTIVE/INTRODUCTION
Although a critical chemotherapeutic, temozolomide's optimal regimen for 2016 World Health Organization (WHO) Grade II gliomas remains elusive, hence there is utility in not only cataloging survival outcomes of Grade II glioma subtypes against the background of temozolomide regimens, but also quantifying differences in progression-free survival (PFS) and overall survival (OS).
MATERIALS AND METHODS
A systematic review of MEDLINE, Embase, and Cochrane Central Register of Controlled Trails was conducted by using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis and the Cochrane Handbook of Systemic Reviews of Interventions.
RESULTS
Each molecular subtype of WHO Grade II glioma had a different temozolomide regimen identified as optimal in prolonging PFS and OS. For PFS, with temozolomide, the 25, 50, and 75 percentiles, were as follows (in months), respectively-A-wt II: 6.90, 12.95, and 19.95; A-mt II: 34.45, 36.01, and 39.60; OD II: 37.90, 46.00, and 55.03 ( = 0.016). For OS, the first quartile (25%), median (50%), third quartile (75%), were respectively identified (in months-A-wt II: 21.6 (median; = 1); A-mt II: 60.6, 85.2, and 109.8; OD II: 86.1, 96.2, and 106.3 ( = 0.37).
CONCLUSION
For each tumor molecular subtype, a different temozolomide regimen was identified as optimal for prolonging PFS and OS. Furthermore, regardless of temozolomide regimen, A-wt II had a significantly shorter PFS than A-mt II and OD-II. Overall, the data can provide useful prognostic insight to patients when making critical treatment decisions. Moreover, by cataloging and assessing survival outcomes per temozolomide regimen, such may facilitate future clinical trial design.
PubMed: 34211862
DOI: 10.4103/ajns.AJNS_186_20 -
Human Vaccines & Immunotherapeutics Nov 2017Autologous dentritic cell immunotherapy has been proven effective in treating tumors outside the central nervous system. Current evidence from phase I and II trials... (Review)
Review
Autologous dentritic cell immunotherapy has been proven effective in treating tumors outside the central nervous system. Current evidence from phase I and II trials suggest a similar efficacy for central nervous system tumors as well and that an active immune response against these tumors can be generated. We aim to review the literature to identify the types of immune responses against gliomas found to be generated by dendritic cell vaccinations and the types of immune cells subsequently infiltrating the glioma microenvironment. A systematic review of the literature was performed by searching the online databases PubMEd, Google Scholar, and EMBASE with use of the keywords intratumoral, infiltration, lymphocytic, vaccination and gliomas. Seven studies reporting lymphocytic infiltration of gliomas microenvironment were identified. Three studies (42.8%) reported presence of tumor infiltrating lymphocytes in 50%, 50% and 28.6% of included patients respectively in the post-vaccination specimens that were not present in the pre-vaccination samples. The remaining 4 (57.2%) reported an up to 6-fold increase in the number of pre-existing lymphocytes following vaccination. Present data indicate that tumor infiltration by lymphocytes can be induced by dentritic cell immunotherapy and that this may positively affect clinical outcome. It still remains unclear which factors influence the above reaction and therefore prediction of response to treatment is still not possible.
Topics: Animals; Brain Neoplasms; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Dendritic Cells; Flow Cytometry; Glioblastoma; Glioma; Humans; Immunotherapy; Lymphocytes, Tumor-Infiltrating; Mice; Tumor Microenvironment; Vaccination
PubMed: 28362548
DOI: 10.1080/21645515.2017.1303582 -
Cellular and Molecular Neurobiology Nov 2023Liquid biopsy research on Low-Grade gliomas (LGG) has remained less conspicuous than that on other malignant brain tumors. Reliable serum markers would be precious for... (Review)
Review
Liquid biopsy research on Low-Grade gliomas (LGG) has remained less conspicuous than that on other malignant brain tumors. Reliable serum markers would be precious for diagnosis, follow- up and treatment. We propose a clinical utility score (CUS) for biomarkers in LGG that mirrors their clinical usefulness. We conducted a PRISMA review. We examined each biomarker classifying them by CUS and Level of Evidence (LOE). We identified four classes of biomarkers: (1). Circulating protein-(a) vitronectin discriminates LGG from HGG (Sn:98%, Sp:91%, CUS: 3, LOE: III), (b) CTLA-4 discriminates LGG from HGG, (cutoff: 220.43 pg/ml, Sn: 82%, Sp: 78%, CUS:3, LOE:III), (c) pre-operative TGF b1 predict astrocytoma (cutoff: 2.52 ng/ml, Sn: 94.9%, Sp: 100%, CUS:3, LOE:VI). (2). micro-RNA (miR)-(a) miR-16 discriminates between WHO IV and WHO II and III groups (AUC = 0.98, CUS:3, LOE: III), (b) miR-454-3p is higher in HGG than in LGG (p = 0.013, CUS:3, LOE: III), (c) miR-210 expression is related to WHO grades (Sn 83.2%, Sp 94.3%, CUS: 3, LOE: III). (3). Circulating DNA-(a) IDH1R132H mutation detected in plasma by combined COLD and digital PCR (Sn: 60%, Sp: 100%, CUS: 3, LOE: III). 4. Exosomes-(a) SDC1 serum levels could discriminate GBM from LGG (Sn: 71%, Sp: 91%, CUS: 2C, LOE: VI). Our investigation showed that miRs appear to have the highest clinical utility. The LOE of the studies assessed is generally low. A combined approach between different biomarkers and traditional diagnostics may be considered. We identified four main classes of biomarkers produced by LGG. We examined each biomarker, classifying them by clinical utility score (CUS) and level of evidence (LOE). Micro-RNA (miRs) appears to have the highest CUS and LOE.
Topics: Humans; Glioma; Brain Neoplasms; Biomarkers, Tumor; Liquid Biopsy; MicroRNAs; Neoplasm Grading
PubMed: 37704931
DOI: 10.1007/s10571-023-01406-9 -
Critical Reviews in Oncology/hematology Apr 2021Glioblastoma, the most common primary brain malignancy, is an exceptionally fatal cancer. Lack of suitable biomarkers and efficient treatment largely contribute to the... (Review)
Review
Glioblastoma, the most common primary brain malignancy, is an exceptionally fatal cancer. Lack of suitable biomarkers and efficient treatment largely contribute to the therapy failure. Cytoskeletal proteins are crucial proteins in glioblastoma pathogenesis and can potentially serve as biomarkers and therapeutic targets. Among them, GFAP, has gained most attention as potential diagnostic biomarker, while vimentin and microtubules are considered as prospective therapeutic targets. Microtubules represent one of the best anti-cancer targets due to their critical role in cell proliferation. Despite testing in clinical trials, the efficiency of taxanes, epothilones, vinca-domain binding drugs, colchicine-domain binding drugs and γ-tubulin binding drugs remains to be confirmed. Moreover, tumor treating field that disrupts microtubules draw attention because of its high efficiency and is called "the fourth cancer treatment modality". Thereby, because of the involvement of cytoskeleton in key physiological and pathological processes, its therapeutic potential in glioblastoma is currently extensively investigated.
Topics: Biomarkers; Cytoskeletal Proteins; Glioblastoma; Humans; Prospective Studies; Tubulin
PubMed: 33667657
DOI: 10.1016/j.critrevonc.2021.103283