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1.
Clin Neuropharmacol ; 44(6): 216-221, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34767325

RESUMO

ABSTRACT: The efficacy of dendritic cell vaccine for newly diagnosed glioblastoma remains controversial. We conduct a systematic review and meta-analysis to explore the influence of dendritic cell vaccine on treatment efficacy for newly diagnosed glioblastoma. We search PubMed, EMBASE, Web of science, EBSCO, and Cochrane library databases through December 2019 for randomized controlled trials assessing the efficacy and safety of dendritic cell vaccine for newly diagnosed glioblastoma. This meta-analysis is performed using the random effect model. Three randomized controlled trials are included in the meta-analysis. Overall, compared with control group for newly diagnosed glioblastoma, dendritic cell vaccine shows no substantial effect on median overall survival [standard mean difference, 0.11; 95% confidence interval (CI), -0.18 to 0.41; P = 0.45], median progression-free survival (standard mean difference, 0.12; 95% CI, -0.24 to 0.48; P = 0.50), progression-free survival rate [risk ratio (RR), 1.29; 95% CI, 0.82-2.04; P = 0.27], overall survival rate (RR, 1.29; 95% CI, 0.61-2.72; P = 0.50), or nervous system disorders (RR, 0.80; 95% CI, 0.59-1.08; P = 0.14). Dendritic cell vaccine may provide no obvious benefits for the newly diagnosed glioblastoma.


Assuntos
Glioblastoma , Vacinas , Células Dendríticas , Glioblastoma/terapia , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
2.
J Pak Med Assoc ; 71(11): 2678, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34783762

RESUMO

The current standard of care in glioblastoma management is surgery followed by chemotherapy and radiotherapy. Temozolomide is an alkylating agent most commonly used with a few other second line options. The efficacy of systemic chemotherapy in brain malignancies is limited due to the nature of the blood-brain barrier. Nanomedicine offers one avenue of improving drug delivery to these tumours in a more focussed and effective way in higher doses than currently possible, while simultaneously reducing systemic toxicity.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Antineoplásicos Alquilantes/uso terapêutico , Barreira Hematoencefálica , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/terapia , Humanos , Nanomedicina , Temozolomida/uso terapêutico
3.
Pan Afr Med J ; 39: 191, 2021.
Artigo em Francês | MEDLINE | ID: mdl-34603572

RESUMO

Glioblastoma is the most common primary malignant brain tumour. Despite advances in diagnostic and therapeutic treatments, it is still associated with poor outcome The purpose of this study of cases is to describe the epidemiological, clinical, therapeutic and evolutionary features of patients with glioblastoma admitted to the Department of Hematology-Oncology (DHO) in Marrakech in 2016 and 2017. We conducted a literature review of epidemiological, clinical, radiological, anatomopathological, therapeutic and evolutionary data from 40 patients. Glioblastoma accounted for 47.6% of treated intracranial tumours. The average age of patients was 52.4±12.3 years. Functional impotence and signs of intracranial hypertension were the main symptoms. Tumours mainly occurred in the parietal region (44%) and were large (57.5%). Aphasia was related to tumour size (p=0.042). Nine cases had glioblastomas-IDH1-wild and one case had glioblastoma-IDH1-mutant. On admission, patients had poor performance-status. This was due to a prolonged time between surgery and DHO admission (p= 0.034). Patients with sensory impairments were older (62.5±3 years) than those without sensory impairments (51.2±12 years) (p=0,045). In-patient women received chemoradiotherapy (1.5±1 month) earlier than men (2.3±1.2 months) (p=0.03). Survival was 13.6±5.3 months; it was unrelated to the time to surgery (p=0.076), the time to DHO (p=0.058), and the time to chemoradiotherapy (p=0.073). The epidemiological, clinical, radiological and evolutionary features of our sample were comparable to literature data. The molecular profiling was not systematically realized. Despite prolonged treatment times, no link to survival was detected.


Assuntos
Neoplasias Encefálicas/epidemiologia , Glioblastoma/epidemiologia , Hipertensão Intracraniana/etiologia , Adulto , Fatores Etários , Afasia/epidemiologia , Afasia/etiologia , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/terapia , Feminino , Glioblastoma/patologia , Glioblastoma/terapia , Hospitais Universitários , Humanos , Masculino , Pessoa de Meia-Idade , Marrocos , Estudos Retrospectivos , Fatores Sexuais , Taxa de Sobrevida , Tempo para o Tratamento
4.
Nat Commun ; 12(1): 5908, 2021 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-34625564

RESUMO

Oncolytic herpes simplex virus-1 is capable of lysing tumor cells while alerting the immune system. CD47, in collaboration with SIRPα, represents an important immune checkpoint to inhibit phagocytosis by innate immune cells. Here we show locoregional control of glioblastoma by an oncolytic herpes virus expressing a full-length anti(α)-human CD47 IgG1 or IgG4 antibody. The antibodies secreted by the virus-infected glioblastoma cells block the CD47 'don't eat me' signal irrespective of the subclass; however, αCD47-IgG1 has a stronger tumor killing effect than αCD47-IgG4 due to additional antibody-dependent cellular phagocytosis by macrophages and antibody-dependent cellular cytotoxicity by NK cells. Intracranially injected αCD47-IgG1-producing virus continuously releases the respective antibody in the tumor microenvironment but not into systemic circulation; additionally, αCD47-IgG1-producing virus also improves the survival of tumor-bearing mice better than control oncolytic herpes virus combined with topical αCD47-IgG1. Results from immunocompetent mouse tumor models further confirm that macrophages, and to a lesser extent NK cells, mediate the anti-tumor cytotoxicity of antibody-producing oncolytic herpesviruses. Collectively, oncolytic herpes simplex virus-1 encoding full-length antibodies could improve immune-virotherapy for glioblastoma.


Assuntos
Anticorpos/farmacologia , Glioblastoma/imunologia , Glioblastoma/terapia , Imunidade Inata , Vírus Oncolíticos/imunologia , Animais , Anticorpos/imunologia , Citotoxicidade Celular Dependente de Anticorpos , Antígeno CD47 , Modelos Animais de Doenças , Feminino , Herpesvirus Humano 1/imunologia , Humanos , Imunoglobulina G , Imunoterapia , Células Matadoras Naturais , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Terapia Viral Oncolítica/métodos , Fagocitose , Microambiente Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Int J Mol Sci ; 22(19)2021 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-34638754

RESUMO

Glioblastoma (GBM) is the most common and malignant primary brain tumor in adults. Radiotherapy has long been an important treatment method of GBM. However, the intrinsic radioresistance of GBM cells is a key reason of poor therapeutic efficiency. Recently, many studies have shown that using the histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA) in radiotherapy may improve the prognosis of GBM patients, but the underlying molecular mechanisms remain unclear. In this study, Gene Expression Omnibus (GEO) datasets GSE153982 and GSE131956 were analyzed to evaluate radiation-induced changes of gene expression in GBM without or with SAHA treatment, respectively. Additionally, the survival-associated genes of GBM patients were screened using the Chinese Glioma Genome Atlas (CGGA) database. Taking the intersection of these three datasets, 11 survival-associated genes were discovered to be activated by irradiation and regulated by SAHA. The expressions of these genes were further verified in human GBM cell lines U251, T98G, and U251 homologous radioresistant cells (U251R) by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). It was found that MMP14 mRNA was considerably highly expressed in the radioresistant cell lines and was reduced by SAHA treatment. Transfection of MMP14 siRNA (siMMP14) suppressed cell survivals of these GBM cells after irradiation. Taken together, our results reveal for the first time that the MMP14 gene contributed to SAHA-induced radiosensitization of GBM.


Assuntos
Quimiorradioterapia , Bases de Dados de Ácidos Nucleicos , Glioblastoma , Inibidores de Histona Desacetilases/farmacologia , Metaloproteinase 14 da Matriz/metabolismo , Proteínas de Neoplasias/metabolismo , Tolerância a Radiação/efeitos dos fármacos , Vorinostat/farmacologia , Linhagem Celular Tumoral , Glioblastoma/enzimologia , Glioblastoma/genética , Glioblastoma/terapia , Humanos , Metaloproteinase 14 da Matriz/genética , Proteínas de Neoplasias/genética , Vorinostat/farmacocinética
6.
Molecules ; 26(19)2021 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-34641347

RESUMO

Glioblastoma (GBM) is the most common primary and aggressive tumour in brain cancer. Novel therapies, despite achievements in chemotherapy, radiation and surgical techniques, are needed to improve the treatment of GBM tumours and extend patients' survival. Gene delivery therapy mostly uses the viral vector, which causes serious adverse events in gene therapy. Graphene-based complexes can reduce the potential side effect of viral carries, with high efficiency of microRNA (miRNA) or antisense miRNA delivery to GBM cells. The objective of this study was to use graphene-based complexes to induce deregulation of miRNA level in GBM cancer cells and to regulate the selected gene expression involved in apoptosis. The complexes were characterised by Fourier transform infrared spectroscopy (FTIR), scanning transmission electron microscopy and zeta potential. The efficiency of miRNA delivery to the cancer cells was analysed by flow cytometry. The effect of the anticancer activity of graphene-based complexes functionalised by the miRNA sequence was analysed using 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxyanilide salt (XTT) assays at the gene expression level. The results partly explain the mechanisms of miRNA deregulation stress, which is affected by graphene-based complexes together with the forced transport of mimic miR-124, miR-137 and antisense miR-21, -221 and -222 as an anticancer supportive therapy.


Assuntos
Neoplasias Encefálicas/terapia , Glioblastoma/terapia , Grafite/química , MicroRNAs/antagonistas & inibidores , RNA Antissenso/administração & dosagem , RNA Antissenso/química , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Sobrevivência Celular , Sistemas de Liberação de Medicamentos , Glioblastoma/genética , Glioblastoma/patologia , Humanos , MicroRNAs/administração & dosagem , Células Tumorais Cultivadas
7.
Biochemistry (Mosc) ; 86(8): 1012-1024, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34488577

RESUMO

Conventional approaches for studying and molecular typing of tumors include PCR, blotting, omics, immunocytochemistry, and immunohistochemistry. The last two methods are the most used, as they enable detecting both tumor protein markers and their localizations within the cells. In this study, we have investigated a possibility of using RNA aptamers, in particular, 2'-F-pyrimidyl-RNA aptamer ME07 (48 nucleotides long), specific to the receptor of epidermal growth factor (EGFR, ErbB1, Her1), as an alternative to monoclonal antibodies for aptacytochemistry and aptahistochemistry for human glioblastoma multiforme (GBM). A specificity of binding of FAM-ME07 to the receptor on the tumor cells has been demonstrated by flow cytometry; an apparent dissociation constant for the complex of aptamer - EGFR on the cell has been determined; a number of EGFR molecules has been semi-quantitatively estimated for the tumor cell lines having different amount of EGFR: A431 (106 copies per cell), U87 (104 copies per cell), MCF7 (103 copies per cell), and ROZH, primary GBM cell culture derived from patient (104 copies per cell). According to fluorescence microscopy, FAM-ME07 interacts directly with the receptors on A431 cells, followed by its internalization into the cytoplasm and translocation to the nucleolus; this finding opens a possibility of ME07 application as an escort aptamer for a delivery of therapeutic agents into tumor cells. FAM-ME07 efficiently stains sections of GBM clinical specimens, which enables an identification of EGFR-positive clones within a heterogeneous tumor; and providing a potential for further studying animal models of GBM.


Assuntos
Aptâmeros de Nucleotídeos/química , Neoplasias Encefálicas/terapia , Glioblastoma/terapia , RNA/química , Anticorpos Monoclonais , Neoplasias Encefálicas/genética , Linhagem Celular Tumoral , Citoplasma/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Fator de Crescimento Epidérmico/metabolismo , Receptores ErbB , Glioblastoma/genética , Humanos , Concentração Inibidora 50 , Células MCF-7 , Microscopia de Fluorescência , Oligonucleotídeos/química , Medicina de Precisão , Transporte Proteico
9.
Cancer J ; 27(5): 371-378, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34570451

RESUMO

ABSTRACT: Gliomas and glioblastoma comprise the majority of brain malignancies and are difficult to treat despite standard of care and advances in immunotherapy. The challenges of controlling glioma growth and recurrence involve the uniquely immunosuppressive tumor microenvironment and systemic blunting of immune responses. In addition to highlighting key features of glioma and glioblastoma composition and immunogenicity, this review presents several future directions for immunotherapy, such as vaccines and synergistic combination treatment regimens, to better combat these tumors.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Glioma , Neoplasias Encefálicas/terapia , Glioblastoma/terapia , Glioma/terapia , Humanos , Imunoterapia , Recidiva Local de Neoplasia , Microambiente Tumoral
10.
Cells ; 10(9)2021 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-34571991

RESUMO

Glioblastoma multiforme (GBM) is an aggressive malignancy of the brain and spinal cord with a poor life expectancy. The low survivability of GBM patients can be attributed, in part, to its heterogeneity and the presence of multiple genetic alterations causing rapid tumor growth and resistance to conventional therapy. The Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-CRISPR associated (Cas) nuclease 9 (CRISPR-Cas9) system is a cost-effective and reliable gene editing technology, which is widely used in cancer research. It leads to novel discoveries of various oncogenes that regulate autophagy, angiogenesis, and invasion and play important role in pathogenesis of various malignancies, including GBM. In this review article, we first describe the principle and methods of delivery of CRISPR-Cas9 genome editing. Second, we summarize the current knowledge and major applications of CRISPR-Cas9 to identifying and modifying the genetic regulators of the hallmark of GBM. Lastly, we elucidate the major limitations of current CRISPR-Cas9 technology in the GBM field and the future perspectives. CRISPR-Cas9 genome editing aids in identifying novel coding and non-coding transcriptional regulators of the hallmarks of GBM particularly in vitro, while work using in vivo systems requires further investigation.


Assuntos
Edição de Genes/métodos , Glioblastoma/genética , Glioblastoma/terapia , Proteína 9 Associada à CRISPR/genética , Sistemas CRISPR-Cas/genética , Endonucleases/genética , Expressão Gênica/genética , Regulação da Expressão Gênica/genética , Técnicas de Transferência de Genes/tendências , Terapia Genética/métodos , Glioblastoma/metabolismo , Humanos , Mutação/genética , Oncogenes/genética
11.
Int J Mol Sci ; 22(18)2021 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-34575921

RESUMO

To treat malignant glioma, standard fractionated radiotherapy (RT; 60 Gy/30 fractions over 6 weeks) was performed post-surgery in combination with temozolomide to improve overall survival. Malignant glioblastoma recurrence rate is extremely high, and most recurrent tumors originate from the excision cavity in the high-dose irradiation region. In our previous study, protoporphyrin IX physicochemically enhanced reactive oxygen species generation by ionizing radiation and combined treatment with 5-aminolevulinic acid (5-ALA) and ionizing radiation, while radiodynamic therapy (RDT) improved tumor growth suppression in vivo in a melanoma mouse model. We examined the effect of 5-ALA RDT on the standard fractionated RT protocol using U251MG- or U87MG-bearing mice. 5-ALA was orally administered at 60 or 120 mg/kg, 4 h prior to irradiation. In both models, combined treatment with 5-ALA slowed tumor progression and promoted regression compared to treatment with ionizing radiation alone. The standard fractionated RT protocol of 60 Gy in 30 fractions with oral administration of 120 and 240 mg/kg 5-ALA, the human equivalent dose of photodynamic diagnosis, revealed no significant increase in toxicity to normal skin or brain tissue compared to ionizing radiation alone. Thus, RDT is expected to enhance RT treatment of glioblastoma without severe toxicity under clinically feasible conditions.


Assuntos
Ácido Aminolevulínico/farmacologia , Fracionamento da Dose de Radiação , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Radiação Ionizante , Radioterapia , Ácido Aminolevulínico/administração & dosagem , Ácido Aminolevulínico/efeitos adversos , Animais , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Neoplasias Encefálicas/terapia , Linhagem Celular Tumoral , Terapia Combinada , Modelos Animais de Doenças , Relação Dose-Resposta à Radiação , Glioblastoma/terapia , Humanos , Camundongos , Fotoquimioterapia/efeitos adversos , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/administração & dosagem , Fármacos Fotossensibilizantes/efeitos adversos , Radioterapia/métodos , Raios X , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Int J Mol Sci ; 22(18)2021 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-34576168

RESUMO

Although treatment outcomes of glioblastoma, the most malignant central nervous system (CNS) tumor, has improved in the past decades, it is still incurable, and survival has only slightly improved. Advances in molecular biology and genetics have completely transformed our understanding of glioblastoma. Multiple classifications and different diagnostic methods were made according to novel molecular markers. Discovering tumor heterogeneity only partially explains the ineffectiveness of current anti-proliferative therapies. Dynamic heterogeneity secures resistance to combined oncotherapy. As tumor growth proceeds, new therapy-resistant sub clones emerge. Liquid biopsy is a new and promising diagnostic tool that can step up with the dynamic genetic change. Getting a 'real-time' picture of a specific tumor, anti-invasion and multi-target treatment can be designed. During invasion to the peri-tumoral brain tissue, glioma cells interact with the extracellular matrix components. The expressional levels of these matrix molecules give a characteristic pattern, the invasion spectrum, which possess vast diagnostical, predictive and prognostic information. It is a huge leap forward combating tumor heterogeneity and searching for novel therapies. Using the invasion spectrum of a tumor sample is a novel tool to distinguish between histological subtypes, specifying the tumor grades or different prognostic groups. Moreover, new therapeutic methods and their combinations are under trial. These are crucial steps towards personalized oncotherapy.


Assuntos
Glioblastoma/terapia , Glioma/terapia , Idoso , Biomarcadores Tumorais/sangue , Encéfalo/metabolismo , Neoplasias Encefálicas/sangue , Epigênese Genética/genética , Exossomos/metabolismo , Feminino , Humanos , Imunoterapia , Biópsia Líquida/métodos , Masculino , Pessoa de Meia-Idade , Ácidos Nucleicos/sangue , Prognóstico
13.
Oncoimmunology ; 10(1): 1960728, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34408922

RESUMO

Glioblastoma (GBM) is the most common and aggressive brain malignancy in adults and is currently incurable with conventional therapies. The use of chimeric antigen receptor (CAR) modified T cells has been successful in clinical treatment of blood cancers, except solid tumors such as GBM. This study generated two third-generation CARs targeting different epitopes of ephrin type-A receptor 2 (EphA2) and examined their anti-GBM efficacy in vitro and in tumor-bearing mice. We observed that these two types of T cells expressing CAR (CAR-T) targeting EphA2 could be activated and expanded by EphA2 positive tumor cells in vitro. The survival of tumor-bearing mice after EphA2 CAR-T cell treatment was significantly improved. T cells transduced with one of the two EphA2 CARs exhibited better anti-tumor activity, which is related to the upregulation of CXCR-1/2 and appropriate interferon-γ (IFN-γ) production. CAR-T cells expressed excessively high level of IFN-γ exhibited poor anti-tumor activity resulting from inducing the upregulation of PD-L1 in GBM cells. The combination of CAR-T cells with poor anti-tumor activity and PD1 blockade improved the efficacy in tumor-bearing mice. In conclusion, both types of EphA2 CAR-T cells eliminated 20%-50% of GBM in xenograft mouse models. The appropriate combination of IFN-γ and CXCR-1/2 levels is a key factor for evaluating the antitumor efficiency of CAR-T cells.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Imunoterapia Adotiva , Receptores de Antígenos Quiméricos , Animais , Antígeno B7-H1 , Neoplasias Encefálicas/terapia , Glioblastoma/terapia , Interferon gama , Camundongos , Linfócitos T/ultraestrutura , Ensaios Antitumorais Modelo de Xenoenxerto
14.
BMC Cancer ; 21(1): 958, 2021 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-34445990

RESUMO

BACKGROUND: Alternative splicing (AS), one of the main post-transcriptional biological regulation mechanisms, plays a key role in the progression of glioblastoma (GBM). Systematic AS profiling in GBM is limited and urgently needed. METHODS: TCGA SpliceSeq data and the corresponding clinical data were downloaded from the TCGA data portal. Survival-related AS events were identified through Kaplan-Meier survival analysis and univariate Cox analysis. Then, splicing correlation network was constructed based on these AS events and associated splicing factors. LASSO regression followed by multivariate Cox analysis was performed to validate independent AS biomarkers and to construct a risk prediction model. Enrichment analysis was subsequently conducted to explore potential signaling pathways of these AS events. RESULTS: A total of 132 TCGA GBM samples and 45,610 AS events were included in our study, among which 416 survival-related AS events were identified. An AS correlation network, including 54 AS events and 94 splicing factors, was constructed, and further functional enrichment was performed. Moreover, the novel risk prediction model we constructed displayed moderate performance (the area under the curves were > 0.7) at both one, two and three years. CONCLUSIONS: Survival-related AS events may be vital factors of both biological function and prognosis. Our findings in this study can deepen the understanding of the complicated mechanisms of AS in GBM and provide novel insights for further study. Moreover, our risk prediction model is ready for preliminary clinical applications. Further verification is required.


Assuntos
Processamento Alternativo , Biomarcadores Tumorais/genética , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Genoma Humano , Glioblastoma/patologia , Fatores de Processamento de RNA/genética , Terapia Combinada , Feminino , Seguimentos , Perfilação da Expressão Gênica , Glioblastoma/genética , Glioblastoma/terapia , Humanos , Masculino , Prognóstico , Taxa de Sobrevida , Transcriptoma
15.
Front Immunol ; 12: 650105, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34394072

RESUMO

Glioblastoma is considered to be the most malignant disease of the central nervous system, and it is often associated with poor survival. The immune microenvironment plays a key role in the development and treatment of glioblastoma. Among the different types of immune cells, tumor-associated microglia/macrophages (TAM/Ms) and CD8-positive (CD8+) T cells are the predominant immune cells, as well as the most active ones. Current studies have suggested that interaction between TAM/Ms and CD8+ T cells have numerous potential targets that will allow them to overcome malignancy in glioblastoma. In this review, we summarize the mechanism and function of TAM/Ms and CD8+ T cells involved in glioblastoma, as well as update on the relationship and crosstalk between these two cell types, to determine whether this association alters the immune status during glioblastoma development and affects optimal treatment. We focus on the molecular factors that are crucial to this interaction, and the role that this crosstalk plays in the biological processes underlying glioblastoma treatment, particularly with regard to immune therapy. We also discuss novel therapeutic targets that can aid in resolving reticular connections between TAM/Ms and CD8+ T cells, including depletion and reprogramming TAM/Ms and novel TAM/Ms-CD8+ T cell cofactors with potential translational usage. In addition, we highlight the challenges and discuss future perspectives of this crosstalk between TAM/Ms and CD8+ T cells.


Assuntos
Neoplasias Encefálicas/imunologia , Comunicação Celular/imunologia , Glioblastoma/imunologia , Microambiente Tumoral/imunologia , Animais , Encéfalo/imunologia , Encéfalo/patologia , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/terapia , Linfócitos T CD8-Positivos/imunologia , Comunicação Celular/efeitos dos fármacos , Ensaios Clínicos como Assunto , Modelos Animais de Doenças , Glioblastoma/patologia , Glioblastoma/terapia , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia Adotiva/métodos , Linfócitos do Interstício Tumoral/imunologia , Microglia/imunologia , Microglia/patologia , Receptores de Antígenos Quiméricos/imunologia , Resultado do Tratamento , Microambiente Tumoral/efeitos dos fármacos , Macrófagos Associados a Tumor/imunologia
16.
J Med Econ ; 24(1): 1018-1024, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34353213

RESUMO

INTRODUCTION: Glioblastoma is the most common primary brain tumor in adults. Standard of care includes maximal surgical resection of the tumor followed by concurrent chemotherapy and radiation. The treatment of glioblastoma must account for an increased disease severity and treatment intensity compared to other cancers which place a significant cost burden on the patient and health system. Cost assessments of glioblastoma treatment have been sparse in comparison to other solid cancer subtypes. This study evaluates all currently available cost literature with an emphasis on the modern treatment paradigm to properly assess the economic implications of this disease. METHODS: A critical review of 21 studies from 13 different countries measuring direct costs related to glioblastoma management was performed. Evaluated data included itemized costs, total costs of treatment regimens from diagnosis until death, the cost of second-line care after recurrence, and the incremental costs and cost-effectiveness of emerging therapies. RESULTS: The average cost of a craniotomy was $10,042 across studies. Imaging for the duration of glioblastoma care had a mean cost of $2,788 ± 3,719. Studies examined different combinations of treatment modalities. Utilization of the modern treatment paradigm led to survival of 16.3 months across studies and had a mean cost of $62,602. Surgery for the recurrent disease had an average cost of $27,442 ± 18,992. LIMITATIONS AND CONCLUSIONS: Direct cost estimates for glioblastoma varied substantially between institutions and countries and often failed to uniformly describe direct cost estimates associated with care for glioblastoma. The limitations of these studies make a true economic assessment of standards of care, costs of recurrence, and incremental costs associated with adjunctive therapy uncertain.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Adulto , Neoplasias Encefálicas/terapia , Terapia Combinada , Análise Custo-Benefício , Glioblastoma/terapia , Humanos , Recidiva Local de Neoplasia
17.
J Clin Neurosci ; 91: 209-213, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34373029

RESUMO

A female survival benefit has been described for glioblastoma patients. Recent studies report that the effect of 06-methylguanine-DNA-methyltransferase gene promoter (MGMTp) methylation is only present in female patients. We retrospectively studied sex-based survival, including MGMTp-methylation, in a cohort of 159 uniformly treated isocitrate dehydrogenase wildtype (IDHwt) patients. All patients were treated with temozolomide-based chemoradiotherapy after surgery. Kaplan-Meier survival curves and Cox regression models were used to evaluate overall survival. The study included 59 female (37.1%) and 100 male patients (62.9%). There were no statistically significant differences between sexes concerning demographic, surgical or radiological characteristics. Female patients harbored MGMTp-methylated tumors in 45.8% of cases and males in 33% (P = 0.129). Median overall survival was 13.4 months for men and women alike. After adjustment of survival for age, Karnofsky Performance Score, extent of resection and MGMTp-methylation, sex did not have a significant survival impact. However, MGMTp-methylation proved to be an independent beneficial prognosticator for both sexes, contradicting earlier reports. Several sex-based molecular subtypes of glioblastoma with different response to current treatment may exist explaining conflicting survival results in different patient cohorts. Further research on sex-based differences in IDHwt glioblastoma patients is needed.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Metilação de DNA , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Feminino , Glioblastoma/diagnóstico por imagem , Glioblastoma/genética , Glioblastoma/terapia , Humanos , Isocitrato Desidrogenase , Masculino , Prognóstico , Estudos Retrospectivos
18.
CNS Oncol ; 10(3): CNS76, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34378977

RESUMO

Aim: Investigate real-world outcomes and healthcare utilization of patients with glioblastoma multiforme (GBM) related to O6-methylguanine DNA methyltransferase (MGMT) promoter testing and methylation. Patients & methods: US Oncology Network data were analyzed for patients receiving first-line (1L) treatment for GBM. Results: Most patients received 1L radiation with temozolomide. Unadjusted median overall survival (OS) was higher in tested versus untested (median:18.1 vs 11.8 months) and in methylated versus unmethylated (median: 25.5 vs 12.4 months). Untested status, unmethylated MGMT and older age were associated with reduced OS and longer 1L treatment with increased OS. Similar findings were observed for progression-free survival. Utilization was similar between cohorts. Conclusion: In community oncology practices, MGMT methylation and testing were predictive of better survival in GBM.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Idoso , Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/terapia , Metilação de DNA , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Dacarbazina/uso terapêutico , Glioblastoma/tratamento farmacológico , Glioblastoma/terapia , Humanos , Estudos Retrospectivos , Proteínas Supressoras de Tumor/genética
19.
J Cancer Res Clin Oncol ; 147(12): 3503-3516, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34459971

RESUMO

BACKGROUND: Glioblastoma peritumoral edema (PE) extent is associated with survival and progression pattern after tumor resection and radiotherapy (RT). To increase tumor control, proton beam was adopted to give high-dose boost (> 90 Gy). However, the correlation between PE extent and prognosis of glioblastoma after postoperative high-dose proton boost (HDPB) therapy stays unknown. We intend to utilize the PE status to classify the survival and progression patterns. METHODS: Patients receiving HDPB (96.6 GyE) were retrospectively evaluated. Limited peritumoral edema (LPE) was defined as PE extent < 3 cm with a ratio of PE extent to tumor maximum diameter of < 0.75. Extended progressive disease (EPD) was defined as progression of tumors extending > 1 cm from the tumor bed edge. RESULTS: After long-term follow-up (median 88.7, range 63.6-113.8 months) for surviving patients with (n = 13) and without (n = 32) LPE, the median overall survival (OS) and progression-free survival (PFS) were 77.2 vs. 16.7 months (p = 0.004) and 13.6 vs. 8.6 months (p = 0.02), respectively. In multivariate analyses combined with factors of performance, age, tumor maximum diameter, and tumor resection extent, LPE remained a significant factor for favorable OS and PFS. The rates of 5-year complete response, EPD, and distant metastasis with and without LPE were 38.5% vs. 3.2% (p = 0.005), 7.7% vs. 40.6% (p = 0.04), and 0% vs. 34.4% (p = 0.02), respectively. CONCLUSIONS: The LPE status effectively identified patients with relative long-term control and specific progression patterns after postoperative HDPB for glioblastoma.


Assuntos
Edema Encefálico/patologia , Neoplasias Encefálicas/patologia , Glioblastoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/terapia , Progressão da Doença , Feminino , Glioblastoma/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Procedimentos Neurocirúrgicos , Terapia com Prótons , Estudos Retrospectivos , Resultado do Tratamento
20.
J Control Release ; 338: 22-32, 2021 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-34391836

RESUMO

Gene therapy has been introduced as an alternative to radiation and chemical therapy for glioblastoma. Biomimetic nanoparticles coated with cell membranes (CM) have advantages such as high biocompatibility and prolong half-life. To apply CM coated nanoparticles to gene delivery, the polyethylenimine (PEI25k)/plasmid DNA (pDNA) complexes were coated with CM from C6 rat glioblastoma cells. With the CM covering, the PEI25k/pDNA complexes formed stable nanoparticles with negative surface charge. The PEI25k/pDNA/CM nanoparticles had high colloidal stability and could be stored for approximately 20 days without aggregation. The transfection efficiency of the PEI25k/pDNA/CM nanoparticles was higher than that of the PEI25k/pDNA complex in serum-containing medium. This suggests that serum does not interfere with transfection efficiency of the nanoparticles. Moreover, the PEI25k/pDNA/CM nanoparticles had lower toxicity than the PEI25k/DNA complex in vitro and in vivo. The PEI25k/pDNA/CM nanoparticles prepared with CMs of different types of cells were transfected into cells. The results showed that the PEI25k/pDNA/CM nanoparticles with the C6 CM had the highest transfection efficiency to C6 cells, suggesting the homotypic targeting effect. The therapeutic effects of the nanoparticles were evaluated in intracranial C6 transplanted glioblastoma animal models. The PEI25k/pDNA/CM nanoparticles were prepared with herpes simplex virus thymidine kinase plasmid (pHSVtk) and injected into the tumor locally. The results showed that the PEI25k/pHSVtk/CM nanoparticles induced higher HSVtk expression compared with the PEI25k/pHSVtk complex. Furthermore, tumor size was reduced more efficiently by the PEI25k/pHSVtk/CM nanoparticles than by the PEI25k/pHSVtk complex. Overall results indicate that PEI25k/pDNA/CM nanoparticles are suitable for pDNA delivery to glioblastoma.


Assuntos
Glioblastoma , Nanopartículas , Animais , Biomimética , Membrana Celular , DNA , Técnicas de Transferência de Genes , Terapia Genética , Glioblastoma/terapia , Tamanho da Partícula , Plasmídeos , Polietilenoimina , Ratos , Transfecção
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