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1.
BMC Cancer ; 22(1): 843, 2022 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-35918659

RESUMO

BACKGROUND: Glioblastoma (GB) is the most common and most aggressive malignant brain tumor. In understanding its resistance to conventional treatments, iron metabolism and related pathways may represent a novel avenue. As for many cancer cells, GB cell growth is dependent on iron, which is tightly involved in red-ox reactions related to radiotherapy effectiveness. From new observations indicating an impact of RX radiations on the expression of ceruloplasmin (CP), an important regulator of iron metabolism, the aim of the present work was to study the functional effects of constitutive expression of CP within GB lines in response to beam radiation depending on the oxygen status (21% O2 versus 3% O2). METHODS AND RESULTS: After analysis of radiation responses (Hoechst staining, LDH release, Caspase 3 activation) in U251-MG and U87-MG human GB cell lines, described as radiosensitive and radioresistant respectively, the expression of 9 iron partners (TFR1, DMT1, FTH1, FTL, MFRN1, MFRN2, FXN, FPN1, CP) were tested by RTqPCR and western blots at 3 and 8 days following 4 Gy irradiation. Among those, only CP was significantly downregulated, both at transcript and protein levels in the two lines, with however, a weaker effect in the U87-MG, observable at 3% O2. To investigate specific role of CP in GB radioresistance, U251-MG and U87-MG cells were modified genetically to obtain CP depleted and overexpressing cells, respectively. Manipulation of CP expression in GB lines demonstrated impact both on cell survival and on activation of DNA repair/damage machinery (γH2AX); specifically high levels of CP led to increased production of reactive oxygen species, as shown by elevated levels of superoxide anion, SOD1 synthesis and cellular Fe2 + . CONCLUSIONS: Taken together, these in vitro results indicate for the first time that CP plays a positive role in the efficiency of radiotherapy on GB cells.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/radioterapia , Linhagem Celular Tumoral , Ceruloplasmina/genética , Ceruloplasmina/metabolismo , Ceruloplasmina/farmacologia , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/radioterapia , Humanos , Ferro/farmacologia , Oxigênio/metabolismo , Tolerância a Radiação/genética
2.
Acta Biomed ; 93(3): e2022067, 2022 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-35775774

RESUMO

COVID-19 pandemic revolutionized the way in which cancer patients are treated worldwide. Regarding neuro-oncological patients, usually considered frail and with lower life-expectancy in respect to other oncological patients, the international scientific community had to urgently reorganize the treatment approach in order to minimize the risk of in-hospital contagious. For GBM patients, adjuvant treatments have been evaluated with even much more attention with regard to the expected efficacy. As a consequence, an hypofractioned radiotherapy regimen has been preferred in order to reduce the daily hospital accesses and, especially in pMGMT unmethylated patients, chemotherapy with Temozolomide was avoided. Here, we made a comprehensive evaluation of the neurooncological community suggestions regarding GBM treatment in the pre-vaccine era of COVID-19 pandemic.


Assuntos
Neoplasias Encefálicas , COVID-19 , Glioblastoma , Vacinas , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/terapia , Dacarbazina/efeitos adversos , Glioblastoma/radioterapia , Hospitais , Humanos , Pandemias/prevenção & controle , SARS-CoV-2 , Vacinas/uso terapêutico
3.
Cells ; 11(14)2022 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-35883571

RESUMO

Systematic recurrence of glioblastoma (GB) despite surgery and chemo-radiotherapy is due to GB stem cells (GBSC), which are particularly invasive and radioresistant. Therefore, there is a need to identify new factors that might be targeted to decrease GBSC invasive capabilities as well as radioresistance. Patient-derived GBSC were used in this study to demonstrate a higher expression of the glycoprotein M6a (GPM6A) in invasive GBSC compared to non-invasive cells. In 3D invasion assays performed on primary neurospheres of GBSC, we showed that blocking GPM6A expression by siRNA significantly reduced cell invasion. We also demonstrated a high correlation of GPM6A with the oncogenic protein tyrosine phosphatase, PTPRZ1, which regulates GPM6A expression and cell invasion. The results of our study also show that GPM6A and PTPRZ1 are crucial for GBSC sphere formation. Finally, we demonstrated that targeting GPM6A or PTPRZ1 in GBSC increases the radiosensitivity of GBSC. Our results suggest that blocking GPM6A or PTPRZ1 could represent an interesting approach in the treatment of glioblastoma since it would simultaneously target proliferation, invasion, and radioresistance.


Assuntos
Glioblastoma , Glicoproteínas de Membrana , Proteínas do Tecido Nervoso , Glioblastoma/genética , Glioblastoma/radioterapia , Humanos , Glicoproteínas de Membrana/metabolismo , Glicoproteínas de Membrana/efeitos da radiação , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/efeitos da radiação , Proteínas do Tecido Nervoso/metabolismo , Proteínas do Tecido Nervoso/efeitos da radiação , Tolerância a Radiação , Proteínas Tirosina Fosfatases Classe 5 Semelhantes a Receptores
4.
Cells ; 11(14)2022 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-35883575

RESUMO

Glioblastoma is a devastating malignant disease with poor patient overall survival. Strong invasiveness and resistance to radiochemotherapy have challenged the identification of molecular targets that can finally improve treatment outcomes. This study evaluates the influence of all six known p21-activated kinase (PAK) protein family members on the invasion capacity and radio-response of glioblastoma cells by employing a siRNA-based screen. In a panel of human glioblastoma cell models, we identified PAK4 as the main PAK isoform regulating invasion and clonogenic survival upon irradiation and demonstrated the radiosensitizing potential of PAK4 inhibition. Mechanistically, we show that PAK4 depletion and pharmacological inhibition enhanced the number of irradiation-induced DNA double-strand breaks and reduced the expression levels of various DNA repair proteins. In conclusion, our data suggest PAK4 as a putative target for radiosensitization and impairing DNA repair in glioblastoma, deserving further scrutiny in extended combinatorial treatment testing.


Assuntos
Glioblastoma , Quinases Ativadas por p21 , Quebras de DNA de Cadeia Dupla/efeitos da radiação , Reparo do DNA/efeitos da radiação , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/radioterapia , Humanos , RNA Interferente Pequeno , Quinases Ativadas por p21/genética , Quinases Ativadas por p21/metabolismo
5.
Sci Rep ; 12(1): 12285, 2022 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-35853933

RESUMO

Radiotherapy can induce an immunological response. One limiting factor is side effects on normal tissue. Using FLASH radiotherapy, side effects could possibly be reduced. The efficacy of FLASH in relation to conventional radiotherapy (CONV-RT) has not been extensively explored in fully immunocompetent animals. Fully immunocompetent Fischer 344 rats were inoculated with NS1 glioblastoma cells subcutaneously or intracranially. Radiotherapy was delivered with FLASH or CONV-RT at 8 Gy × 2 (subcutaneous tumors) and 12.5 Gy × 2 (intracranial tumors). Cured animals were re-challenged in order to explore long-term anti-tumor immunity. Serum analytes and gene expression were explored. The majority of animals with subcutaneous tumors were cured when treated with FLASH or CONV-RT at 8 Gy × 2. Cured animals could reject tumor re-challenge. TIMP-1 in serum was reduced in animals treated with FLASH 8 Gy × 2 compared to control animals. Animals with intracranial tumors survived longer when treated with FLASH or CONV-RT at 12.5 Gy × 2, but cure was not reached. CONV-RT and FLASH were equally effective in fully immunocompetent animals with glioblastoma. Radiotherapy was highly efficient in the subcutaneous setting, leading to cure and long-term immunity in the majority of the animals.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Animais , Neoplasias Encefálicas/etiologia , Neoplasias Encefálicas/radioterapia , Glioblastoma/etiologia , Glioblastoma/radioterapia , Radioterapia/efeitos adversos , Dosagem Radioterapêutica , Ratos
6.
Cell Death Dis ; 13(6): 573, 2022 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-35764612

RESUMO

Channelling of glucose via glycogen, known as the glycogen shunt, may play an important role in the metabolism of brain tumours, especially in hypoxic conditions. We aimed to dissect the role of glycogen degradation in glioblastoma (GBM) response to ionising radiation (IR). Knockdown of the glycogen phosphorylase liver isoform (PYGL), but not the brain isoform (PYGB), decreased clonogenic growth and survival of GBM cell lines and sensitised them to IR doses of 10-12 Gy. Two to five days after IR exposure of PYGL knockdown GBM cells, mitotic catastrophy and a giant multinucleated cell morphology with senescence-like phenotype developed. The basal levels of the lysosomal enzyme alpha-acid glucosidase (GAA), essential for autolysosomal glycogen degradation, and the lipidated forms of gamma-aminobutyric acid receptor-associated protein-like (GABARAPL1 and GABARAPL2) increased in shPYGL U87MG cells, suggesting a compensatory mechanism of glycogen degradation. In response to IR, dysregulation of autophagy was shown by accumulation of the p62 and the lipidated form of GABARAPL1 and GABARAPL2 in shPYGL U87MG cells. IR increased the mitochondrial mass and the colocalisation of mitochondria with lysosomes in shPYGL cells, thereby indicating reduced mitophagy. These changes coincided with increased phosphorylation of AMP-activated protein kinase and acetyl-CoA carboxylase 2, slower ATP generation in response to glucose loading and progressive loss of oxidative phosphorylation. The resulting metabolic deficiencies affected the availability of ATP required for mitosis, resulting in the mitotic catastrophy observed in shPYGL cells following IR. PYGL mRNA and protein levels were higher in human GBM than in normal human brain tissues and high PYGL mRNA expression in GBM correlated with poor patient survival. In conclusion, we show a major new role for glycogen metabolism in GBM cancer. Inhibition of glycogen degradation sensitises GBM cells to high-dose IR indicating that PYGL is a potential novel target for the treatment of GBMs.


Assuntos
Glioblastoma , Trifosfato de Adenosina , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/radioterapia , Glucose/farmacologia , Glicogênio/metabolismo , Glicogênio Fosforilase/genética , Glicogênio Fosforilase/metabolismo , Humanos , Fígado/metabolismo , Isoformas de Proteínas , RNA Mensageiro
7.
Phys Med Biol ; 67(14)2022 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-35714611

RESUMO

Objective.Bioluminescence imaging (BLI) is a valuable tool for non-invasive monitoring of glioblastoma multiforme (GBM) tumor-bearing small animals without incurring x-ray radiation burden. However, the use of this imaging modality is limited due to photon scattering and lack of spatial information. Attempts at reconstructing bioluminescence tomography (BLT) using mathematical models of light propagation show limited progress.Approach.This paper employed a different approach by using a deep convolutional neural network (CNN) to predict the tumor's center of mass (CoM). Transfer-learning with a sizeable artificial database is employed to facilitate the training process for, the much smaller, target database including Monte Carlo (MC) simulations of real orthotopic glioblastoma models. Predicted CoM was then used to estimate a BLI-based planning target volume (bPTV), by using the CoM as the center of a sphere, encompassing the tumor. The volume of the encompassing target sphere was estimated based on the total number of photons reaching the skin surface.Main results.Results show sub-millimeter accuracy for CoM prediction with a median error of 0.59 mm. The proposed method also provides promising performance for BLI-based tumor targeting with on average 94% of the tumor inside the bPTV while keeping the average healthy tissue coverage below 10%.Significance.This work introduced a framework for developing and using a CNN for targeted radiation studies for GBM based on BLI. The framework will enable biologists to use BLI as their main image-guidance tool to target GBM tumors in rat models, avoiding delivery of high x-ray imaging dose to the animals.


Assuntos
Aprendizado Profundo , Glioblastoma , Animais , Glioblastoma/diagnóstico por imagem , Glioblastoma/patologia , Glioblastoma/radioterapia , Método de Monte Carlo , Redes Neurais de Computação , Ratos , Tomografia
8.
Int J Hyperthermia ; 39(1): 796-805, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35676615

RESUMO

PURPOSE: Improvements of heat-delivery systems have led to hyperthermia (HT) being increasingly recognized as an adjunct treatment modality also for brain tumors. But how HT affects the immune phenotype of glioblastoma cells is only scarcely known. MATERIALS AND METHODS: We therefore investigated the effect of in vitro HT, radiotherapy (RT), and the combination of both (RHT) on cell death modalities, immune checkpoint molecule (ICM) expression and release of the danger signal HSP70 of two human glioblastoma cell lines (U87 and U251) by using multicolor flow cytometry and ELISA. Hyperthermia was performed once or twice for 60-minute sessions reaching temperatures of 39 °C, 41 °C, and 44 °C, respectively. RT was administered with 5 x 2 Gy. RESULTS: A hyperthermia chamber for cell culture t-flasks regulating the temperature via a contact sensor was developed. While the glioblastoma cells were rather radioresistant, particularly in U251 cells, the combination of RT with HT significantly increased the percentage of apoptotic and necrotic cells for all temperatures examined and for both, single and double HT application. In line with that, an increased release of HSP 70 was seen only in U251 cells, mainly following treatment with HT at temperatures of 44 °C alone or in combination with RT. In contrast, immune suppressive (PD-L1, PD-L2, HVEM) and immune stimulatory (ICOS-L, CD137-L and Ox40-L) ICMs were significantly increased mostly on U87 cells, and particularly after RHT with 41 °C. CONCLUSIONS: Individual assessment of the glioblastoma immune cell phenotype with regard to the planned treatment is mandatory to optimize multimodal radio-immunotherapy protocols including HT.


Assuntos
Glioblastoma , Hipertermia Induzida , Morte Celular , Terapia Combinada , Glioblastoma/radioterapia , Proteínas de Choque Térmico HSP70/metabolismo , Humanos , Hipertermia , Necrose , Fenótipo
9.
Sci Rep ; 12(1): 9602, 2022 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-35688846

RESUMO

In this work, an intercomparison of sensitization effects produced by gold (GNP) and dextran-coated iron oxide (SPION-DX) nanoparticles in M059J and U87 human glioblastoma cells was performed using 6 MV-photons. Three variables were mapped: the nanoparticle material, treatment concentration, and cell radiosensitivity. For U87, GNP treatments resulted in high sensitization enhancement ratios (SER[Formula: see text] up to 2.04). More modest effects were induced by SPION-DX, but still significant reductions in survival were achieved (maximum SER[Formula: see text] ). For the radiosensitive M059J, sensitization by both NPs was poor. SER[Formula: see text] increased with the degree of elemental uptake in the cells, but not necessarily with treatment concentration. For GNP, where exposure concentration and elemental uptake were found to be proportional, SER[Formula: see text] increased linearly with concentration in both cell lines. For SPION-DX, saturation of sensitization enhancement and metal uptake occurred at high exposures. Fold change in the [Formula: see text] ratios extracted from survival curves are reduced by the presence of SPION-DX but strongly increased by GNPs , suggesting that sensitization by GNPs occurs mainly via promotion of lethal damage, while for SPION-DX repairable damage dominates. The NPs were more effective in eliminating the radioresistant glioblastoma cells, an interesting finding, as resistant cells are key targets to improve treatment outcome.


Assuntos
Glioblastoma , Nanopartículas Metálicas , Radiossensibilizantes , Glioblastoma/radioterapia , Ouro/farmacologia , Humanos , Nanopartículas Magnéticas de Óxido de Ferro , Fótons , Radiossensibilizantes/farmacologia
10.
Sci Rep ; 12(1): 7505, 2022 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-35525840

RESUMO

A personalized approach to chemoradiation is important in reducing its potential side effects and identifying a group of patients prone to toxicity. MicroRNAs have been shown to have a predictive potential for radiotoxicity. The goal of the study was to test if levels of miRNA in peripheral blood mononuclear cells of glioblastoma patients are associated with toxicity and to identify the peak time point for toxicity. MicroRNA-10b/21/34a levels were measured in 43 patients with and without toxicity, at baseline, at the 15th, and at the 30th fraction by Real-Time quantitative Polymerase Chain Reaction. MicroRNA-10b/21 levels increased with toxicity grade (p = 0.014; p = 0.013); miR-21/34a levels were significantly different between patients with and without toxicity at the 15th fraction (p = 0.030; p = 0.045), while miR-34a levels significantly changed during treatment (p < 0.001). All three miRNAs showed a significantly high positive correlation with one another. MiR-34a might be considered as a predictive factor for toxicity due to its changes during treatment, and differences between the groups with and without toxicity; miR-10b might be used to predict toxicity; miR-10b/21 might be used for predicting the grade of toxicity in GB patients.


Assuntos
Glioblastoma , MicroRNAs , Temozolomida , Glioblastoma/tratamento farmacológico , Glioblastoma/radioterapia , Humanos , Leucócitos Mononucleares , MicroRNAs/genética , Reação em Cadeia da Polimerase em Tempo Real , Temozolomida/efeitos adversos
11.
Clin Cancer Res ; 28(14): 3011-3020, 2022 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-35552391

RESUMO

PURPOSE: Dual timepoint fluoro-ethyl-tyrosine (FET)-PET acquisition (10 and 60 minutes after FET injection) improves the definition of glioblastoma (GBM) location and shape. Here we evaluated the safety and efficacy of simultaneous integrated boost (SIB) planned using dual FET-PET for postoperative GBM treatment. PATIENTS AND METHODS: In this prospective pilot study (March 2017-December 2020), 17 patients qualified for FET-PET-based SIB intensity-modulated radiotherapy after resection. The prescribed dose was 78 and 60 Gy (2.6 and 2.0 Gy per fraction, respectively) for the FET-PET- and magnetic resonance (MR)-based target volumes. Eleven patients had FET-PET within 9 months to precisely define biological responses. Progression-free survival (PFS), overall survival (OS), toxicities, and radiation necrosis were evaluated. Six patients (35%) had tumors with MGMT promoter methylation. RESULTS: The 1- and 2-year OS and PFS rates were 73% and 43% and 53% and 13%, respectively. The median OS and PFS were 24 [95% confidence interval (CI), 9-26] and 12 (95% CI, 6-18) months, respectively. Two patients developed uncontrolled seizures during radiotherapy and could not receive treatment per protocol. In patients treated per protocol, 7 of 15 presented with new or increased neurologic deficits in the first month after irradiation. Radiation necrosis was diagnosed by MRI 3 months after SIB in 5 patients and later in another 2 patients. In 2 patients, the tumor was larger in FET-PET images after 6 months. CONCLUSIONS: Survival outcomes using our novel dose-escalation concept (total 78 Gy) were promising, even within the MGMT unmethylated subgroup. Excessive neurotoxicity was not observed, but radionecrosis was common and must be considered in future trials.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/radioterapia , Glioblastoma/diagnóstico por imagem , Glioblastoma/radioterapia , Humanos , Necrose , Projetos Piloto , Tomografia por Emissão de Pósitrons/métodos , Estudos Prospectivos , Tirosina/efeitos adversos
12.
Strahlenther Onkol ; 198(6): 507-526, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35503461

RESUMO

BACKGROUND: Glioblastoma is the most common malignant brain tumor in human adults. Despite several improvements in resective as well as adjuvant therapy over the last decades, its overall prognosis remains poor. As a means of improving patient outcome, the possibility of enhancing radiation response by using radiosensitizing agents has been tested in an array of studies. METHODS: A comprehensive review of clinical trials involving radiation therapy in combination with radiosensitizing agents on patients diagnosed with glioblastoma was performed in the National Center for Biotechnology Information's PubMed database. RESULTS: A total of 96 papers addressing this matter were published between 1976 and 2021, of which 63 matched the subject of this paper. All papers were reviewed, and their findings discussed in the context of their underlining mechanisms of radiosensitization. CONCLUSION: In the history of glioblastoma treatment, several approaches of optimizing radiation-effectiveness using radiosensitizers have been made. Even though several different strategies and agents have been explored, clear evidence of improved patient outcome is still missing. Tissue-selectiveness and penetration of the blood-brain barrier seem to be major roadblocks; nevertheless, modern strategies try to circumvent these obstacles, using novel sensitizers based on preclinical data or alternative ways of delivery.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Radiossensibilizantes , Adulto , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/radioterapia , Terapia Combinada , Glioblastoma/radioterapia , Humanos , Prognóstico , Radiossensibilizantes/uso terapêutico
13.
CNS Oncol ; 11(2): CNS86, 2022 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-35603818

RESUMO

Glioblastoma (GBM) accounts for over 50% of gliomas and carries the worst prognosis of all solid tumors. Owing to the limited local control afforded by surgery alone, efficacious adjuvant treatments such as radiotherapy (RT) and chemotherapy are fundamental in achieving durable disease control. The best clinical outcomes are achieved with tri-modality treatment consisting of surgery, RT and systemic therapy. While RT-chemotherapy combination regimens are well established in oncology, this approach was largely unsuccessful in GBM until the introduction of temozolomide. The success of this combination has stimulated the search for other candidate drugs for concomitant use with RT in GBM. This review seeks to collate the current evidence for these agents and synthesize possible future directions for the field.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Glioma , Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/radioterapia , Terapia Combinada , Combinação de Medicamentos , Glioblastoma/tratamento farmacológico , Glioblastoma/radioterapia , Glioma/tratamento farmacológico , Humanos , Temozolomida/uso terapêutico
14.
J Vis Exp ; (181)2022 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-35404343

RESUMO

A rat glioblastoma model to mimic chemo-radiation treatment of human glioblastoma in the clinic was previously established. Similar to the clinical treatment, computed tomography (CT) and magnetic resonance imaging (MRI) were combined during the treatment-planning process. Positron emission tomography (PET) imaging was subsequently added to implement sub-volume boosting using a micro-irradiation system. However, combining three imaging modalities (CT, MRI, and PET) using a micro-irradiation system proved to be labor-intensive because multimodal imaging, treatment planning, and dose delivery have to be completed sequentially in the preclinical setting. This also results in a workflow that is more prone to human error. Therefore, a user-friendly algorithm to further optimize preclinical multimodal imaging-based radiation treatment planning was implemented. This software tool was used to evaluate the accuracy and efficiency of dose painting radiation therapy with micro-irradiation by using an in silico study design. The new methodology for dose painting radiation therapy is superior to the previously described method in terms of accuracy, time efficiency, and intra- and inter-user variability. It is also an important step towards the implementation of inverse treatment planning on micro-irradiators, where forward planning is still commonly used, in contrast to clinical systems.


Assuntos
Glioblastoma , Animais , Glioblastoma/diagnóstico por imagem , Glioblastoma/patologia , Glioblastoma/radioterapia , Imageamento por Ressonância Magnética/métodos , Imagem Multimodal/métodos , Tomografia por Emissão de Pósitrons/métodos , Planejamento da Radioterapia Assistida por Computador/métodos , Ratos , Tomografia Computadorizada por Raios X/métodos
15.
Clin Nucl Med ; 47(6): e428-e436, 2022 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-35439178

RESUMO

PURPOSE: To evaluate the diagnostic potential of decision-tree model of diffusion kurtosis imaging (DKI) and 11C-methionine (11C-MET) PET, for the differentiation of radiotherapy (RT) injury from glioblastoma recurrence. METHODS: Eighty-six glioblastoma cases with suspected lesions after RT were retrospectively enrolled. Based on histopathology or follow-up, 48 patients were diagnosed with local glioblastoma recurrence, and 38 patients had RT injury between April 2014 and December 2019. All the patients underwent PET/MRI examinations. Multiple parameters were derived based on the ratio of tumor to normal control (TNR), including SUVmax and SUVmean, mean value of kurtosis and diffusivity (MK, MD) from DKI, and histogram parameters. The diagnostic models were established by decision trees. Receiver operating characteristic analysis was used for evaluating the diagnostic accuracy of each independent parameter and all the diagnostic models. RESULTS: The intercluster correlations of DKI, PET, and texture parameters were relatively weak, whereas the intracluster correlations were strong. Compared with models of DKI alone (sensitivity =1.00, specificity = 0.70, area under the curve [AUC] = 0.85) and PET alone (sensitivity = 0.83, specificity = 0.90, AUC = 0.89), the combined model demonstrated the best diagnostic accuracy (sensitivity = 1.00, specificity = 0.90, AUC = 0.95). CONCLUSIONS: Diffusion kurtosis imaging, 11C-MET PET, and histogram parameters provide complementary information about tissue. The decision-tree model combined with these parameters has the potential to further increase diagnostic accuracy for the discrimination between RT injury and glioblastoma recurrence over the standard Response Assessment in Neuro-Oncology criteria. 11C-MET PET/MRI may thus contribute to the management of glioblastoma patients with suspected lesions after RT.


Assuntos
Glioblastoma , Lesões por Radiação , Radioisótopos de Carbono , Imagem de Difusão por Ressonância Magnética/métodos , Glioblastoma/diagnóstico por imagem , Glioblastoma/radioterapia , Humanos , Imageamento por Ressonância Magnética , Metionina , Tomografia por Emissão de Pósitrons , Estudos Retrospectivos , Sensibilidade e Especificidade
16.
Free Radic Biol Med ; 185: 25-35, 2022 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-35476930

RESUMO

Radiotherapy is an important treatment modality for glioblastoma (GBM), yet the initial effectiveness of radiotherapy is eventually lost due to the development of adaptive radioresistance during fractionated radiation therapy. Defining the molecular mechanism(s) responsible for the adaptive radioresistance in GBM is necessary for the development of effective treatment options. The cellular labile iron pool (LIP) is very important for determining the cellular response to radiation, as it contributes to radiation-induced production of reactive oxygen species (ROS) such as lipid radicals through Fenton reactions. Recently, cytochrome c oxidase (CcO), a mitochondrial heme-containing enzyme also involved in regulating ROS production, was found to be involved in GBM chemoresistance. However, the role of LIP and CcO in GBM radioresistance is not known. Herein, we tested the hypothesis that CcO-mediated alterations in the level of labile iron contribute to adaptive radioresistance. Using an in vitro model of GBM adaptive radioresistance, we found an increase in CcO activity in radioresistant cells that associated with a decrease in the cellular LIP, decrease in lipid peroxidation, and a switch in the CcO subunit 4 (COX4) isoform expressed, from COX4-2 to COX4-1. Furthermore, knockdown of COX4-1 in radioresistant GBM cells decreased CcO activity and restored radiosensitivity, whereas overexpression of COX4-1 in radiosensitive cells increased CcO activity and rendered the cells radioresistant. Overexpression of COX4-1 in radiosensitive cells also significantly reduced the cellular LIP and lipid peroxidation. Pharmacological manipulation of the cellular labile iron level using iron chelators altered CcO activity and the radiation response. Overall, these results demonstrate a mechanistic link between CcO activity and LIP in GBM radioresistance and identify the CcO subunit isoform switch from COX4-2 to COX4-1 as a novel biochemical node for adaptive radioresistance of GBM. Manipulation of CcO and the LIP may restore the sensitivity to radiation in radioresistant GBM cells and thereby provide a strategy to improve therapeutic outcome in patients with GBM.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/radioterapia , Linhagem Celular Tumoral , Complexo IV da Cadeia de Transporte de Elétrons/genética , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Glioblastoma/genética , Glioblastoma/radioterapia , Humanos , Ferro , Tolerância a Radiação/genética , Espécies Reativas de Oxigênio
17.
Molecules ; 27(8)2022 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-35458626

RESUMO

Radiotherapy is a vital approach for brain tumor treatment. The standard treatment for glioblastoma (GB) is maximal surgical resection combined with radiotherapy and chemotherapy. However, the non-sensitivity of tumor cells in the hypoxic area of solid tumors to radiotherapy may cause radioresistance. Therefore, radiotherapy sensitizers that increase the oxygen concentration within the tumor are promising for increasing the effectiveness of radiation. Inspired by hemoglobin allosteric oxygen release regulators, a series of novel phenoxyacetic acid analogues were designed and synthesized. A numerical method was applied to determine the activity and safety of newly synthesized compounds. In vitro studies on the evaluation of red blood cells revealed that compounds 19c (∆P50 = 45.50 mmHg) and 19t (∆P50 = 44.38 mmHg) improve the oxygen-releasing property effectively compared to positive control efaproxiral (∆P50 = 36.40 mmHg). Preliminary safety evaluation revealed that 19c exhibited no cytotoxicity towards HEK293 and U87MG cells, while 19t was cytotoxic toward both cells with no selectivity. An in vivo activity assay confirmed that 19c exhibited a radiosensitization effect on orthotopically transplanted GB in mouse brains. Moreover, a pharmacokinetic study in rats showed that 19c was orally available.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Radiossensibilizantes , Animais , Neoplasias Encefálicas/tratamento farmacológico , Linhagem Celular Tumoral , Glioblastoma/tratamento farmacológico , Glioblastoma/radioterapia , Células HEK293 , Humanos , Camundongos , Oxigênio , Radiossensibilizantes/farmacologia , Radiossensibilizantes/uso terapêutico , Ratos
19.
Jpn J Clin Oncol ; 52(8): 835-841, 2022 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-35453150

RESUMO

BACKGROUND: To investigate the current variability in radiotherapy practice for elderly glioblastoma patients. METHODS: A questionnaire comprising general information on elderly glioblastoma, treatment selection, radiotherapy and 16 clinical case-scenario-based questions (based on age, performance, extent of resection and MGMT promoter methylation) was sent to brain tumor radiation oncologists. RESULTS: Twenty-one responses were recorded. Most (71.4%) stated that 70 years is an adequate cut-off for 'elderly' individuals. The most preferred hypofractionated short-course radiotherapy schedule was 40-45 Gy over 3 weeks (81.3%). The median margin for high-dose target volume was 5 mm (range, 0-20 mm) from the T1-enhancement for short-course radiotherapy. The case-scenario-based questions revealed a near-perfect consensus on 6-week standard radiotherapy plus concurrent/adjuvant temozolomide as the most appropriate adjuvant treatment in good performing patients aged 65-70 years, regardless of surgery and MGMT promoter methylation. Notably, in 75-year-old patients with good performance, the most preferred treatment was 6-week radiotherapy (81.0-90.5%) plus concurrent/adjuvant temozolomide (71.4-95.2%) rather than short-course radiotherapy or radiotherapy alone. Although the use of 3-week short-course radiotherapy increased with age and decreased performance status (all P < 0.05), 6-week radiotherapy was adopted in a significant proportion of responders (14.3-23.8%) even for wheelchair-bound, 75-year-old patients. Temozolomide use was affected by age, performance and MGMT promoter (all P < 0.05). CONCLUSIONS: A high level of consensus was observed in treating elderly glioblastoma patients with good performance status. However, the variability increased, especially for older patients and those with poor performance. This study serves as a basis for designing future clinical trials in elderly glioblastoma.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Idoso , Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/radioterapia , Dacarbazina/efeitos adversos , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Glioblastoma/radioterapia , Humanos , República da Coreia , Inquéritos e Questionários , Temozolomida/uso terapêutico
20.
Cells ; 11(7)2022 04 04.
Artigo em Inglês | MEDLINE | ID: mdl-35406779

RESUMO

Glioblastoma is a highly aggressive, invasive and treatment-resistant tumour. The DNA damage response (DDR) provides tumour cells with enhanced ability to activate cell cycle arrest and repair treatment-induced DNA damage. We studied the expression of DDR, its relationship with standard treatment response and patient survival, and its activation after treatment. The transcriptomic profile of DDR pathways was characterised within a cohort of isocitrate dehydrogenase (IDH) wild-type glioblastoma from The Cancer Genome Atlas (TCGA) and 12 patient-derived glioblastoma cell lines. The relationship between DDR expression and patient survival and cell line response to temozolomide (TMZ) or radiation therapy (RT) was assessed. Finally, the expression of 84 DDR genes was examined in glioblastoma cells treated with TMZ and/or RT. Although distinct DDR cluster groups were apparent in the TCGA cohort and cell lines, no significant differences in OS and treatment response were observed. At the gene level, the high expression of ATP23, RAD51C and RPA3 independently associated with poor prognosis in glioblastoma patients. Finally, we observed a substantial upregulation of DDR genes after treatment with TMZ and/or RT, particularly in RT-treated glioblastoma cells, peaking within 24 h after treatment. Our results confirm the potential influence of DDR genes in patient outcome. The observation of DDR genes in response to TMZ and RT gives insight into the global response of DDR pathways after adjuvant treatment in glioblastoma, which may have utility in determining DDR targets for inhibition.


Assuntos
Glioblastoma , Antineoplásicos Alquilantes/farmacologia , Antineoplásicos Alquilantes/uso terapêutico , Dano ao DNA/genética , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Glioblastoma/radioterapia , Humanos , Temozolomida/farmacologia , Temozolomida/uso terapêutico , Transcriptoma/genética
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