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1.
Life Sci ; 258: 118152, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32735881

RESUMO

AIMS: Cancer stem cells (CSCs) are the source of tumors and play a key role in the resistance of cancer to therapies. To improve the current therapies against CSCs, in this work we developed a novel system of electrospun polycaprolactone (PCL) nanofibers containing hydroxylated multi-walled carbon nanotubes (MWCNTs-OH) and all-trans retinoic acid (ATRA). MATERIALS AND METHODS: The nanofiber membranes were forged by electrospinning, and the physical and chemical properties of the nanofiber membranes were evaluated by scanning electron microscopy, XRD and Raman etc. The photothermal properties of nanofiber membranes and their effects on CSCs differentiation and cytotoxicity were investigated. Finally, the anti-tumor effect of nanofiber membranes in vivo was evaluated. KEY FINDINGS: The nanofibers formed under optimal conditions were smooth without beads. The nanofibrous membranes with MWCNTs-OH could increase temperature of the medium under near-infrared (NIR) illumination to suppress the viability of glioma stem cells (GSCs). Meanwhile, the added ATRA could further induce the differentiation of GSCs to destroy their stemness and reduce their resistance to heat treatment. Compared with no NIR irradiation, after 2min NIR irradiation, the membranes reduced the in-vitro viability of GSCs by 13.41%, 14.83%, and 26.71% after 1, 2, and 3 days, respectively. After 3 min daily illumination for 3 days, the viability of GSCs was only 22.75%, and similar results were observed in vivo. SIGNIFICANCE: These results showed efficiently cytotoxicity to CSCs by combining heat therapy and differentiation therapy. The nanofiber membranes if inserted at the site after surgical tumor removal, may hinder tumor recurrence.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/terapia , Glioma/terapia , Nanofibras/uso terapêutico , Células-Tronco Neoplásicas/efeitos dos fármacos , Tretinoína/uso terapêutico , Animais , Antineoplásicos/administração & dosagem , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sistemas de Liberação de Medicamentos/métodos , Glioma/patologia , Humanos , Hipertermia Induzida/métodos , Masculino , Camundongos Endogâmicos BALB C , Nanofibras/química , Nanotubos de Carbono/química , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/prevenção & controle , Células-Tronco Neoplásicas/patologia , Poliésteres/química , Poliésteres/uso terapêutico , Tretinoína/administração & dosagem
2.
PLoS One ; 15(7): e0236374, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32735564

RESUMO

We recently reported the development of a fully-human, CD3-binding bispecific antibody for immunotherapy of malignant glioma. To translate this therapeutic (hEGFRvIII-CD3- bi-scFv) to clinical trials and to help further the translation of other similar CD3-binding therapeutics, some of which are associated with neurologic toxicities, we performed a good laboratory practice (GLP) toxicity study to assess for potential behavioral, chemical, hematologic, and pathologic toxicities including evaluation for experimental autoimmune encephalomyelitis (EAE). To perform this study, male and female C57/BL6 mice heterozygous for the human CD3 transgene (20/sex) were allocated to one of four designated groups. All animals were administered one dose level of hEGFRvIII-CD3 bi-scFv or vehicle control. Test groups were monitored for feed consumption, changes in body weight, and behavioral disturbances including signs of EAE. Urinalysis, hematologic, and clinical chemistry analysis were also performed. Vehicle and test chemical-treated groups were humanely euthanized 48 hours or 14 days following dose administration. Complete gross necropsy of all tissues was performed, and selected tissues plus all observed gross lesions were collected and evaluated for microscopic changes. This included hematoxylin-eosin histopathological evaluation and Fe-ECR staining for myelin sheath enumeration. There were no abnormal clinical observations or signs of EAE noted during the study. There were no statistical changes in food consumption, body weight gain, or final body weight among groups exposed to hEGFRvIII-CD3 bi-scFv compared to the control groups for the 2- and 14-day timepoints. There were statistical differences in some clinical chemistry, hematologic and urinalysis endpoints, primarily in the females at the 14-day timepoint (hematocrit, calcium, phosphorous, and total protein). No pathological findings related to hEGFRvIII-CD3 bi-scFv administration were observed. A number of gross and microscopic observations were noted but all were considered to be incidental background findings. The results of this study allow for further translation of this and other important CD3 modulating bispecific antibodies.


Assuntos
Anticorpos Biespecíficos/farmacologia , Complexo CD3/imunologia , Receptores ErbB/imunologia , Glioma/imunologia , Animais , Anticorpos Biespecíficos/imunologia , Peso Corporal/efeitos dos fármacos , Peso Corporal/imunologia , Complexo CD3/farmacologia , Modelos Animais de Doenças , Receptores ErbB/farmacologia , Feminino , Glioma/patologia , Glioma/terapia , Humanos , Imunoterapia/efeitos adversos , Masculino , Camundongos , Anticorpos de Cadeia Única/imunologia , Anticorpos de Cadeia Única/farmacologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia
3.
Lancet Oncol ; 21(6): e317-e329, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32502458

RESUMO

Response criteria for paediatric high-grade glioma vary historically and across different cooperative groups. The Response Assessment in Neuro-Oncology working group developed response criteria for adult high-grade glioma, but these were not created to meet the unique challenges in children with the disease. The Response Assessment in Pediatric Neuro-Oncology (RAPNO) working group, consisting of an international panel of paediatric and adult neuro-oncologists, clinicians, radiologists, radiation oncologists, and neurosurgeons, was established to address issues and unique challenges in assessing response in children with CNS tumours. We established a subcommittee to develop response assessment criteria for paediatric high-grade glioma. Current practice and literature were reviewed to identify major challenges in assessing the response of paediatric high-grade gliomas to various treatments. For areas in which scientific investigation was scarce, consensus was reached through an iterative process. RAPNO response assessment recommendations include the use of MRI of the brain and the spine, assessment of clinical status, and the use of corticosteroids or antiangiogenics. Imaging standards for brain and spine are defined. Compared with the recommendations for the management of adult high-grade glioma, for paediatrics there is inclusion of diffusion-weighted imaging and a higher reliance on T2-weighted fluid-attenuated inversion recovery. Consensus recommendations and response definitions have been established and, similar to other RAPNO recommendations, prospective validation in clinical trials is warranted.


Assuntos
Neoplasias do Sistema Nervoso Central/diagnóstico por imagem , Neoplasias do Sistema Nervoso Central/terapia , Imagem de Difusão por Ressonância Magnética/normas , Determinação de Ponto Final/normas , Glioma/diagnóstico por imagem , Glioma/terapia , Neuroimagem/normas , Adolescente , Idade de Início , Neoplasias do Sistema Nervoso Central/epidemiologia , Neoplasias do Sistema Nervoso Central/patologia , Criança , Consenso , Feminino , Glioma/epidemiologia , Glioma/patologia , Humanos , Masculino , Gradação de Tumores , Valor Preditivo dos Testes , Fatores de Tempo , Resultado do Tratamento , Carga Tumoral
4.
Brain Tumor Pathol ; 37(3): 81-88, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32529280

RESUMO

The objective of this study is to clarify clinical significance of the H3F3A K27M mutation (H3K27M) and analyze the correlation between H3K27M, H3K27me3 status, and EZH2 expression and prognosis in spinal cord gliomas. Patients with spinal cord diffuse glioma regardless of World Health Organization (WHO) grade underwent genetic analysis for H3F3A, HIST1H3B, TERT promoter, IDH1/2, and BRAF. H3K27me3 status and EZH2 expression were analyzed through immunohistochemistry. Thereafter, the association between H3K27M, H3K27me3 status, and EZH2 expression and prognosis was retrospectively analyzed using the log-rank test. A total of 26 cases, 5 with WHO grade 4, 9 with grade 3, and 12 with grade 2 glioma, were analyzed. Although WHO grade 2 cases tended to present favorable overall survival, the difference was not statistically significant. H3K27M, which was detected in four grade 4 cases (80%) and three grade 3 cases (33%), was not associated with prognosis among grade 3 and 4 cases. Among WHO grade 2-4 cases, the combination of retained H3K27me3 and negative EZH2 expression was correlated with favorable overall survival (p = 0.03). The combination of H3K27me3 status and EZH2 expression was considered as a potential prognostic marker in WHO grade 2-4 diffuse spinal cord gliomas.


Assuntos
Proteína Potenciadora do Homólogo 2 de Zeste/genética , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Expressão Gênica , Glioma/genética , Histonas/metabolismo , Mutação de Sentido Incorreto , Neoplasias da Medula Espinal/genética , Glioma/terapia , Histonas/genética , Humanos , Metilação , Prognóstico , Estudos Retrospectivos , Neoplasias da Medula Espinal/terapia
5.
Lancet Oncol ; 21(6): e305-e316, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32502457

RESUMO

Paediatric low-grade gliomas (also known as pLGG) are the most common type of CNS tumours in children. In general, paediatric low-grade gliomas show clinical and biological features that are distinct from adult low-grade gliomas, and the developing paediatric brain is more susceptible to toxic late effects of the tumour and its treatment. Therefore, response assessment in children requires additional considerations compared with the adult Response Assessment in Neuro-Oncology criteria. There are no standardised response criteria in paediatric clinical trials, which makes it more difficult to compare responses across studies. The Response Assessment in Pediatric Neuro-Oncology working group, consisting of an international panel of paediatric and adult neuro-oncologists, clinicians, radiologists, radiation oncologists, and neurosurgeons, was established to address issues and unique challenges in assessing response in children with CNS tumours. We established a subcommittee to develop consensus recommendations for response assessment in paediatric low-grade gliomas. Final recommendations were based on literature review, current practice, and expert opinion of working group members. Consensus recommendations include imaging response assessments, with additional guidelines for visual functional outcomes in patients with optic pathway tumours. As with previous consensus recommendations, these recommendations will need to be validated in prospective clinical trials.


Assuntos
Neoplasias do Sistema Nervoso Central/diagnóstico por imagem , Neoplasias do Sistema Nervoso Central/terapia , Determinação de Ponto Final/normas , Glioma/diagnóstico por imagem , Glioma/terapia , Neuroimagem/normas , Idade de Início , Neoplasias do Sistema Nervoso Central/epidemiologia , Neoplasias do Sistema Nervoso Central/patologia , Criança , Consenso , Feminino , Glioma/epidemiologia , Glioma/patologia , Humanos , Imagem por Ressonância Magnética/normas , Masculino , Gradação de Tumores , Imagem de Perfusão/normas , Tomografia por Emissão de Pósitrons/normas , Valor Preditivo dos Testes , Fatores de Tempo , Resultado do Tratamento , Carga Tumoral
6.
Nat Commun ; 11(1): 3015, 2020 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-32541784

RESUMO

The interplay between glioma stem cells (GSCs) and the tumor microenvironment plays crucial roles in promoting malignant growth of glioblastoma (GBM), the most lethal brain tumor. However, the molecular mechanisms underlying this crosstalk are incompletely understood. Here, we show that GSCs secrete the Wnt-induced signaling protein 1 (WISP1) to facilitate a pro-tumor microenvironment by promoting the survival of both GSCs and tumor-associated macrophages (TAMs). WISP1 is preferentially expressed and secreted by GSCs. Silencing WISP1 markedly disrupts GSC maintenance, reduces tumor-supportive TAMs (M2), and potently inhibits GBM growth. WISP1 signals through Integrin α6ß1-Akt to maintain GSCs by an autocrine mechanism and M2 TAMs through a paracrine manner. Importantly, inhibition of Wnt/ß-catenin-WISP1 signaling by carnosic acid (CA) suppresses GBM tumor growth. Collectively, these data demonstrate that WISP1 plays critical roles in maintaining GSCs and tumor-supportive TAMs in GBM, indicating that targeting Wnt/ß-catenin-WISP1 signaling may effectively improve GBM treatment and the patient survival.


Assuntos
Neoplasias Encefálicas/genética , Proteínas de Sinalização Intercelular CCN/genética , Glioma/genética , Macrófagos/metabolismo , Células-Tronco Neoplásicas/metabolismo , Proteínas Proto-Oncogênicas/genética , Animais , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/terapia , Proteínas de Sinalização Intercelular CCN/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Doxiciclina/farmacologia , Glioma/metabolismo , Glioma/terapia , Humanos , Estimativa de Kaplan-Meier , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Interferência de RNA , Transdução de Sinais/genética , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética , Células U937 , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
7.
Sheng Wu Yi Xue Gong Cheng Xue Za Zhi ; 37(3): 469-479, 2020 Jun 25.
Artigo em Chinês | MEDLINE | ID: mdl-32597089

RESUMO

Tripartite motif 5 (TRIM5) plays a significant function in autophagy and involves in immune and tumor processes. While the function of TRIM5 remains poorly understood in glioma. We purpose to evaluate the possible prognostic role of TRIM5 in glioma via bioinformatics analyses. The database clinical samples of glioma in this study included low grade glioma (LGG) and glioblastoma multiforme (GBM). TRIM5 expression in glioma tissues were explored in Oncomine, GEPIA and The Cancer Genome Atlas (TCGA) databases. Survival analysis and the multivariate Cox regression analysis of TRIM5 based on TCGA were used to evaluate the prognostic role of TRIM5. The protein networks of TRIM5 was detected by STRING database. KEGG enrichment analyses were performed to predict the potential molecular pathways of TRIM5 in glioma. In addition, immune infiltration analysis was conducted by CIBERSORT and TIMER databases. We found that TRIM5 was strongly increased in glioma samples compared with normal samples in Oncomine, GEPIA and TCGA databases. Higher TRIM5 was significantly contributed to worse overall survival (OS) in LGG+GBM patients and LGG patients, while was no correlated with OS of GBM patients. Interaction networks analysis identified that IRF3, IRF7, OAS1, OAS2, OAS3, OASL, GBP1, PML, BTBD1 and BTBD2 proteins were contacted with TRIM5. Moreover, KEGG revealed that apoptosis and cancer- and immune-related pathways were enriched with elevated TRIM5. Specifically, TRIM5 could influence the immune infiltration levels, such as activated NK cells, monocytes, activated mast cells and macrophages in glioma. In conclusion, our data indicated that TRIM5 was upregulated in glioma tissues and associated with poor prognosis and immune infiltration. TRIM5 may be acted as a biomarker in prognosis and immunotherapy guidance of glioma.


Assuntos
Neoplasias Encefálicas , Glioma , Proteínas com Motivo Tripartido , Ubiquitina-Proteína Ligases , Biomarcadores Tumorais , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/terapia , Proteínas de Transporte , Biologia Computacional , Glioma/metabolismo , Glioma/terapia , Humanos , Imunoterapia , Prognóstico , Análise de Sobrevida , Proteínas com Motivo Tripartido/metabolismo , Ubiquitina-Proteína Ligases/metabolismo
8.
Anticancer Res ; 40(6): 3453-3457, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32487644

RESUMO

BACKGROUND/AIM: Gliomas present a uniquely challenging clinical situation in the context of pregnancy, with no standard recommendations. This case series aimed to describe the treatment regimen and outcomes of five pregnant patients with gliomas. PATIENTS AND METHODS: This is a retrospective study. A patient database from electronic medical records was evaluated to identify pregnant patients with gliomas treated at our institution between 2008-2018. RESULTS: Five study patients who were pregnant with gliomas were identified. Of these, 4 were diagnosed during pregnancy, while 1 was diagnosed prior to her pregnancy. One patient had grade 2 astrocytoma, 1 had grade 3 anaplastic astrocytoma, and 3 had grade 4 glioblastomas (GBM). All patients received surgery, and one patient received radiation therapy without concurrent chemotherapy during her pregnancy. All delivered healthy babies. Three of the 5 patients remain alive, and 2 of the 5 were progression-free at the last follow-up. CONCLUSION: Treatment plans must be specifically tailored to the individual patient based on the glioma grade, the mother's desire to continue the pregnancy, and the risks of delaying treatment until after pregnancy. Additional studies need to be performed to definitively establish uniform guidelines for the treatment of pregnant patients with glioma.


Assuntos
Neoplasias Encefálicas/diagnóstico , Glioma/diagnóstico , Complicações Neoplásicas na Gravidez/diagnóstico , Adulto , Biomarcadores , Neoplasias Encefálicas/etiologia , Neoplasias Encefálicas/terapia , Terapia Combinada , Feminino , Glioma/etiologia , Glioma/terapia , Humanos , Imagem por Ressonância Magnética , Mutação , Gradação de Tumores , Gravidez
9.
World Neurosurg ; 139: e700-e707, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32389863

RESUMO

OBJECTIVE: To assess the early mortality in pediatric glioma and identify predictors of early mortality, which may provide insight into the therapeutic strategies for children with a high risk of early mortality. METHODS: We used SEER∗Stat 8.3.5 software to extract data of pediatric glioma from the Surveillance, Epidemiology, and End Results database. Logistical regression to identify the independent factors in predicting early mortality. RESULTS: A total of 3035 male and 2741 female patients were enrolled in the present study. The death rates within 1 month and 3 months after diagnosis were 1.32% and 2.44%, respectively. Early mortality decreased significantly during the past 40 years. Our results showed that glioblastoma, anaplastic glioma, and oligodendroglioma were risk factors of early mortality for children diagnosed with glioma, whereas advanced age, gross total resection, radiation, and chemotherapy were associated with decreased early mortality. CONCLUSIONS: We found a decrease in early mortality during the past 40 years. The death rates within 1 month and 3 months after diagnosis were 1.32% and 2.44%, respectively. Age at diagnosis, histologic subtype, the extent of resection, chemotherapy, and radiation were associated with early mortality in pediatric glioma.


Assuntos
Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/terapia , Glioma/mortalidade , Glioma/terapia , Adolescente , Fatores Etários , Quimiorradioterapia , Criança , Pré-Escolar , Bases de Dados Factuais , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Margens de Excisão , Procedimentos Neurocirúrgicos , Valor Preditivo dos Testes , Prognóstico , Fatores de Risco , Programa de SEER
11.
World Neurosurg ; 139: e345-e354, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32298824

RESUMO

BACKGROUND: Laser interstitial thermal therapy (LITT) is a novel, minimally invasive alternative to craniotomy, and as with any new technology, comes with a learning curve. OBJECTIVE: We present our experience detailing the evolution of this technology in our practice in one of the largest patient cohorts to date regarding LITT in neuro-oncology. METHODS: We reviewed 238 consecutive patients with brain tumor treated with LITT at our institution. Data on patient, surgery and tumor characteristics, and follow-up were collected. Patients were categorized into 2 cohorts: early (<2014, 100 patients) and recent (>2015, 138 patients). Median follow-up for the entire cohort was 8.4 months. RESULTS: The indications for LITT included gliomas (70.2%), radiation necrosis (21.0%), and metastasis (8.8%). Patient demographics stayed consistent between the 2 cohorts, with the exception of age (early, 54.3; recent, 58.4; P = 0.04). Operative time (6.6 vs. 3.5; P < 0.001) and number of trajectories (53.1% vs. 77.9% with 1 trajectory; P < 0.001) also decreased in the recent cohort. There was a significant decrease in permanent motor deficits over time (15.5 vs. 4.4%; P = 0.005) and 30-day mortality (4.1% vs. 1.5%) also decreased (not statistically significant) in the recent cohort. In terms of clinical outcomes, poor preoperative Karnofsky Performance Status (≤70) were significantly correlated with increased permanent deficits (P = 0.001) and decreased overall survival (P < 0.001 for all time points). CONCLUSIONS: We observed improvement in operative efficiency and permanent deficits over time and also patients with poor preoperative Karnofsky Performance Status achieved suboptimal outcomes with LITT. As many other treatment modalities, patient selection is important in this procedure.


Assuntos
Neoplasias Encefálicas/terapia , Terapia a Laser/métodos , Adulto , Idoso , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/cirurgia , Estudos de Coortes , Terapia Combinada , Feminino , Seguimentos , Glioma/diagnóstico por imagem , Glioma/cirurgia , Glioma/terapia , Humanos , Avaliação de Estado de Karnofsky , Terapia a Laser/mortalidade , Masculino , Pessoa de Meia-Idade , Procedimentos Cirúrgicos Minimamente Invasivos , Transtornos dos Movimentos/etiologia , Metástase Neoplásica , Duração da Cirurgia , Seleção de Pacientes , Complicações Pós-Operatórias/epidemiologia , Análise de Sobrevida , Resultado do Tratamento
12.
Nature ; 580(7804): 517-523, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32322066

RESUMO

A high tumour mutational burden (hypermutation) is observed in some gliomas1-5; however, the mechanisms by which hypermutation develops and whether it predicts the response to immunotherapy are poorly understood. Here we comprehensively analyse the molecular determinants of mutational burden and signatures in 10,294 gliomas. We delineate two main pathways to hypermutation: a de novo pathway associated with constitutional defects in DNA polymerase and mismatch repair (MMR) genes, and a more common post-treatment pathway, associated with acquired resistance driven by MMR defects in chemotherapy-sensitive gliomas that recur after treatment with the chemotherapy drug temozolomide. Experimentally, the mutational signature of post-treatment hypermutated gliomas was recapitulated by temozolomide-induced damage in cells with MMR deficiency. MMR-deficient gliomas were characterized by a lack of prominent T cell infiltrates, extensive intratumoral heterogeneity, poor patient survival and a low rate of response to PD-1 blockade. Moreover, although bulk analyses did not detect microsatellite instability in MMR-deficient gliomas, single-cell whole-genome sequencing analysis of post-treatment hypermutated glioma cells identified microsatellite mutations. These results show that chemotherapy can drive the acquisition of hypermutated populations without promoting a response to PD-1 blockade and supports the diagnostic use of mutational burden and signatures in cancer.


Assuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Glioma/genética , Glioma/terapia , Mutação , Animais , Antineoplásicos Alquilantes/farmacologia , Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/imunologia , Reparo de Erro de Pareamento de DNA/genética , Frequência do Gene , Genoma Humano/efeitos dos fármacos , Genoma Humano/genética , Glioma/imunologia , Humanos , Masculino , Camundongos , Repetições de Microssatélites/efeitos dos fármacos , Repetições de Microssatélites/genética , Mutagênese/efeitos dos fármacos , Mutação/efeitos dos fármacos , Fenótipo , Prognóstico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Análise de Sequência de DNA , Temozolomida/farmacologia , Temozolomida/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Top Magn Reson Imaging ; 29(2): 95-102, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32271286

RESUMO

Glioblastoma (GBM) is the deadliest form of brain cancer and recurs uniformly. Despite aggressive treatment with maximal safe surgical resection, adjuvant radiation with temozolomide chemotherapy, and alternating electrical field therapy, median survival for newly diagnosed GBM remains <2 years. Novel therapies are desperately needed. Immunotherapy, which has led to significant improvement in patient outcomes across many tumor types, is currently being studied in a large number of GBM clinical trials. One of the biggest challenges in immunotherapy trials in GBM has been accurate response assessment using currently available imaging modalities, including magnetic resonance imaging. In this review, we will discuss the rationale for immunotherapy for GBM, immunotherapeutic modalities currently under clinical evaluation in GBM, and the challenges and recent advances in imaging response assessment in GBM immunotherapy.


Assuntos
Neoplasias Encefálicas/terapia , Glioma/terapia , Imunoterapia/métodos , Animais , Encéfalo/diagnóstico por imagem , Neoplasias Encefálicas/patologia , Glioma/patologia , Humanos , Resultado do Tratamento
14.
Asian Pac J Cancer Prev ; 21(3): 755-760, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32212804

RESUMO

BACKGROUND: The standard of care in high grade glioma (HGG) is maximal safe surgical resection followed by adjuvant radiotherapy (RT) with/without chemotherapy. For anaplastic gliomas, studies have shown use of procarbazine, lomustine, vincristine (PCV) improves overall survival (OS) and progression free survival (PFS). Currently, there is substantial evidence that molecular markers strongly predict prognosis and response to treatment. METHODS: Between January 2016 to January 2018, 42 patients were accrued and followed up till April 2019. The primary end points were to correlate molecular markers with response to therapy in terms of OS and PFS in HGG. The secondary end point was to evaluate frequency of 1p/19q codeletion, IDH 1 mutation, ATRX deletion and p53 in HGG patients. RESULTS: The median age was 46 years (range 18-67) with M:F ratio 30:12. The frequency of IDH1 mutation,1p/19q codeletion, p53 mutation and ATRX mutation were 42.8%, 16.6%, 42.8% and 14.2% respectively. All the seven patients with 1p/19q codeletion had IDH1 mutation. Median follow up was 22 months. The 20-months PFS for different mutations were as follows; IDH1-mutated vs wild type: 53.6% vs 29.8%; p-0.035, 1p/19q codeleted vs non-codeleted: 85.7% vs 62.3%; p-0.011, p53 wild type vs mutated 32.1% vs 35.6%; p-0.035 and ATRX lost vs retained: 55.6% vs 53.3%; p- 0.369. The 20-months OS for IDH1 mutated vs wild type: 82.4% vs 30.6%; p-0.014, 1p/19q codeleted vs non-codeleted: 85.7% vs 65.8%; p-0.104, p53 wild-type vs mutated 45.5% vs 73.9%; p-0.036 and ATRX lost vs retained: 100% vs 60.3%; p-0.087. CONCLUSION: Codeletion of 1p/19q with IDH1 mutation in HGG is associated with a significantly favourable PFS. However, larger studies with longer follow up are required to evaluate OS and PFS in all the molecular subgroups.


Assuntos
Quimiorradioterapia , Glioma/terapia , Adulto , Idoso , Biomarcadores Tumorais/metabolismo , Cromossomos Humanos Par 1 , Cromossomos Humanos Par 19 , Feminino , Glioma/metabolismo , Glioma/patologia , Humanos , Isocitrato Desidrogenase/genética , Pessoa de Meia-Idade , Mutação , Gradação de Tumores
15.
J Clin Neurosci ; 74: 187-193, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32169363

RESUMO

High grade gliomas are associated with poor prognosis and high mortality. Conventional treatments and management of high grade gliomas have shown little improvement in 5-year overall survival. This phase I trial evaluated the safety, immunogenicity, and potential synergy of surgical resection with Gliadel Wafer implantation, followed by autologous tumor lysate-pulsed dendritic cell (DC) vaccine in patients with malignant glioma. Primary end points of this study were safety and surrogate markers of immunogenicity, overall survival, and progression free survival. Following surgical resection, Gliadel Wafers were placed along the resection cavity. Patients subsequently received intradermal injections of autologous tumor lysate-pulsed DC vaccines 3 times at 2 week intervals. Treatment response was evaluated clinically and through MRI at regular intervals. Twenty-eight patients received Gliadel Wafers and DC vaccination: 11 newly diagnosed (8 glioblastoma [GBM], 2 anaplastic astrocytoma [AA], and 1 anaplastic oligodendroglioma [AO]) and 17 recurrent (15 GBMs, 1 AA, and 1 AO) high grade gliomas. Immunogenicity data was collected for 20 of the 28 patients. Five of 20 patients showed elevated IFN-γ responses following vaccination. Median progression-free survival and overall survival for all GBM patients in the trial from the start of vaccination were 3.6 months and 16.9 months respectively. Comparisons between vaccine responders and non-vaccine responders were not statistically significant. Adjuvant autologous dendritic cells pulsed with tumor-lysate following resection and Gliadel Wafer placement is safe, elicits modest immunogenicity and shows similar clinical outcomes in patients who had DC vaccination in previous studies.


Assuntos
Neoplasias Encefálicas/terapia , Vacinas Anticâncer/uso terapêutico , Carmustina/uso terapêutico , Ácidos Decanoicos/uso terapêutico , Células Dendríticas/transplante , Glioma/terapia , Poliésteres/uso terapêutico , Adulto , Idoso , Antígenos de Neoplasias/imunologia , Antineoplásicos/uso terapêutico , Terapia Combinada/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Vacinação/métodos
16.
J Clin Neurosci ; 75: 112-116, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32184042

RESUMO

The utilization of proton beam therapy (PBT) as the primary treatment of adults with primary brain tumors (APBT) was evaluated through query of the National Cancer Database (NCDB) between the years 2004 and 2015. International Classification of Diseases for Oncology code for each patient was stratified into six histology categories; high-grade gliomas, medulloblastomas, ependymomas, other gliomas, other malignant tumors, or other benign intracranial tumors. Demographics of the treatment population were also analyzed. A total of 1,296 patients received PBT during the 11-year interval for treatment of their primary brain tumor. High-grade glioma, medulloblastoma, ependymoma, other glioma, other malignant, and other benign intracranial histologies made up 39%, 20%, 13%, 12%, 13%, and 2% of the cohort, respectively. The number of patients treated per year increased from 34 to 300 in years 2004 to 2015. Histologies treated with PBT varied over the 11-year interval with high-grade gliomas comprising 75% and 45% at years 2004 and 2015, respectively. The majority of the patient population was 18-29 years of age (59%), Caucasian race (73%), had median reported income of over $63,000 (46%), were privately insured (68%), and were treated at an academic institution (70%). This study characterizes trends of malignant and benign APBT histologies treated with PBT. Our data from 2004 through 2015 illustrates a marked increase in the utilization of PBT in the treatment of APBT and shows variability in the tumor histology treated over this time.


Assuntos
Neoplasias Encefálicas/terapia , Terapia com Prótons/estatística & dados numéricos , Adolescente , Adulto , Neoplasias Encefálicas/classificação , Ependimoma/terapia , Grupo com Ancestrais do Continente Europeu/estatística & dados numéricos , Feminino , Glioma/terapia , Humanos , Seguro Médico Ampliado/estatística & dados numéricos , Masculino , Meduloblastoma/terapia , Classe Social , Estados Unidos , Adulto Jovem
17.
Hum Cell ; 33(2): 416-426, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32072565

RESUMO

Glioma is one of the most common malignant tumors and shows a high metastasis rate and poor prognosis. Abnormal expression of long non-coding RNAs (lncRNAs) contributes to various human tumors including gliomas. This study aimed to investigate the regulatory role of the antisense RNA of growth arrest special 5 (GAS5-AS1), a novel lncRNA, in gliomas. Expression of GAS5-AS1 and microRNA-106b-5p (miR-106b-5p) in glioma tissues and cells was detected by quantitative reverse transcription PCR, northern blotting, or fluorescent in situ hybridization. Cell proliferation, migration, and invasion were analyzed by CCK-8 and Transwell assays. BALB/c nude mice were used to establish a glioma xenograft animal model by subcutaneous injection of U251 cells transfected with small interfering RNA targeting GAS5-AS1. A dual-luciferase reporter assay was conducted to confirm the targeting relationship between GAS5-AS1 and miR-106b-5p. GAS5-AS1 expression was downregulated in glioma tissues and cells, and upregulation of GAS5-AS1 expression inhibited glioma cell proliferation, migration, and invasion. GAS5-AS1 expression was correlated with the glioma tumor grade. In nude mice, upregulation of GAS5-AS1 markedly suppressed glioma tumor growth. GAS5-AS1 overexpression significantly increased the miR-106b-5p level in glioma cells, and GAS5-AS1 expression was negatively related to miR-106b-5p expression in glioma tissues. Overexpression of miR-106b-5p reversed the inhibitory effects of GAS5-AS1 upregulation on glioma cell proliferation and metastasis, while restoration of TUSC2 rescued the proliferation and invasion of glioma cells transfected with miR-106b-5p mimics. In summary, lncRNA GAS5-AS1 inhibited glioma proliferation, migration, and invasion by sponging miR-106b-5p and regulating the expression of TUSC2. Our results suggest GAS5-AS1 as a novel target for the treatment and prognosis prediction of gliomas.


Assuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Movimento Celular/genética , Proliferação de Células/genética , Glioma/genética , Glioma/patologia , MicroRNAs , RNA Longo não Codificante/fisiologia , Neoplasias Encefálicas/terapia , Glioma/terapia , Humanos , Terapia de Alvo Molecular , Invasividade Neoplásica/genética
18.
Lancet Oncol ; 21(2): e97-e103, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32007210

RESUMO

Clinical trials of treatments for high-grade gliomas have traditionally relied on measures of response or time-dependent metrics; however, these endpoints have limitations because they do not characterise the functional or symptomatic effect of the condition on the person. Including clinical outcome assessments, such as patient- reported outcomes (PROs), to determine net clinical benefit of a treatment strategy is needed because of the substantial burden of symptoms and impaired functioning in this patient population. The US National Cancer Institute convened a meeting to review previous recommendations and existing PRO measures of symptoms and function that can be applied to current trials and clinical practice for high-grade gliomas. Measures were assessed for relevance, relationship to disease and therapy, sensitivity to change, psychometric properties, response format, patient acceptability, and use of self-report. The group also relied on patient input including the results of an online survey, a literature review on available clinical outcomes, expert opinion, and alignment with work done by other organisations. A core set of priority constructs was proposed that allows more comprehensive evaluation of therapies and comparison of outcomes among studies, and enhances efforts to improve the measurement of these core clinical outcomes. The proposed set of constructs was then presented to the Society for Neuro-Oncology Response Assessment in Neuro-Oncology Working Group and feedback was solicited.


Assuntos
Neoplasias Encefálicas/terapia , Assistência à Saúde , Glioma/terapia , Avaliação de Resultados da Assistência ao Paciente , Medidas de Resultados Relatados pelo Paciente , Ensaios Clínicos como Assunto , Humanos , Resultado do Tratamento
19.
Phys Ther ; 100(3): 564-574, 2020 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-32043148

RESUMO

BACKGROUND: It is recommended that people with gliomas engage in rehabilitation, but high-quality evidence to support this recommendation is lacking. OBJECTIVE: This study assesses the effectiveness of a physical therapy- and occupational therapy-based rehabilitation intervention compared with usual rehabilitation care for quality of life (QoL) during active anticancer treatment. DESIGN: This study was a randomized controlled trial. SETTING: The study took place in Odense University Hospital, Denmark. PARTICIPANTS: The trial included people with gliomas who were functionally independent. INTERVENTION: The participants were randomly assigned to a supervised rehabilitation intervention or usual rehabilitation care during the active anticancer period. The supervised rehabilitation included physical therapy and occupational therapy-based interventions. MEASUREMENTS: The primary outcome was the between-group difference in the overall QoL from baseline to the 6-week follow-up. It was self-rated with the global health status (GHS)/QoL domains from the European Organization for Research and Treatment of Cancer Questionnaire. Eighty-eight participants per group were required to find a 10% between-group difference from baseline to the 6-week follow-up. Secondary outcomes were the health-related QoL domains, symptomatology, and functional performance. RESULTS: A total of 64 participants were included (32 in the intervention group and 32 in the control group). At follow-up, the intervention group self-rated a nonsignificantly better score for GHS/QoL than the control group (adjusted mean difference = 8.7% [95% confidence interval = -4.36 to 21.79]). Compared with the control group, the intervention group had consistently better results on self-rated secondary outcomes, including cognitive functioning (ß = 16.2) and fatigue (ß = -13.4), and objectively measured aerobic power (ß = 2.6). LIMITATIONS: The number of participants and duration of follow-up were inadequate to determine if the intervention was superior to the current usual rehabilitation care. CONCLUSIONS: The physical therapy- and occupational therapy-based rehabilitation intervention did not affect GHS/QoL. However, the trial found promising significant effects on both objective and self-reported secondary outcomes, making rehabilitation efforts during active anticancer treatment promising.


Assuntos
Neoplasias Encefálicas/reabilitação , Terapia por Exercício , Glioma/reabilitação , Terapia Ocupacional , Qualidade de Vida , Neoplasias Encefálicas/terapia , Análise de Dados , Feminino , Glioma/terapia , Humanos , Análise de Intenção de Tratamento , Masculino , Pessoa de Meia-Idade , Tamanho da Amostra , Método Simples-Cego , Resultado do Tratamento
20.
Life Sci ; 247: 117438, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32070708

RESUMO

AIMS: This study intends to investigate the mechanisms of ubiqutin-specific protease 22 (USP22)/B cell-specific Moloney murine leukemia virus integration site 1 (BMI1) on the biological phenotypes of glioma stem cells (GSCs) under hypoxia. MAIN METHODS: Western blot, Cell Counting Kit-8, colony formation and flow cytometry assays were preformed to evaluate cells biological behaviors. Luciferase assay was utilized to identify the associations among USP22, HIF-1α and BMI1. KEY FINDINGS: Silencing USP22 reduced the stemness and proliferation of GSCs, and increased its apoptosis in response to hypoxia. Whilst, overexpression of BMI1 reversed these phenomena. Whilst, a significant decrease in proliferation and stemness of GSCs caused by HIF-1α exhaustion were inversed by overexpression of USP22 or BMI1. SIGNIFICANCE: Function of USP22-BMI1 on biological behaviors of GSCs was regulated by HIF-1α in response to hypoxia.


Assuntos
Glioma/terapia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Hipóxia/metabolismo , Complexo Repressor Polycomb 1/metabolismo , Ubiquitina Tiolesterase/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Células-Tronco Neoplásicas/metabolismo , Complexo Repressor Polycomb 1/genética , Transdução de Sinais , Hipóxia Tumoral , Ubiquitina Tiolesterase/genética
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