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1.
Medicine (Baltimore) ; 99(5): e18455, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32000358

RESUMO

INTRODUCTION: Whole brain radiotherapy (WBRT) has been the mainstay treatment of brain metastases (BM) in non-small cell lung cancer (NSCLC) patients for years. Temozolomide (TMZ) could penetrate the blood-brain barrier and some studies showed that TMZ plus MBRT may improve clinical effectiveness. This meta-analysis is aim to evaluate the clinical effectiveness and safety of TMZ plus MBRT in the NSCLC patients with BM. METHODS AND ANALYSIS: We systematically searched databases including PubMed, EMBASE, Cochrane Central Register of Controlled Trials, and four Chinese databases (Chinese Biomedical Database, China National Knowledge Infrastructure, Wanfang Database and Chinese Scientific Journal Database) without language restrictions from inception until July 26, 2019. Randomized controlled trials (RCTs) which compared TMZ plus WBRT with single WBRT in the advanced NSCLC patients with BM were included. The outcomes analysis reported objective response rate (ORR), disease control rate (DCR), overall survival (OS), progression-free survival (PFS), quality of life (QOL), and adverse effects. Two reviewers will independently extract data from the selected studies and assess the quality of studies. Statistical analyses will be performed using Review manager 5.3 software. Random-effects or fixed models were used to estimate pooled hazard ratio and relative risk. RESULTS: This systemic review and meta-analysis will evaluate the effects of TMZ plus MBRT in the NSCLC patients with BM in RCTs. CONCLUSION: Our study will provide evidence to judge if TMZ plus MBRT are effective treatment for NSCLC patients with BM.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Temozolomida/uso terapêutico , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/secundário , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Carcinoma Pulmonar de Células não Pequenas/secundário , Humanos , Neoplasias Pulmonares/patologia , Metanálise como Assunto , Revisão Sistemática como Assunto
2.
Medicine (Baltimore) ; 99(2): e18591, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31914038

RESUMO

This analysis aimed to investigate whether the long-term administration of temozolomide (TMZ) claimed a survival advantage for patients with glioblastoma in China.A total of 75 patients with newly diagnosed glioblastoma at the Department of Radiation Oncology, Shenzhen People's Hospital between August 2008 and August 2016 were retrospectively evaluated during analysis. A propensity-matched analysis was performed to balance the basic characteristics of patients between compared groups. Kaplan-Meier method and Cox proportional hazards model were used to assess progression-free survival (PFS) and overall survival (OS) of patients receiving 6 adjuvant TMZ cycles compared with patients treated with more than 6 cycles.Twenty of 75 patients received more than 6 cycles of TMZ, and the other 55 patients were treated with a median of 6 cycles ranging from 1 to 6. The patients with long-term administration of TMZ had better OS (47.0 months, 95% CI 20.0-73.9 vs 20.6 months, 95% CI 17.9-23.2, P = .014) but not PFS (17.0 months, 95% CI 10.1-24.5 vs 14.2 months, 95% CI 11.8-16.6, P = .133). Balancing the clinical factors with a propensity-matched analysis also showed the significant advantage of prolonged TMZ application in terms of OS but not PFS.Prolonged administration of TMZ beyond 6 cycles did demonstrate survival benefits for patients with initially diagnosed glioblastoma.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/mortalidade , Glioblastoma/tratamento farmacológico , Glioblastoma/mortalidade , Temozolomida/uso terapêutico , Adolescente , Adulto , Idoso , Antineoplásicos Alquilantes/administração & dosagem , Neoplasias Encefálicas/terapia , Quimioterapia Adjuvante , Esquema de Medicação , Feminino , Glioblastoma/terapia , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Pontuação de Propensão , Estudos Retrospectivos , Temozolomida/administração & dosagem , Adulto Jovem
3.
J Clin Pathol ; 73(2): 112-115, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31422371

RESUMO

AIMS: O(6)-methylguanine-DNA-methyltransferase (MGMT) promoter methylation is a high predictive factor for therapy results of temozolomide in patients with glioma. The objective of this work was to analyse the impact of MGMT promoter methylation in patients with primary diagnosed glioblastoma (GBM) relating to survival using a quantitative method (methylation quantification of endonuclease-resistant DNA, MethyQESD) by verifying a cut-off point for MGMT methylation provided by the literature (

Assuntos
Biomarcadores Tumorais/genética , Neoplasias Encefálicas/genética , Metilação de DNA , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Glioblastoma/genética , Regiões Promotoras Genéticas , Proteínas Supressoras de Tumor/genética , Adulto , Idoso , Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/enzimologia , Neoplasias Encefálicas/mortalidade , Feminino , Glioblastoma/tratamento farmacológico , Glioblastoma/enzimologia , Glioblastoma/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Temozolomida/uso terapêutico , Fatores de Tempo
4.
Int J Cancer ; 146(3): 803-809, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30980539

RESUMO

Metformin has been linked to improve survival of patients with various cancers. There is little information on survival of glioblastoma patients after use of metformin. We assessed the association between metformin use and survival in a pooled analysis of patient data from 1,731 individuals from the randomized AVAglio, CENTRIC and CORE trials. We performed multivariate Cox analyses for overall survival (OS) and progression-free survival (PFS) comparing patients' use of metformin at baseline and/or during concomitant radiochemotherapy (TMZ/RT). Further exploratory analyses investigated the effect of metformin with a history of diabetes and nonfasting glucose levels in relation to OS or PFS of glioblastoma patients. Metformin alone or in any combination was not significantly associated with OS or PFS (at baseline, hazard ratio [HR] for OS = 0.87; 95% confidence interval [CI] = 0.65-1.16; HR for PFS = 0.84; 95% CI = 0.64-1.10; during TMZ/RT HR for OS = 0.97; 95% CI = 0.68-1.38; HR for PFS = 1.02; 95% CI = 0.74-1.41). We found a statistically nonsignificant association of metformin monotherapy with glioblastoma survival at baseline (HR for OS = 0.68; 95% CI = 0.42-1.10; HR for PFS = 0.57; 95% CI = 0.36-0.91), but not during the TMZ/RT period (HR for OS = 0.90; 95% CI = 0.51-1.56; HR for PFS = 1.05; 95% CI = 0.64-1.73). Diabetes mellitus or increased nonfasting glucose levels were not associated with a difference in OS or PFS in our selected study population. Metformin did not prolong survival of patients with newly diagnosed glioblastoma in our analysis. Additional studies may identify patients with specific tumor characteristics that are associated with potential benefit from treatment with metformin, possibly due to metabolic vulnerabilities.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/mortalidade , Glioblastoma/mortalidade , Metformina/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/terapia , Quimiorradioterapia , Feminino , Glioblastoma/terapia , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Ensaios Clínicos Controlados Aleatórios como Assunto , Temozolomida/uso terapêutico , Adulto Jovem
5.
Int J Cancer ; 146(2): 424-438, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31241171

RESUMO

Stem cell chemoresistance remains challenging the efficacy of the front-line temozolomide against glioblastoma. Novel therapies are urgently needed to fight those cells in order to control tumor relapse. Here, we report that anti-O-acetyl-GD2 adjuvant immunotherapy controls glioma stem-like cell-driven chemoresistance. Using patient-derived glioblastoma cells, we found that glioma stem-like cells overexpressed O-acetyl-GD2. As a result, monoclonal antibody 8B6 immunotherapy significantly increased temozolomide genotoxicity and tumor cell death in vitro by enhancing temozolomide tumor uptake. Furthermore, the combination therapy decreased the expression of the glioma stem-like cell markers CD133 and Nestin and compromised glioma stem-like cell self-renewal capabilities. When tested in vivo, adjuvant 8B6 immunotherapy prevented the extension of the temozolomide-resistant glioma stem-like cell pool within the tumor bulk in vivo and was more effective than the single agent therapies. This is the first report demonstrating that anti-O-acetyl-GD2 monoclonal antibody 8B6 targets glioblastoma in a manner that control temozolomide-resistance driven by glioma stem-like cells. Together our results offer a proof of concept for using anti-O-acetyl GD2 reagents in glioblastoma to develop more efficient combination therapies for malignant gliomas.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Gangliosídeos/antagonistas & inibidores , Glioblastoma/tratamento farmacológico , Células-Tronco Neoplásicas/efeitos dos fármacos , Adjuvantes Imunológicos/farmacologia , Adjuvantes Imunológicos/uso terapêutico , Animais , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linhagem Celular Tumoral , Autorrenovação Celular/efeitos dos fármacos , Autorrenovação Celular/imunologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/imunologia , Sinergismo Farmacológico , Gangliosídeos/imunologia , Glioblastoma/imunologia , Glioblastoma/patologia , Humanos , Camundongos , Células-Tronco Neoplásicas/imunologia , Temozolomida/farmacologia , Temozolomida/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Anticancer Res ; 39(12): 6731-6741, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31810938

RESUMO

BACKGROUND/AIM: Histone deacetylase 6 (HDAC6) is considered as one of the most promising targets in drug development for cancer therapy. Drug resistance is a major cause of treatment failure in many cancers including glioblastoma (GBM), the most lethal malignant tumor. The role of HDAC6 in GBM resistance and its underlying mechanisms have not been well elucidated. Herein, we investigated the function of HDAC6 in modulating GBM resistance. MATERIALS AND METHODS: The anticancer effects of four structurally distinct selective HDAC6 inhibitors were addressed using western blot, flow cytometry, CCK-8 assay, and CI in temozolomide (TMZ)-resistant GBM cells. RESULTS: We showed that HDAC6-selecitve inhibitors block activation of the EGFR and p53 pathways in TMZ-resistant GBM cells. Importantly, the inhibition of HDAC6 correlates with increased levels of MSH2 and MSH6, key DNA mismatch repair proteins, in TMZ-resistant GBM cells. In addition to the MSH, HDAC6 inhibitors decrease MGMT expression in TMZ-resistant GBM cells. Furthermore, HDAC6 inhibitors increase TMZ sensitivity and efficiently induce apoptosis in TMZ-resistant GBM cells. CONCLUSION: Selective inhibition of HDAC6 may be a promising strategy for the treatment of TMZ-resistant GBM.


Assuntos
Neoplasias Encefálicas/enzimologia , Proteínas de Ligação a DNA/metabolismo , Resistencia a Medicamentos Antineoplásicos , Glioblastoma/enzimologia , Desacetilase 6 de Histona/antagonistas & inibidores , Proteína 2 Homóloga a MutS/metabolismo , Antineoplásicos Alquilantes/uso terapêutico , Derivados de Benzeno/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Linhagem Celular Tumoral , Sobrevivência Celular , Reparo de Erro de Pareamento de DNA/fisiologia , Metilases de Modificação do DNA/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Receptores ErbB/metabolismo , Glioblastoma/tratamento farmacológico , Desacetilase 6 de Histona/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Humanos , Ácidos Hidroxâmicos/farmacologia , Indóis/farmacologia , Pirimidinas/farmacologia , Temozolomida/uso terapêutico , Proteína Supressora de Tumor p53/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Regulação para Cima
7.
Anticancer Res ; 39(12): 6743-6750, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31810939

RESUMO

BACKGROUND: Glioblastoma (GBM) is the most aggressive type of primary malignant brain tumour. The interaction between high-mobility group box 1 (HMGB1) and receptor for advanced glycation end-products (RAGE) is important for tumour cell growth. Previously, we identified an anticancer candidate, papaverine, that inhibited the HMGB1-RAGE interaction. MATERIALS AND METHODS: Our study assessed the anticancer effects of papaverine alone or in combination with temozolomide on U87MG and T98G human GBM cells using clonogenicity assays, as well as in a U87MG xenograft mouse model. The radiosensitizing efficacy of papaverine was measured based on the clonogenicity of T98G cells. RESULTS: Papaverine significantly inhibited the clonogenicity of U87MG and T98G cells. Compared with single treatment, the combination of papaverine and temozolomide more highly suppressed the clonogenicity of T98G cells and delayed tumour growth in the U87MG xenograft mouse model. Furthermore, papaverine increased the radiosensitivity of T98G cells. CONCLUSION: Papaverine is a potential anticancer drug in GBM treatment.


Assuntos
Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Glioblastoma/tratamento farmacológico , Papaverina/uso terapêutico , Temozolomida/uso terapêutico , Animais , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/radioterapia , Linhagem Celular Tumoral , Glioblastoma/metabolismo , Glioblastoma/patologia , Glioblastoma/radioterapia , Proteína HMGB1/antagonistas & inibidores , Proteína HMGB1/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Tolerância a Radiação/efeitos dos fármacos , Receptor para Produtos Finais de Glicação Avançada/antagonistas & inibidores , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Medicine (Baltimore) ; 98(45): e17759, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31702627

RESUMO

BACKGROUND: Glioblastoma (GB) is one of the most common malignancies with limited standard therapies such as surgery, radiotherapy (RT) plus temozolomide (TMZ). Molecularly targeted drugs have been investigated among various clinical trials and are expected to develop in the field of tumor therapy, while the efficacy remains uncertain due to limited previous results. Thus, we focus on the evaluation of molecularly targeted drugs to clarify its overall effectiveness in terms of treating newly diagnosed GB. METHODS: Electronic databases were searched for eligible literatures updated to April 2018. Randomized-controlled trials were included to assess the efficacy and safety of molecularly targeted drugs in patients with newly diagnosed GB. The main outcomes were further calculated including the following parameters: PFS (progression-free survival), OS (overall survival) as well as AEs (adverse events). All data were pooled along with their 95% confidence interval using RevMan software. Sensitivity analyses and heterogeneity were evaluated quantitatively. RESULTS: The combination of molecularly targeted drugs with TMZ + RT had no significant effects on OS (OR = 0.96, 95%CI = 0.89-1.04, P = .36). Meanwhile, the combination regimen significantly improved the PFS of patients with newly diagnosed GB (OR = 0.86 ,95% CI 0.75-0.98, P = .02). The rate of AEs (OR = 1.68,95%CI = 1.44-1.97, P < .00001) was higher in patients receiving molecularly targeted drugs, which was comparable to the contemporary group. CONCLUSION: Longer PFS and a higher rate of AEs were observed with the addition of molecularly targeted drugs to standard chemoradiation in patients harboring newly diagnosed GB. Nevertheless, compared with the control arm, the regimen did not significantly prolong OS.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Temozolomida/uso terapêutico , Neoplasias Encefálicas/radioterapia , Quimiorradioterapia , Feminino , Glioblastoma/radioterapia , Humanos , Masculino , Terapia de Alvo Molecular , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Análise de Sobrevida , Resultado do Tratamento
9.
J Neurooncol ; 145(1): 115-123, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31556015

RESUMO

INTRODUCTION: The optimal management of high risk WHO grade II gliomas after surgery is debated including the role of initial temozolomide to delay radiotherapy and risk of cognitive defects. METHODS: A post-hoc analysis of a phase II multicenter study on high risk WHO grade II gliomas, receiving initial temozolomide alone, has re-evaluated the long-term results within the molecular subgroups of WHO 2016. The primary endpoint of the study was response according to RANO, being seizure response, PFS and OS secondary endpoints. RESULTS: Response rate among oligodendrogliomas IDH-mutant and 1p/19q codeleted (76%) was significantly higher than that among diffuse astrocytomas either mutant (55%) or wild-type (36%). A reduction of seizure frequency > 50% was observed in 87% of patients and a seizure freedom in 72%. The probability of seizure reduction > 50% was significantly associated with the presence of an IDH mutation. Median PFS, PFS at 5 and 10 years, median OS and OS at 5 and 10 years were significantly longer in oligodendrogliomas IDH-mutant and 1p/19q codeleted. Sixty-seven percent of patients with oligodendroglioma IDH mutant and 1p/19q codeleted did not recur with a median follow up of 9.3 years, while 59% did not receive radiotherapy at recurrence with a median follow up of 8.2 years. CONCLUSIONS: The beneficial effects of initial temozolomide prevail in oligodendrogliomas IDH-mutant and 1p/19q codeleted: thus, these tumors, when incompletely resected or progressive after surgery alone, or with intractable seizures, should receive temozolomide as initial treatment with salvage radiotherapy and/o reoperation and/or second-line chemotherapy at recurrence.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Glioma/tratamento farmacológico , Temozolomida/uso terapêutico , Adulto , Idoso , Neoplasias Encefálicas/classificação , Neoplasias Encefálicas/patologia , Feminino , Seguimentos , Glioma/classificação , Glioma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Taxa de Sobrevida , Organização Mundial da Saúde
10.
Neurosurg Clin N Am ; 30(4): 499-508, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31471057

RESUMO

Medical therapy for Cushing disease is primarily used to control hypercortisolism in patients whose disease persists or with recurrent disease after pituitary surgery, including those awaiting the salutary effects of radiation therapy. In can also be used to control hypercortisolism preoperatively, and in patients who decline surgery or whose tumor location is unknown. Steroidogenesis inhibitors, centrally acting agents, and glucocorticoid receptor antagonists are currently available to treat hypercortisolism, and several novel agents are in development. Given the absence of head-to-head clinical trials, choice between treatments has to be individualized based on careful consideration of patient, tumor, and disease characteristics.


Assuntos
Hipersecreção Hipofisária de ACTH/tratamento farmacológico , Cabergolina/uso terapêutico , Etomidato/uso terapêutico , Humanos , Cetoconazol/uso terapêutico , Metirapona/uso terapêutico , Mitotano/uso terapêutico , Hipersecreção Hipofisária de ACTH/complicações , Somatostatina/análogos & derivados , Somatostatina/uso terapêutico , Temozolomida/uso terapêutico , Resultado do Tratamento
11.
Oncogene ; 38(42): 6867-6879, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31406250

RESUMO

Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Since surviving patients experience severe neurocognitive disabilities, better and more effective treatments are needed to enhance their quality of life. Casein kinase 2 (CK2) is known to regulate cell growth and survival in multiple cancers; however, the role of CK2 in MB is currently being studied. In this study, we verified the importance of CK2 in MB tumorigenesis and discovered that inhibition of CK2 using the small molecule inhibitor, CX-4945, can sensitize MB cells to a well-known and tolerated chemotherapeutic, temozolomide (TMZ). To study the role of CK2 in MB we modulated CK2 expression in multiple MB cells. Exogenous expression of CK2 enhanced cell growth and tumor growth in mice, while depletion or inhibition of CK2 expression decreased MB tumorigenesis. Treatment with CX-4945 reduced MB growth and increased apoptosis. We conducted a high-throughput screen where 4000 small molecule compounds were analyzed to identify compounds that increased the anti-tumorigenic properties of CX-4945. TMZ was found to work synergistically with CX-4945 to decrease cell survival and increase apoptosis in MB cells. O-6-methylguanine-DNA methyltransferase (MGMT) activity is directly correlated to TMZ sensitivity. We found that loss of CK2 activity reduced ß-catenin expression, a known MGMT regulator, which in turn led to a decrease in MGMT expression and an increased sensitivity to TMZ. Our findings show that CK2 is important for MB maintenance and that treatment with CX-4945 can sensitize MB cells to TMZ treatment.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Caseína Quinase II/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Meduloblastoma/tratamento farmacológico , Temozolomida/uso terapêutico , Neoplasias Encefálicas/enzimologia , Humanos , Meduloblastoma/enzimologia , Prognóstico
12.
Int J Radiat Oncol Biol Phys ; 105(5): 1106-1112, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31461674

RESUMO

PURPOSE: Malignant transformation (MT) of adult grade 2 glioma (low-grade glioma [LGG]) is associated with adverse survival. We sought to describe the incidence, outcomes, and risk factors for MT of molecularly classified LGG. METHODS AND MATERIALS: We reviewed a single-institutional database of adults who received a diagnosis of LGG with data allowing for molecular classification from 1980 to 2018 to evaluate time to MT and its associated risk factors. MT was defined as pathologic confirmation of grade 3-4 glioma and/or imaging characteristics consistent with MT by multidisciplinary consensus. RESULTS: Among the included 486 adults with molecularly classified LGG, median age was 39 years (range, 18-78), median tumor size was 3.9 cm (range, 0.3-13.0), and 262 (54%) were male. Molecular classification was IDHmut1p/19qcodel in 169 (35%), IDHmut1p/19qintact in 125 (26%), and IDHwt in 192 (40%) patients. Adjuvant management was observation in 246 (51%) patients, temozolomide alone in 82 (16%), radiation therapy alone in 63 (13%), and radiation therapy concurrent with temozolomide in 81 (17%). Temozolomide monotherapy was more likely to be given to IDHmut1p/19qcodel patients (P < .001). Median follow-up was 5.3 years. MT occurred in 84 (17%) patients, with a 5-year freedom from MT of 86% (95% confidence interval [CI], 82%-90%). Median overall survival after MT was 2.4 years (95% CI, 1.5-3.3) and was associated with molecular classification (P = .03) and grade at MT (P < .001). Factors associated with MT were male sex (hazard ratio [HR], 2.1; 95% CI, 1.2-3.6; P = .009), tumor size ≥5 cm (HR, 3.5; 95% CI, 2.0-6.2; P < .001), IDHmut1p/19qintact (HR, 2.7; 95% CI, 1.3-5.6; P = .009) or IDHwt classification (HR, 5.5; 95% CI, 2.5-11.8; P < .001), and adjuvant temozolomide monotherapy (HR, 3.8; 95% CI, 1.4-10.3; P = .008). CONCLUSIONS: MT of LGG has a poor prognosis associated with unfavorable molecular groups. Analysis of our large cohort identified adjuvant temozolomide monotherapy as the only modifiable risk factor for MT and provides the first clinical evidence of temozolomide-associated MT among molecularly classified adult LGG. This novel finding supplements our understanding of temozolomide-induced hypermutation and informs precision management of LGG.


Assuntos
Neoplasias Encefálicas/patologia , Transformação Celular Neoplásica/patologia , Glioma/patologia , Adulto , Idoso , Antineoplásicos Alquilantes/efeitos adversos , Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/terapia , Transformação Celular Neoplásica/induzido quimicamente , Transformação Celular Neoplásica/genética , Quimiorradioterapia/métodos , Quimioterapia Adjuvante , Feminino , Glioma/genética , Glioma/mortalidade , Glioma/terapia , Humanos , Isocitrato Desidrogenase/genética , Masculino , Pessoa de Meia-Idade , Mutação , Fatores Sexuais , Temozolomida/efeitos adversos , Temozolomida/uso terapêutico , Carga Tumoral , Conduta Expectante
13.
Oncology ; 97(5): 255-263, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31288238

RESUMO

BACKGROUND: Recent studies have shown that the peripheral blood pretreatment neutrophil/lymphocyte ratio (NLR) is a prognostic measure in various cancers. The few studies evaluating NLR in glioblastoma multiforme (GBM) patients yielded inconsistent results. OBJECTIVES: The primary objective of our study was to test the ability of pretreatment NLR to predict the overall survival (OS) and progression-free survival (PFS) of patients with GBM treated by combined modality therapy (surgery, radiation, and temozolomide chemotherapy). A secondary objective was to evaluate the toxicity of the combined modality protocol in a consecutive series of patients treated in our center, in the context of a real-world universal health-care setting. METHODS: We analyzed 89 patients with GBM in a retrospective cohort analysis who were treated in Soroka University Medical Center's Oncology Department between the years 2005-2016. We analyzed NLR as a dichotomous variable at 3 cut-off points, 2.5, 3 and 4, as a predictor of OS and PFS. Methylation status of the O6-methylguanine-DNA methyltransferase (MGMT) promoter was not determined. RESULTS: No significant correlation was found between NLR and either OS or PFS. Factors that predicted a shorter OS were age and extent of surgery. Patients over 70 years of age had a statistically significant shorter OS, 12.5 months (95% CI: 10.4-14.5 months) versus 17.6 months (95% CI: 14.2-21.1 months) in those 70 years of age and younger (p = 0.004). The OS of patients undergoing partial resection (12.7 months 95% CI: 8.3-17.1 months) or biopsy only (9.3 months 95% CI: 7.8-24.6 months), was significantly shorter than that of patients undergoing total resection (18.9 months, 95% CI: 11.8-26.0 months; p = 0.035). There were no treatment-related deaths. The most common grade III-IV toxicities were thrombocytopenia, 12.4%, and fatigue, 13.5%. CONCLUSIONS: In our cohort of GBM patients treated with combined modality therapy, pretreatment NLR was not prognostic. Toxicity of treatment was acceptable. Investigation of the NLR with larger groups of patients selected by MGMT status is warranted.


Assuntos
Neoplasias Encefálicas/terapia , Glioblastoma/terapia , Linfócitos , Neutrófilos , Temozolomida/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/sangue , Neoplasias Encefálicas/mortalidade , Terapia Combinada , Feminino , Glioblastoma/sangue , Glioblastoma/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Adulto Jovem
14.
Ann Pharm Fr ; 77(5): 426-434, 2019 Sep.
Artigo em Francês | MEDLINE | ID: mdl-31288930

RESUMO

OBJECTIVES: The oral route is becoming increasingly important in the panel of anti-cancer therapeutics, but it generates difficulties (adherence, management of adverse effects...). In order to secure medication management, the pharmaceutic team chose to set up pharmaceutical consultations. Its objectives are multiple: understanding of treatment for better adherence, pharmaceutical analysis, enhancement of the city-hospital link. This work presents the setting up of the pharmaceutical consultations and makes an assessment after one year. METHODS: The initial step was a meeting with institutional health professionals who work with patients to define the place, the objectives, and the patients targeted by the pharmaceutical consultation. The targeted patients are all patients receiving temozolomide and some patients initiating oral chemotherapy, considered at risk, on medical solicitation. Documents were created to standardize practices in the team from the collection of information and pharmaceutical analysis until the conduct of the consultation and the consultation report (integrated into the computerized patient's medical file). Activity indicators were defined and collected. RESULTS: Over one year, 65 pharmaceutical consultations were conducted, of which 23 % resulted in pharmaceutical interventions. The average duration of consultation was 34minutes. The whole team (four pharmacists and two residents) was involved in this activity. CONCLUSIONS: Pharmaceutical consultations help secure medical care of patients, providing tools, dedicated and personalized time, pharmaceutical analysis, etc. Ultimately, the goal is to accompany the patient throughout his treatment by having follow-up pharmaceutical consultations, in collaboration with community pharmacists thanks to the city-hospital link that we have established.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Encaminhamento e Consulta , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos Alquilantes/uso terapêutico , Prestação Integrada de Cuidados de Saúde , Feminino , Humanos , Masculino , Oncologia , Pessoa de Meia-Idade , Equipe de Assistência ao Paciente , Farmacêuticos , Temozolomida/administração & dosagem , Temozolomida/uso terapêutico
15.
Radiat Oncol ; 14(1): 104, 2019 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-31196126

RESUMO

PURPOSE: Despite recent advances in multimodal treatments, the prognosis of patients with glioblastoma multiforme (GBM) remains poor. The aim of this study was to evaluate the efficacy of moderately hypofractionated simultaneous integrated boost intensity-modulated radiotherapy (SIB-IMRT) combined with temozolomide (TMZ) for the postoperative treatment of GBM. MATERIALS AND METHODS: From February 2012 to February 2018, 80 patients with newly diagnosed and histologically confirmed GBM in our institute were reviewed retrospectively. All patients underwent complete resection or partial resection surgery and then received hypofractionated SIB-IMRT with concomitant TMZ followed by adjuvant TMZ. A total dose of 64 Gy over 27 fractions was delivered to the gross tumor volume (GTV), clinical target volume 1 (CTV1) received 60 Gy over 27 fractions, and CTV2 received 54 Gy over 27 fractions. The progression-free survival (PFS) and overall survival (OS) rates and the toxicities were evaluated. Prognostic factors were analyzed using univariate and multivariate Cox models. RESULTS: The median follow-up was 16 months (range, 5~72 months). The median PFS was 15 months, and the 1-, 2-, and 3-year PFS rates were 56.0, 27.6, and 19.5%, respectively. The median OS was 21 months, and the 1-, 2-, 3-, and 5-year OS rates were 77.6, 41.6, 32.8, and 13.4%, respectively. The toxicities were mild and acceptable. Age, KPS scores and the total number of TMZ cycles were significant factors influencing patient survival. CONCLUSION: Moderately hypofractionated SIB-IMRT combined with TMZ is a feasible and safe treatment option with mild toxicity and good PFS and OS.


Assuntos
Neoplasias Encefálicas/terapia , Quimiorradioterapia/métodos , Glioblastoma/terapia , Cuidados Pós-Operatórios , Radioterapia de Intensidade Modulada/métodos , Temozolomida/uso terapêutico , Adulto , Idoso , Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/patologia , Feminino , Glioblastoma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Hipofracionamento da Dose de Radiação , Dosagem Radioterapêutica , Planejamento da Radioterapia Assistida por Computador/métodos , Estudos Retrospectivos , Taxa de Sobrevida , Adulto Jovem
16.
Cancer Control ; 26(1): 1073274819855118, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31167546

RESUMO

Low-grade gliomas (LGGs) are a highly heterogeneous group of slow-growing, lethal, diffusive brain tumors. Temozolomide (TMZ) is a frequently used primary chemotherapeutic agent for LGGs. Currently there is no consensus as to the optimal biomarkers to predict the efficacy of TMZ, which calls for decision-making for each patient while considering molecular profiles. Low-grade glioma data sets were retrieved from The Cancer Genome Atlas. Cox regression and survival analyses were applied to identify clinical features significantly associated with survival. Subsequently, Ordinal logistic regression, co-expression, and Cox regression analyses were applied to identify genes that correlate significantly with response rate, disease-free survival, and overall survival of patients receiving TMZ as primary therapy. Finally, gene expression and methylation analyses were exploited to explain the mechanism between these gene expression and TMZ efficacy in LGG patients. Overall survival was significantly correlated with age, Karnofsky Performance Status score, and histological grade, but not with IDH1 mutation status. Using 3 distinct efficacy end points, regression and co-expression analyses further identified a novel 4-gene signature of ASPM, CCNB1, EXO1, and KIF23 which negatively correlated with response to TMZ therapy. In addition, expression of the 4-gene signature was associated with those of genes involved in homologous recombination. Finally, expression and methylation profiling identified a largely unknown olfactory receptor OR51F2 as potential mediator of the roles of the 4-gene signature in reducing TMZ efficacy. Taken together, these findings propose the 4-gene signature as a novel panel of efficacy predictors of TMZ therapy, as well as potential downstream mechanisms, including homologous recombination, OR51F2, and DNA methylation independent of MGMT.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/tratamento farmacológico , Glioma/tratamento farmacológico , Temozolomida/uso terapêutico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidade , Metilação de DNA , Intervalo Livre de Doença , Feminino , Perfilação da Expressão Gênica , Glioma/genética , Glioma/mortalidade , Recombinação Homóloga , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Gradação de Tumores , Prognóstico , Análise de Sobrevida , Transcriptoma/genética
17.
BMJ Case Rep ; 12(5)2019 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-31154345

RESUMO

Glioblastoma multiforme (GBM) is an aggressive tumour that can lead to lymphopaenia. Its standard treatment involves temozolomide (TMZ) chemotherapy with radiation, often with addition of corticosteroids for symptomatic management. Although TMZ is also immunosuppressive, patients receiving TMZ rarely develop disseminated opportunistic infections. Here, we report the case of a patient with GBM receiving TMZ, radiotherapy and corticosteroids, who develops an incidental new brain lesion that is found to be disseminated Aspergillus within a new GBM tumour site. The patient received successful early treatment of her central nervous system aspergillosis. This case illustrates the profound immunosuppressive potential of GBM in conjunction with TMZ and corticosteroids, which can lead to high-morbidity opportunistic infections concurrently with tumour progression. Future research is needed to elucidate GBM, TMZ and corticosteroids' compound immune effects and guide management that strikes a balance between treating high-morbidity infections and continuing with immunosuppressive chemotherapy.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Aspergilose/diagnóstico , Abscesso Encefálico/diagnóstico , Neoplasias Encefálicas/terapia , Lobo Frontal , Glioblastoma/terapia , Temozolomida/uso terapêutico , Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos Alquilantes/efeitos adversos , Aspergilose/diagnóstico por imagem , Aspergilose/etiologia , Abscesso Encefálico/diagnóstico por imagem , Abscesso Encefálico/etiologia , Neoplasias Encefálicas/patologia , Terapia Combinada , Diagnóstico Diferencial , Feminino , Glioblastoma/patologia , Humanos , Imagem por Ressonância Magnética , Pessoa de Meia-Idade , Temozolomida/administração & dosagem , Temozolomida/efeitos adversos
18.
PLoS One ; 14(6): e0217881, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31170245

RESUMO

BACKGROUND: Hypofractionated radiation therapy is a feasible and safe treatment option in elderly and frail patients with glioblastoma. The aim of this study was to evaluate the effectiveness of hypofractionated radiation therapy with concurrent temozolomide in terms of feasibility and disease control in primary glioblastoma patients with poor prognostic factors other than advanced age, such as post-surgical neurological complications, high tumor burden, unresectable or multifocal lesions, and potential low treatment compliance due to social factors or rapidly progressive disease. MATERIAL AND METHODS: GTV included the surgical cavity plus disease visible in T1WI-MRI, FLAIR-MRI and in the MET-uptake. The CTV was defined as the GTV plus 1.5-2 cm margin; the PTV was the CTV+0.3 cm margin. Forty, fourty-five, and fifty grays in 15 fractions were prescribed to 95% of PTV, CTV, and GTV, respectively. Treatment was delivered using IMRT or the VMAT technique. Simultaneously, 75 mg/m2/day of temozolomide were administered. RESULTS: Between January 2010 and November 2017, we treated a total of 17 patients. The median age at diagnosis was 68-years; median KPS was 50-70%. MGMT-methylation status was negative in 5 patients, and 8 patients were IDH-wildtype. Eight of 18 patients were younger than 65-years. Median tumor volume was 26.95cc; median PTV volume was 322cc. Four lesions were unresectable; 6 patients underwent complete surgical resection. Median residual volume was 1.14cc. Progression-free survival was 60% at 6 months, 33% at 1-year and 13% at 2-years (median OS = 7 months). No acute grade 3-5 toxicities were documented. Symptomatic grade 3 radiation necrosis was observed in one patient. CONCLUSIONS: Patients with poor clinical factors other than advanced age can be selected for hypofractionated radiotherapy. The OS and PFS rates obtained in our series are similar to those in patients treated with standard fractionation, assuring good treatment adherence, low rates of toxicity and probable improved cost-effectiveness.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/radioterapia , Glioblastoma/tratamento farmacológico , Glioblastoma/radioterapia , Hipofracionamento da Dose de Radiação , Temozolomida/uso terapêutico , Idoso , Neoplasias Encefálicas/diagnóstico por imagem , Análise Fatorial , Feminino , Glioblastoma/diagnóstico por imagem , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Necrose , Recidiva Local de Neoplasia/patologia , Prognóstico , Intervalo Livre de Progressão , Estudos Prospectivos , Temozolomida/efeitos adversos
19.
J Neurooncol ; 144(1): 127-135, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31175579

RESUMO

OBJECTIVE: The optimal timing of chemoradiotherapy in patients with newly diagnosed glioblastoma (GBM) remains unclear. In this study, we explored the clinical efficacy of super-early initiation of temozolomide (TMZ) in the treatment interval from surgery to radiotherapy. METHODS: We retrospectively reviewed the clinical data of 375 patients with GBM in our institution from 2012 to 2018. One hundred and sixty-three patients received super-early TMZ within 7 days after craniotomy based on standard Stupp protocol (super-early group, SEG), while two hundred and twelve patients underwent standard Stupp protocol alone (control group, CG). We performed propensity score matching (PSM) to reduce patient selection bias between the two groups. RESULTS: Before PSM, both median progression-free survival (PFS) and overall survival (OS) of patients in SEG were longer than those in CG (PFS 11.5 vs. 9.0 months, P = 0.0384 and OS 23.0 vs. 17.0 months, P = 0.0014). After PSM, the clinical efficacy of super-early initiation of TMZ only remained significant in term of OS, which was further validated in Cox hazard proportional model (HR = 0.583, 95% CI 0.384-0.884, P = 0.011). In the subgroup analysis, patients without gross total resection (GTR) or with O6-methylguanine DNA methyltransferase promoter methylation could benefit from super-early initiation of TMZ in both PFS and OS (P < 0.05). No significant difference of treatment emerging adverse events was observed between the two groups (P > 0.05). CONCLUSIONS: This retrospective study highlights that super-early initiation of TMZ in newly diagnosed GBM may confer to survival benefit, especially for those without GTR.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/mortalidade , Glioblastoma/mortalidade , Temozolomida/uso terapêutico , Tempo para o Tratamento , Adolescente , Adulto , Idoso , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Feminino , Seguimentos , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Adulto Jovem
20.
World Neurosurg ; 128: e427-e433, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31042598

RESUMO

OBJECTIVE: We conducted a retrospective analysis to explore the prognostic effect of the cumulative score based on neutrophil-lymphocyte ratio (NLR) and fibrinogen in patients with glioblastoma multiforme (GBM). METHODS: The clinical data of patients with GBM from January 2014 to December 2017 in our hospital were retrospectively analyzed. X-tile software was used to identify the optimal cutoff points of NLR and fibrinogen in predicting prognosis of GBM. Fibrinogen-NLR (F-NLR) score was calculated as following: fibrinogen >3.4 g/dL and NLR >4.1 was identified as F-NLR score of 2, only 1 abnormal index was defined as F-NLR score of 1, and no abnormal indices were classified as F-NLR score of 0. RESULTS: A total of 187 patients with primary GBM were enrolled in this study. Of these patients, 116 patients were men and 71 were women, and the mean age was 55 ± 13.55 years. The cutoffs of lymphocyte, NLR, fibrinogen, and platelet-lymphocyte ratio (PLR) identified by X-tile were 1.8 × 109/L, 4.1 × 109/L, 3.4 mg/dL, and 228.6. There were 87 patients with F-NLR score of 0, 50 patients with F-NLR score of 1, and 50 patients with F-NLR score of 2. In the univariate survival analysis, age, lymphocyte count, fibrinogen, NLR, PLR, F-NLR score of 2, chemotherapy, and radiotherapy were significant predictors of overall survival (OS) in patients with GBM (all P < 0.05). After excluding related parameters, F-NLR score of 2 (hazard ratio [HR], 2.103; 95% confidence interval [CI], 1.401-3.155; P < 0.001) and chemotherapy (HR, 0.650; 95% CI, 0.432-0.977; P = 0.038) were predictive factors of OS for patients with GBM. When stratified by extent of resection, age, and adjuvant chemotherapy and radiotherapy, F-NLR score maintained the prognostic value in patients with GBM (all P < 0.05). CONCLUSIONS: F-NLR score of 2 was a risk predictor of prognosis for patients with GBM.


Assuntos
Neoplasias Encefálicas/mortalidade , Fibrinogênio/metabolismo , Glioblastoma/mortalidade , Contagem de Linfócitos , Neutrófilos , Adulto , Idoso , Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/sangue , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/terapia , Feminino , Glioblastoma/sangue , Glioblastoma/metabolismo , Glioblastoma/terapia , Humanos , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Procedimentos Neurocirúrgicos , Contagem de Plaquetas , Prognóstico , Modelos de Riscos Proporcionais , Radioterapia , Estudos Retrospectivos , Taxa de Sobrevida , Temozolomida/uso terapêutico
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