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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.
Medicine (Baltimore) ; 99(2): e18689, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31914068

RESUMO

RATIONALE: Trabectedin is an antitumor drug considered to be effective for liposarcoma, leiomyosarcoma, and translocation-related sarcoma. Concerning liposarcoma subtypes, evidence of the efficacy of trabectedin for dedifferentiated liposarcoma (DDLPS) is poor, whereas it is known to have high efficacy against myxoid liposarcoma. Moreover, there are few reports of long-term trabectedin treatment of cases of DDLPS. Here, we present a case of advanced metastatic DDLPS that achieved long-term disease control by trabectedin treatment. PATIENT CONCERNS: A 68-year-old man presented with a mass in his back. Magnetic resonance imaging showed a tumorous mass in his back which exhibited low intensity on T1-weighted and high intensity on T2-weighted images. DIAGNOSIS: The mass was diagnosed as DDLPS by open biopsy. INTERVENTIONS: The patient underwent gemcitabine+docetaxel combination therapy followed by pazopanib and eribulin; all these therapies failed to halt disease progression. Subsequently, we changed the regimen to trabectedin as fourth-line therapy. OUTCOME: The patient achieved stable disease for approximately 18 months during 11 cycles of trabectedin therapy. LESSONS: Trabectedin should be considered as a treatment option for DDLPS even in cases of numerous failed prior chemotherapy regimens.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Lipossarcoma/tratamento farmacológico , Lipossarcoma/patologia , Trabectedina/uso terapêutico , Idoso , Humanos , Masculino , Metástase Neoplásica
4.
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
5.
J Cancer Res Clin Oncol ; 146(3): 659-670, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31754832

RESUMO

BACKGROUND: The use of alkylating chemotherapy versus bevacizumab for recurrent glioblastoma remains controversial. Here, we tested the hypothesis that the activity of alkylators, but not that of bevacizumab, would be associated with the O6-methylguanine DNA methyltransferase (MGMT) promoter methylation status. METHODS: We analyzed a cohort of patients treated at centers of the German Glioma Network or the University Hospital Zurich with alkylating agent-based chemotherapy (n = 260) or bevacizumab without or with irinotecan (n = 84) for first recurrence of glioblastoma. Outcome was stratified for O6-methylguanine DNA methyltransferase (MGMT) status and crossover to bevacizumab or alkylators at further progression. RESULTS: Median post-recurrence survival-1 (PRS-1) for patients receiving alkylating agents at first recurrence was longer than with bevacizumab (11.1 versus 7.4 months, p < 0.001). The use of alkylators was associated with longer PRS-1 for patients with a methylated versus unmethylated MGMT promoter (p = 0.017). For patients receiving bevacizumab, PRS-1 was not different with or without MGMT promoter methylation. PRS-1 was longer in patients receiving alkylating chemotherapy compared to bevacizumab for patients with methylated (p < 0.001) or unmethylated MGMT promoter (p = 0.034). For patients with alkylators at first recurrence receiving bevacizumab at any further recurrence, PRS-1 was longer than in patients receiving bevacizumab first and alkylators thereafter (p = 0.002). CONCLUSIONS: This study confirms limited value of bevacizumab in recurrent glioblastoma independent of MGMT status. Alkylating agents have activity in recurrent glioblastoma, especially in the context of MGMT promoter methylation.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Bevacizumab/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/genética , Metilação de DNA/genética , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Feminino , Glioblastoma/genética , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Intervalo Livre de Progressão , Regiões Promotoras Genéticas/genética , Estudos Retrospectivos , Proteínas Supressoras de Tumor/genética , Adulto Jovem
6.
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
7.
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
8.
BMC Cancer ; 19(1): 961, 2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31619207

RESUMO

BACKGROUND: Neuroblastoma is the most common extra-cranial solid tumor among children. Despite intensive treatment, patients with advanced disease mostly experience dismal outcomes. Here, we proposed the use of topotecan and cyclophosphamide containing induction regimen as an upfront therapy to high risk neuroblastoma patients. METHODS: Patients with high risk neuroblastoma undergoing ThaiPOG high risk neuroblastoma protocol from 2016 to 2017 were studied. All patients received 6 cycles of induction regimen consisting of 2 cycles topotecan (1.2 mg/m2/day) and cyclophosphamide (400 mg/m2/day) for 5 days followed by cisplatin (50 mg/m2/day) for 4 days combined with etoposide (200 mg/m2/day) for 3 days on the third and fifth cycles and cyclophosphamide (2100 mg/m2/day) for 2 days combined with doxorubicin (25 mg/m2/day) and vincristine (0.67 mg/m2/day) for 3 days on the fourth and sixth cycles. Treatment response after the 5th cycle before surgery and treatment-related toxicities after each topotecan containing induction cycle were evaluated. Relevant prognostic factors were analyzed to measure the treatment response among those patients. RESULTS: In all, 107 high risk neuroblastoma patients were enrolled in the study. After the 5th cycle of induction regimen, the patients achieved complete response (N = 2), very good partial response (N = 40), partial response (N = 46) and mixed response (N = 19). None of the patients experienced stable disease or disease progression. The most significant prognostic factor was type of healthcare system. The most common adverse effect was febrile neutropenia followed by mucositis, diarrhea and elevated renal function. CONCLUSION: The topotecan and cyclophosphamide containing induction regimen effectively provides favorable treatment response. The regimen is well tolerated with minimal toxicity among patients with high risk neuroblastoma in Thailand.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ciclofosfamida/uso terapêutico , Quimioterapia de Indução/métodos , Neuroblastoma/tratamento farmacológico , Inibidores da Topoisomerase I/uso terapêutico , Topotecan/uso terapêutico , Adolescente , Antineoplásicos Alquilantes/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Criança , Pré-Escolar , Cisplatino/administração & dosagem , Cisplatino/uso terapêutico , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Doxorrubicina/uso terapêutico , Etoposídeo/administração & dosagem , Etoposídeo/uso terapêutico , Feminino , Humanos , Lactente , Masculino , Prognóstico , Estudos Prospectivos , Tailândia , Inibidores da Topoisomerase I/administração & dosagem , Topotecan/administração & dosagem , Resultado do Tratamento , Vincristina/administração & dosagem , Vincristina/uso terapêutico
9.
BMC Cancer ; 19(1): 966, 2019 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-31623635

RESUMO

BACKGROUND: Lymphoma and dysplasia are rare complications of long-standing Crohn's disease. We report an exceptional case of a synchronous intestinal marginal zone B-cell lymphoma (MALT lymphoma) and colonic adenoma in a Crohn's disease patient. CASE PRESENTATION: A 50-year-old male patient presented with right lower quadrant for the last 9 months. He also had associated weight loss and diarrhea alternating with constipation. Ileo-colonoscopy revealed a pseudopolypoid appearance of the colonic and ileal mucosa with many discontinuous ulcerations with a 3 cm sessile polypoid mass at 17 cm from the anal verge. Histological examination of the polypoid lesion revealed an adenoma with high grade dysplasia, while the biopsies of colonic mucosa showed histologic features of Crohn's disease. Abdominal computed tomography scan (CT scan) and magnetic resonance imaging (MRI) showed circumferential wall thickening of the colon and ileum, enlarged mesenteric lymph nodes and a sessile polypoid mass of the rectosigmoid junction. The patient was scheduled for an ileocoletectomy with resection of the upper rectum and ileorectostomy. The histological examination of the resected segment showed histologic features of Crohn's disease, a recto-sigmoid polyp with high grade. dysplasia and extensive small lymphocytic infiltrate in both colonic and ileal wall which is strongly stained by CD20 and BCL2. The diagnosis of MALT lymphoma with adenoma on a background of Crohn's disease was made. The patient successfully completed 8 cycles of Rituximab+ chlorambucil chemotherapy. Nowadays the patient is asymptomatic without evidence of lymphoproliferative recurrence 10 months after surgery. CONCLUSION: We report the first case in the literature of Malt lymphoma with colonic adenoma associated with Crohn's disease, and discuss his unique macroscopic and histological features in a patient. Without immunosuppressive therapy.


Assuntos
Adenoma/complicações , Neoplasias do Colo/complicações , Doença de Crohn/complicações , Linfoma de Zona Marginal Tipo Células B/complicações , Adenoma/tratamento farmacológico , Adenoma/cirurgia , Antineoplásicos Alquilantes/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Biópsia , Clorambucila/uso terapêutico , Colo/patologia , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/cirurgia , Doença de Crohn/tratamento farmacológico , Doença de Crohn/cirurgia , Humanos , Ileostomia , Mucosa Intestinal/patologia , Linfoma de Zona Marginal Tipo Células B/tratamento farmacológico , Linfoma de Zona Marginal Tipo Células B/cirurgia , Masculino , Pessoa de Meia-Idade , Protectomia , Rituximab/uso terapêutico , Resultado do Tratamento
10.
Mol Carcinog ; 58(12): 2327-2339, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31544312

RESUMO

Autologous stem cell transplant (ASCT) with high-dose melphalan (HDM) is the standard treatment for fit multiple myeloma (MM) patients. It is generally believed that some DNA repair proteins impact the activity to repair melphalan-induced DNA damage, thus potentially contributing to the patient's clinical response. However, knowledge of these proteins is limited. In the current study, we investigated the roles of XRCC1, a protein involved in base excision repair and single-strand break repair, in melphalan response in MM cells. Small interfering RNA knockdown of XRCC1 significantly increased the accumulation of melphalan-induced DNA damage in MM cells and sensitized them to melphalan treatment, indicating that genetic variation in XRCC1 may impact response to melphalan treatment. We then evaluated the association between an XRCC1 variant with reduced activity, rs25487 (R399Q), and clinical outcomes of 108 MM patients with melphalan therapy. Our results showed that XRCC1 rs25487 was associated with prolonged progression-free survival (PFS) in MM patients. The adjusted hazard ratio for PFS between patients carrying rs25487 AA/AG and GG was 0.42 (95% confidence interval: 0.25, 0.84, P = .014). Taken together, these results indicate that XRCC1 is involved in the repair of melphalan-induced DNA damage and XRCC1 rs25487 variant with impaired DNA repair function influences the clinical responses of HDM in MM patients.


Assuntos
Reparo do DNA , Transplante de Células-Tronco Hematopoéticas/métodos , Melfalan/uso terapêutico , Mieloma Múltiplo/terapia , Proteína 1 Complementadora Cruzada de Reparo de Raio-X/metabolismo , Idoso , Antineoplásicos Alquilantes/efeitos adversos , Antineoplásicos Alquilantes/uso terapêutico , Quebras de DNA de Cadeia Simples/efeitos dos fármacos , Dano ao DNA , Relação Dose-Resposta a Droga , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Melfalan/efeitos adversos , Pessoa de Meia-Idade , Mieloma Múltiplo/genética , Mieloma Múltiplo/metabolismo , Polimorfismo de Nucleotídeo Único , Intervalo Livre de Progressão , Interferência de RNA , Transplante Autólogo , Proteína 1 Complementadora Cruzada de Reparo de Raio-X/genética
11.
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
12.
In Vivo ; 33(5): 1609-1614, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31471412

RESUMO

BACKGROUND/AIM: Trabectedin is a synthetic antineoplastic agent approved for advanced soft tissue sarcoma (STS) in Japan. The aim of this study was to evaluate the efficacy and safety of the Japan-approved dose of trabectedin for advanced STS. PATIENTS AND METHODS: We retrospectively reviewed 38 patients with advanced STS who received salvage chemotherapy with trabectedin. RESULTS: The overall response and disease control rates were 16% (5 patients) and 67% (20 patients), respectively. The median progression-free and overall survival were 7.3 and 17.8 months, respectively. There were no significant differences between patients with liposarcoma or leiomyosarcoma and those without, or between patients with TRS and those without. The most common grade 3-4 AEs were elevated transaminases and neutropenia. CONCLUSION: Trabectedin 1.2 mg/m2, as the approved dose in Japan, showed similar efficacy to the dose of 1.5 mg/m2 used in Western countries. Trabectedin could be an option for advanced STS in Japan, regardless of histological subtype.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Sarcoma/tratamento farmacológico , Trabectedina/uso terapêutico , Adulto , Idoso , Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos Alquilantes/efeitos adversos , Biomarcadores Tumorais , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Terapia de Salvação , Sarcoma/diagnóstico , Sarcoma/etiologia , Sarcoma/mortalidade , Trabectedina/administração & dosagem , Trabectedina/efeitos adversos , Resultado do Tratamento , Adulto Jovem
13.
Arch Esp Urol ; 72(7): 712-715, 2019 Sep.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-31475684

RESUMO

OBJECTIVE: Estramustine is an stable estradiol and nitrogenated mustard conjugatewith antymicotic properties. Currently, with the appearance of chemotherapy and new molecules, estramustin acetate is not a drug of choice for castration resistant prostate cancer. METHODS: We describe two patients with castration resistant prostate cancer under treatment with estramustine acetate and complete biochemical response and stable disease. We review the literature to elucidate if the drug should be stopped and changed for the new molecules that have demonstrated survival increase. RESULTS: To our knowledge, there are not data in the literature to either solve the questions posed or shed light regarding cumulative toxicity due to prolongued use of estramustine acetate. CONCLUSIONS: We recognize that these clinical cases do not translate that estramustine acetate is a first line treatment for patients with CRPC. Nevertheless, they translate the heterogeneity of CRPC. It would be interesting to investigate the combination of new agents with estramustine acetate as well as the search of biomarkers that enable selection of candidates who could respond to estramustine acetate.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Estramustina/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Humanos , Masculino
14.
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
15.
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
16.
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
17.
Anticancer Res ; 39(7): 3553-3563, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262879

RESUMO

BACKGROUND/AIM: Trabectedin is a DNA-damaging agent and has been approved for the treatment of patients with advanced soft tissue sarcoma. Schlafen 11 (SLFN11) was identified as a dominant determinant of the response to DNA-damaging agents. The aim of the study was to clarify the association between SLFN11 expression and the antitumor activity of trabectedin. MATERIALS AND METHODS: The antitumor activity of trabectedin was evaluated under different expression levels of SLFN11 regulated by RNA interference and CRISPR-Cas9 systems, and the combined antitumor activity of ataxia telangiectasia and Rad3-related protein kinase (ATR) inhibitor and trabectedin in sarcoma cell lines using in vitro a cell viability assay and in vivo xenograft models. RESULTS: SLFN11-knockdown cell lines had a lower sensitivity to trabectedin, compared to parental cells. ATR inhibitor enhanced the antitumor activity of trabectedin in SLFN11-knockdown cells and in a SLFN11-knockout xenograft model. CONCLUSION: SLFN11 expression might be a key factor in the antitumor activity of trabectedin.


Assuntos
Antineoplásicos Alquilantes/farmacologia , Proteínas Nucleares/metabolismo , Sarcoma/metabolismo , Neoplasias de Tecidos Moles/metabolismo , Trabectedina/farmacologia , Animais , Antineoplásicos Alquilantes/uso terapêutico , Linhagem Celular Tumoral , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas Nucleares/genética , Sarcoma/tratamento farmacológico , Neoplasias de Tecidos Moles/tratamento farmacológico , Trabectedina/uso terapêutico
18.
J Zoo Wildl Med ; 50(2): 474-477, 2019 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-31260218

RESUMO

After a history of intermittent vomiting, endoscopic biopsies of stomach and duodenum were collected from a 13-yr-old male snow leopard (Uncia uncia). On microscopic examination, monomorphic small lymphocytes expanded the duodenal mucosa and occasionally formed intraepithelial nests. Immunohistochemistry of the infiltrating small lymphocytes in the mucosa and within the epithelium had strong, perimembranous labeling for CD3e, with few CD79a-positive lymphocytes located at the base of the villi. Polymerase chain reaction (PCR) for antigen receptor rearrangements (PARR) of feline T-cell receptor gamma (TCRG) detected a monoclonal cell population. The sequence of the PCR product was 100% homologous with the feline TCRG gene. By histology, immunophenotyping, and PARR testing, a final diagnosis of enteropathy-associated T-cell lymphoma, small cell type, was made. Homology in the nucleotide sequence between U. uncia and the domestic cat (Felis catus) indicates that feline PARR testing for TCRG may be diagnostic in snow leopards.


Assuntos
Linfoma de Células T Associado a Enteropatia/veterinária , Felidae , Doenças Inflamatórias Intestinais/veterinária , Animais , Antineoplásicos Alquilantes/uso terapêutico , Antineoplásicos Hormonais/uso terapêutico , Clorambucila/uso terapêutico , Linfoma de Células T Associado a Enteropatia/diagnóstico , Linfoma de Células T Associado a Enteropatia/tratamento farmacológico , Linfoma de Células T Associado a Enteropatia/patologia , Doenças Inflamatórias Intestinais/diagnóstico , Masculino , Prednisolona/uso terapêutico , Vitamina B 12/administração & dosagem , Vitamina B 12/uso terapêutico , Complexo Vitamínico B/uso terapêutico
19.
BMJ Case Rep ; 12(7)2019 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-31300605

RESUMO

Acquired C1-inhibitor (C1-INH) deficiency is a rare and potentially life-threatening disorder, which presents with recurrent attacks of non-pitting oedema to the face, airway, limbs or gastrointestinal tract. It is often associated with underlying B-cell lymphoproliferative disorders. We describe a case of a 73-year-old man with acquired C1-INH deficiency who presented with nephrotic syndrome due to glomerular IgM deposition, secondary to an underlying secretory lymphoplasmacytic lymphoma. Both the acquired C1-INH deficiency and the nephrotic syndrome resolved when the underlying B-cell lymphoma was treated with rituximab and bendamustine, suggesting the underlying lymphoproliferative malignancy was driving both disorders.


Assuntos
Angioedemas Hereditários/diagnóstico , Antineoplásicos Alquilantes/uso terapêutico , Cloridrato de Bendamustina/uso terapêutico , Síndrome Nefrótica/diagnóstico , Rituximab/uso terapêutico , Macroglobulinemia de Waldenstrom/diagnóstico , Idoso , Angioedemas Hereditários/tratamento farmacológico , Angioedemas Hereditários/etiologia , Angioedemas Hereditários/fisiopatologia , Humanos , Masculino , Síndrome Nefrótica/tratamento farmacológico , Síndrome Nefrótica/etiologia , Síndrome Nefrótica/fisiopatologia , Qualidade de Vida , Retorno ao Trabalho , Resultado do Tratamento , Macroglobulinemia de Waldenstrom/complicações , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Macroglobulinemia de Waldenstrom/fisiopatologia
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