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1.
Anticancer Res ; 40(1): 393-399, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31892592

RESUMO

AIM: This study was performed to confirm the superior overall survival (OS) after pulmonary oligo-recurrence compared to pulmonary sync-oligometastases in a large nationwide study. PATIENTS AND METHODS: Patients that met the following criteria were included: 1 to 5 lung-only metastases at the beginning of stereotactic body radiation therapy (SBRT) was performed between January 2004 and June 2015, and the biological effective dose (BED) of SBRT was 75 Gy or more. The parameters included in the analyses were age, gender, ECOG PS, primary lesion, pathology, oligoetastatic state, SBRT date, chemotherapy before SBRT, chemotherapy concurrent SBRT, chemotherapy after SBRT, maximum tumor diameter, number of metastases, field coplanarity, dose prescription, BED10, OTT of SBRT. RESULTS: In total, 1,378 patients with 1,547 tumors were enrolled. Oligo-recurrence occurred in 1,016 patients, sync-oligometastases in 118, and unclassified oligometastases in 121. The three-year OS was 64.0% for oligo-recurrence and 47.5% for sync-oligometastasis (p<0.001). In the multivariate analysis, the hazard ratio (HR) for sync-oligometastases versus oligo-recurrence was 1.601 (p=0.014). Adverse events of Grade 5 were occurred in 3 patients. CONCLUSION: This is the first nationwide to indicate that the OS of patients with pulmonary oligo-recurrence is better than that of patients with sync-oligometastases.


Assuntos
Neoplasias Pulmonares/radioterapia , Neoplasias Pulmonares/secundário , Radiocirurgia , Inquéritos e Questionários , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Adulto Jovem
2.
Anticancer Res ; 38(11): 6121-6126, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30396927

RESUMO

BACKGROUND: Colorectal cancer (CRC) is a major cause of morbidity and mortality throughout the world. It is the third most common cancer worldwide and the fourth most common cause of cancer-related death. FOLFOX, a combination of leucovorin calcium, fluorouracil, and oxaliplatin, is the first-line chemotherapy for stage III and stage IV CRC. However, patients with FOLFOX-resistant CRC have a poor prognosis. In recent years, virochemotherapy has been proposed as a potential treatment for chemotherapy-resistant cancer. MATERIALS AND METHODS: Through our first screening assay, we found that coxsackievirus A11 (CVA11) displayed potent oncolytic activities. We tested whether coxsackievirus A11 (CVA11) has oncolytic activity in human CRC cells in vitro and in vivo. We also examined whether pretreatment of oxaliplatin-resistant CRC cells with oxaliplatin enhances the oncolytic activity of CVA11. RESULTS: We found that CVA11 was potently oncolytic against the oxaliplatin-sensitive Caco-2 cell line, but had little effect on the oxaliplatin-resistant line WiDr. However, pretreatment of WiDr cells with oxaliplatin enhanced the oncolytic activity of CVA11, and the combination therapy was more cytotoxic than either oxaliplatin treatment or CVA11 infection alone. Furthermore, growth of subcutaneous WiDr tumors in a xenograft model was significantly lower in mice treated with oxaliplatin followed by intratumoral CVA11 injection compared with mice receiving either treatment alone. CONCLUSION: Oxaliplatin pretreatment sensitized oxaliplatin-resistant CRC cells to lysis by CVA11 infection in vitro and in vivo. Taken together, these findings identify a novel potential chemovirotherapeutic modality for the treatment of oxaliplatin-resistant human CRC.


Assuntos
Neoplasias Colorretais/terapia , Enterovirus/fisiologia , Terapia Viral Oncolítica/métodos , Oxaliplatina/farmacologia , Animais , Antígenos CD55/biossíntese , Células CACO-2 , Linhagem Celular Tumoral , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/virologia , Terapia Combinada , Resistencia a Medicamentos Antineoplásicos , Enterovirus/efeitos dos fármacos , Feminino , Humanos , Molécula 1 de Adesão Intercelular/biossíntese , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Anticancer Res ; 38(10): 5937-5941, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30275222

RESUMO

BACKGROUND/AIM: The aim of this study was to reveal risk factors for lung injury following irinotecan administration for the treatment of neoplasms. PATIENTS AND METHODS: This study included 204 patients who received irinotecan from October 2005 to November 2014 and had evaluable chest CT images before initiation of irinotecan. RESULTS: Six (2.9%) patients developed lung injury and, of these, 2 had preexisting interstitial lung disease (pre-ILD). The frequency of lung injury in patients with pre-ILD was 11% (2 of 19) while that in patients without pre-ILD was 2.2%. Risk factor analysis for the lung injury showed pre-ILD was the most predictable factor [odds ratio (OR) 5.00, p=0.07]. Combination with other agents, origin of neoplasms (lung or not), initial dose or minimum interval were not observed to be related to risk. CONCLUSION: The risk of lung injury with irinotecan was high when pre-ILD was present and the risk was comparable with previously reported other agents.


Assuntos
Antineoplásicos Fitogênicos/efeitos adversos , Camptotecina/análogos & derivados , Doenças Pulmonares Intersticiais/complicações , Lesão Pulmonar/etiologia , Neoplasias/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Camptotecina/efeitos adversos , Feminino , Seguimentos , Humanos , Irinotecano , Lesão Pulmonar/patologia , Masculino , Pessoa de Meia-Idade , Neoplasias/patologia , Prognóstico , Estudos Retrospectivos , Fatores de Risco
4.
Acta Oncol ; 57(9): 1232-1239, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29722594

RESUMO

BACKGROUND: The adaptation criteria for administration of stereotactic body radiotherapy (SBRT) to patients with lung cancer who previously underwent surgery and subsequently developed a second primary lung cancer (SPLC) or intra-parenchymal lung metastasis (IPLM) are controversial, unlike the criteria for repeat surgery. We aimed to evaluate the feasibility of SBRT for these patients. Factors associated with decreased respiratory function were also evaluated. MATERIAL AND METHODS: Sixty-nine patients with 89 lesions who underwent SBRT between 2008 and 2017 were analyzed. Of these, 29 were diagnosed with SPLC while the remaining 40 had IPLM. The distribution of histological types was as follows: squamous cell carcinoma (n = 13 lesions); adenocarcinoma (n = 25); non-small cell carcinoma (n = 1); unknown histological type (n = 49). The prescribed doses to the planning target volume (PTV) were 50 Gy in five fractions for 85 lesions and 60 Gy in 10 fractions for four lesions at PTV mean. RESULTS: Over a median follow-up period of 55 months, the 4-year overall survival and local control rates were 50.3% and 87.6%, respectively. Six patients experienced grade 2 radiation pneumonitis and one experienced grade 3. Two patients experienced grade 5 pulmonary fibrosis. Decreased respiratory function was observed in 10 patients (15.1%). On multivariate analysis, the presence of pulmonary disease before SBRT was the only statistically significant factor associated with decreased respiratory function. CONCLUSIONS: SBRT is safe and feasible in patients with SPLC or IPLM previously treated surgically. Pre-existing pulmonary disease was a predictive factor for decreased respiratory function.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/radioterapia , Neoplasias Pulmonares/radioterapia , Pulmão/fisiologia , Segunda Neoplasia Primária/radioterapia , Tecido Parenquimatoso/patologia , Radiocirurgia/métodos , Transtornos Respiratórios/etiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/secundário , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Terapia Combinada , Fracionamento da Dose de Radiação , Estudos de Viabilidade , Feminino , Seguimentos , Humanos , Pulmão/efeitos da radiação , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/cirurgia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Segunda Neoplasia Primária/cirurgia , Tecido Parenquimatoso/efeitos da radiação , Pneumonite por Radiação/etiologia , Radiocirurgia/efeitos adversos , Radioterapia Adjuvante/efeitos adversos , Testes de Função Respiratória , Estudos Retrospectivos
5.
Rinsho Ketsueki ; 59(1): 45-50, 2018.
Artigo em Japonês | MEDLINE | ID: mdl-29415937

RESUMO

A 35-year-old man who previously underwent splenectomy for hereditary spherocytosis at age 29 visited our hospital complaining of fatigue that had started 7 days ago and right upper abdominal pain. Laboratory data showed increased white blood cell and eosinophil count accompanied by severe transaminitis and clotting abnormalities. Computed tomography scan showed multiple embolisms in the portal vein, superior mesenteric vein, right pulmonary artery, and inferior vena cava. Severe liver damage presumably caused by portal vein thrombosis was also observed. Anticoagulant therapies consisting of continuous arterial infusion of urokinase from the superior mesenteric artery and an intravenous infusion of recombinant human thrombomodulin and heparin dissolved the systemic thrombosis. Concurrently administered prednisone decreased the eosinophil count. With regard to eosinophilia, we were unable to find any connective tissue diseases, antibodies to parasites, or genetic anomalies including PDGFRA, PDGFRB, and FGFR1. Hence we diagnosed the patient with idiopathic hypereosinophilic syndrome (HES). Although thromboembolisms in patients with HES have been reported, the literature on portal vein thrombosis associated with HES is scarce. In the present case, the previous splenectomy may have contributed to the portal vein thrombosis.


Assuntos
Síndrome Hipereosinofílica/complicações , Veia Porta , Trombose Venosa/etiologia , Adulto , Humanos , Hepatopatias/etiologia , Masculino , Esplenectomia
6.
J Adolesc Young Adult Oncol ; 7(3): 389-394, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29406798

RESUMO

A novel induction therapy, including intensive L-asparaginase, was designed in 2007 for patients aged <45 years with Philadelphia-negative acute lymphoblastic leukemia (ALL). We analyzed seven de novo cases and one case of recurrence who received this treatment. The median age was 21 years (range: 16-35 years). Four patients had T-ALL and the others had B-ALL. All the patients achieved complete remission and proceeded to cord blood transplantation. In the median 72-month follow-up, there were no cases of observed mortality or recurrence. Our results indicate scope for further development of both induction therapy and postremission therapy.


Assuntos
Antineoplásicos/uso terapêutico , Asparaginase/uso terapêutico , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Adolescente , Adulto , Terapia Combinada , Feminino , Seguimentos , Humanos , Masculino , Prognóstico , Indução de Remissão , Estudos Retrospectivos , Fatores de Tempo , Adulto Jovem
7.
PLoS One ; 13(1): e0187878, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29293510

RESUMO

The objective of this study was to investigate the safety and the tolerability of combined cellular immunotherapy with low-dose cyclophosphamide (CPA) in patients with advanced solid tumors. This study targeted a novel tumor-associated antigen, ring finger protein 43 (RNF43). Eligible patients were resistant to standard therapy, HLA-A*24:02- or A*02:01-positive and exhibiting high RNF43 expression in their tumor cells. They were administered 300 mg/m2 CPA followed by autologous lymphocytes, preliminarily cultured with autologous RNF43 peptide-pulsed dendritic cells (DCs), RNF43 peptide-pulsed DCs and systemic low dose interleukin-2. The primary endpoint was safety whereas the secondary endpoint was immunological and clinical response to treatment. Ten patients, in total, were enrolled in this trial. Primarily, no adverse events greater than Grade 3 were observed. Six out of 10 patients showed stable disease (SD) on day 49, while 4 other patients showed progressive disease. In addition, one patient with SD exhibited a partial response after the second trial. The frequency of regulatory T cells (Tregs) in patients with SD significantly decreased after CPA administration. The ratio of interferon-γ-producing, tumor-reactive CD8+ T cells increased with time in patients with SD. We successfully showed that the combination of immune cell therapy and CPA was safe, might induce tumor-specific immune responses and clinical efficacy, and was accompanied by a decreased ratio of Tregs in patients with RNF43-positive advanced solid tumors.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Ciclofosfamida/uso terapêutico , Proteínas de Ligação a DNA/química , Imunoterapia , Neoplasias/terapia , Proteínas Oncogênicas/química , Peptídeos/uso terapêutico , Adulto , Idoso , Terapia Combinada , Relação Dose-Resposta a Droga , Estudos de Viabilidade , Feminino , Humanos , Imunofenotipagem , Masculino , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Peptídeos/efeitos adversos , Reação em Cadeia da Polimerase em Tempo Real
8.
Strahlenther Onkol ; 192(6): 386-93, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27169391

RESUMO

AIM: To evaluate the efficacy and toxicity of hypofractionated stereotactic radiotherapy (HSRT) for brain metastases (BMs) from lung cancer, and to explore prognostic factors associated with local control (LC) and indication. PATIENTS AND METHODS: We evaluated patients who were treated with linac-based HSRT for BMs from lung cancer. Lesions treated with stereotactic radiosurgery (SRS) in the same patients during the same periods were analysed and compared with HSRT in terms of LC or toxicity. There were 53 patients with 214 lesions selected for this analysis (HSRT: 76 lesions, SRS: 138 lesions). For HSRT, the median prescribed dose was 35 Gy in 5 fractions. RESULTS: The 1­year LC rate was 83.6 % in HSRT; on multivariate analysis, a planning target volume (PTV) of <4 cm(3), biologically effective dose (BED10) of ≥51 Gy, and adenocarcinoma were significantly associated with better LC. Moreover, in PTVs ≥ 4 cm(3), there was a significant difference in LC between BED10 < 51 Gy and ≥ 51 Gy (p = 0.024). On the other hand, in PTVs < 4 cm(3), both HSRT and SRS had good LC with no significant difference (p = 0.195). Radiation necrosis emerged in 5 of 76 lesions (6.6 %) treated with HSRT and 21 of 138 (15.2 %) lesions treated with SRS (p = 0.064). CONCLUSION: Linac-based HSRT was safe and effective for BMs from lung cancer, and hence might be particularly useful in or near an eloquent area. PTV, BED10, and pathological type were significant prognostic factors. Furthermore, in BMs ≥ 4 cm(3), a dose of BED ≥ 51 Gy should be considered.


Assuntos
Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/secundário , Neoplasias Pulmonares/epidemiologia , Recidiva Local de Neoplasia/prevenção & controle , Hipofracionamento da Dose de Radiação , Radiocirurgia/estatística & dados numéricos , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/epidemiologia , Feminino , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/diagnóstico , Prevalência , Prognóstico , Reprodutibilidade dos Testes , Estudos Retrospectivos , Sensibilidade e Especificidade , Resultado do Tratamento
9.
Cancer Chemother Pharmacol ; 77(5): 1031-8, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-27048413

RESUMO

PURPOSE: Pre-existing interstitial lung disease (pre-ILD) increases the risk of chemotherapy-related lung injury (CRLI). However, whether the risk varies by type of anti-cancer cytotoxic agent in patients with pre-ILD is unknown. In this study, we hypothesized that S-1, an oral fluoropyrimidine agent, is associated with a smaller CRLI risk than docetaxel (DTX) and investigated these agents together with radiological evaluations of pre-ILD via pre-treatment chest computed tomography (CT). METHODS: After reviewing 234 and 352 patients who underwent evaluable chest CT within 6 months prior to the administration of S-1 or DTX, respectively, from January 2006 to October 2014, 60 and 89, respectively, of these patients with pre-ILD were retrospectively analysed. RESULTS: In total, 2 persons administered S-1 (3 %) and 16 treated with DTX (18 %) developed CRLI (p = 0.007) after the initial treatment (mean, 61 days), of whom 1 and 7, respectively, died because of respiratory failure. Pre-treatment CT revealed that 9 S-1-treated patients (16 %) and 15 DTX-treated patients (17 %) had pre-ILD occupying more than 25 % of the lung field. Multivariate analysis demonstrated that DTX administration increased the risk of CRLI by 6.47-fold versus S-1 therapy (p = 0.016). Of note, the area occupied by pre-ILD was also associated with the risk of CRLI (<25 %; odds ratio 0.309, p = 0.045). CONCLUSIONS: Our results indicated that S-1 is associated with a smaller risk of CRLI than DTX. The area occupied by pre-ILD should also be noted when administrating anti-cancer agents.


Assuntos
Antineoplásicos/efeitos adversos , Doenças Pulmonares Intersticiais/tratamento farmacológico , Lesão Pulmonar/induzido quimicamente , Neoplasias Pulmonares/tratamento farmacológico , Ácido Oxônico/efeitos adversos , Taxoides/efeitos adversos , Tegafur/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Docetaxel , Combinação de Medicamentos , Feminino , Humanos , Modelos Logísticos , Doenças Pulmonares Intersticiais/complicações , Doenças Pulmonares Intersticiais/diagnóstico por imagem , Lesão Pulmonar/diagnóstico por imagem , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/diagnóstico por imagem , Masculino , Registros Médicos , Pessoa de Meia-Idade , Ácido Oxônico/administração & dosagem , Ácido Oxônico/uso terapêutico , Valor Preditivo dos Testes , Estudos Retrospectivos , Risco , Taxoides/administração & dosagem , Taxoides/uso terapêutico , Tegafur/administração & dosagem , Tegafur/uso terapêutico , Tomografia Computadorizada por Raios X
10.
Clin Immunol ; 166-167: 48-58, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-27072896

RESUMO

We designed a phase I trial to investigate the safety, immune responses and clinical benefits of a five-peptide cancer vaccine in combination with chemotherapy. Study subjects were patients positive for HLA-A2402 with locally advanced, metastatic, and/or recurrent gastrointestinal, lung or cervical cancer. Eighteen patients including nine cases of colorectal cancer were treated with escalating doses of cyclophosphamide 4days before vaccination. Five HLA-A2402-restricted, tumor-associated antigen (TAA) epitope peptides from KOC1, TTK, URLC10, DEPDC1 and MPHOSPH1 were injected weekly for 4weeks. Treatment was well tolerated without any adverse events above grade 3. Analysis of peripheral blood lymphocytes showed that the number of regulatory T cells dropped from baseline after administration of cyclophosphamide and confirmed that TAA-specific T cell responses were associated significantly with longer overall survival. This phase I clinical trial demonstrated safety and promising immune responses that correlated with vaccine-induced T-cell responses. Therefore, this approach warrants further clinical studies.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Vacinas Anticâncer/imunologia , Ciclofosfamida/imunologia , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Vacinas de Subunidades/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/imunologia , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/efeitos adversos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/imunologia , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Relação Dose-Resposta a Droga , Esquema de Medicação , Epitopos/administração & dosagem , Epitopos/imunologia , Feminino , Antígeno HLA-A24/genética , Antígeno HLA-A24/imunologia , Humanos , Estimativa de Kaplan-Meier , Leucopenia/induzido quimicamente , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Masculino , Pessoa de Meia-Idade , Neoplasias/genética , Peptídeos/administração & dosagem , Peptídeos/imunologia , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Neoplasias Gástricas/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Resultado do Tratamento , Vacinas de Subunidades/administração & dosagem , Vacinas de Subunidades/efeitos adversos
11.
Mol Cancer ; 14: 189, 2015 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-26546412

RESUMO

BACKGROUND: Temozolomide (TMZ) is an oral DNA-alkylating agent used for treating patients with glioblastoma. However, therapeutic benefits of TMZ can be compromised by the expression of O6-methylguanine methyltransferase (MGMT) in tumor tissue. Here we used MGMT-expressing glioblastoma stem cells (GSC) lines as a model for investigating the molecular mechanism underlying TMZ resistance, while aiming to explore a new treatment strategy designed to possibly overcome resistance to the clinically relevant dose of TMZ (35 µM). METHODS: MGMT-expressing GSC cultures are resistant to TMZ, and IC50 (half maximal inhibitory concentration) is estimated at around 500 µM. Clonogenic GSC surviving 500 µM TMZ (GSC-500 µM TMZ), were isolated. Molecular signatures were identified via comparative analysis of expression microarray against parental GSC (GSC-parental). The recombinant protein of top downregulated signature was used as a single agent or in combination with TMZ, for evaluating therapeutic effects of treatment of GSC. RESULTS: The molecular signatures characterized an activation of protective stress responses in GSC-500 µM TMZ, mainly including biotransformation/detoxification of xenobiotics, blocked endoplasmic reticulum stress-mediated apoptosis, epithelial-to-mesenchymal transition (EMT), and inhibited growth/differentiation. Bone morphogenetic protein 7 (BMP7) was identified as the top down-regulated gene in GSC-500 µM TMZ. Although augmenting BMP7 signaling in GSC by exogenous BMP7 treatment did not effectively stop GSC growth, it markedly sensitized both GSC-500 µM TMZ and GSC-parental to 35 µM TMZ treatment, leading to loss of self-renewal and migration capacity. BMP7 treatment induced senescence of GSC cultures and suppressed mRNA expression of CD133, MGMT, and ATP-binding cassette drug efflux transporters (ABCB1, ABCG2), as well as reconfigured transcriptional profiles in GSC by downregulating genes associated with EMT/migration/invasion, stemness, inflammation/immune response, and cell proliferation/tumorigenesis. BMP7 treatment significantly prolonged survival time of animals intracranially inoculated with GSC when compared to those untreated or treated with TMZ alone (p = 0.0017), whereas combination of two agents further extended animal survival compared to BMP7 alone (p = 0.0489). CONCLUSIONS: These data support the view that reduced endogenous BMP7 expression/signaling in GSC may contribute to maintained stemness, EMT, and chemoresistant phenotype, suggesting that BMP7 treatment may provide a novel strategy in combination with TMZ for an effective treatment of glioblastoma exhibiting unmethylated MGMT.


Assuntos
Proteína Morfogenética Óssea 7/metabolismo , Metilases de Modificação do DNA/metabolismo , Dacarbazina/análogos & derivados , Glioblastoma/enzimologia , Glioblastoma/metabolismo , Guanina/análogos & derivados , Células-Tronco Neoplásicas/enzimologia , Antineoplásicos Alquilantes , Proteína Morfogenética Óssea 7/genética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Metilases de Modificação do DNA/genética , Dacarbazina/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Glioblastoma/genética , Guanina/metabolismo , Humanos , Células-Tronco Neoplásicas/metabolismo , Temozolomida , Células Tumorais Cultivadas
12.
PLoS One ; 10(10): e0140437, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26460792

RESUMO

INTRODUCTION: This study investigated the clinical characteristics and predictive factors for developing acute extended radiation pneumonitis with a focus on the presence and radiological characteristics of preexisting interstitial lung disease. METHODS: Of 1429 irradiations for lung cancer from May 2006 to August 2013, we reviewed 651 irradiations involving the lung field. The presence, compatibility with usual interstitial pneumonia, and occupying area of preexisting interstitial lung disease were retrospectively evaluated by pretreatment computed tomography. Cases of non-infectious, non-cardiogenic, acute respiratory failure with an extended bilateral shadow developing within 30 days after the last irradiation were defined as acute extended radiation pneumonitis. RESULTS: Nine (1.4%) patients developed acute extended radiation pneumonitis a mean of 6.7 days after the last irradiation. Although preexisting interstitial lung disease was found in 13% of patients (84 patients), 78% of patients (7 patients) with acute extended radiation pneumonitis cases had preexisting interstitial lung disease, which resulted in incidences of acute extended radiation pneumonitis of 0.35 and 8.3% in patients without and with preexisting interstitial lung disease, respectively. Multivariate logistic analysis indicated that the presence of preexisting interstitial lung disease (odds ratio = 22.6; 95% confidence interval = 5.29-155; p < 0.001) and performance status (≥2; odds ratio = 4.22; 95% confidence interval = 1.06-20.8; p = 0.049) were significant predictive factors. Further analysis of the 84 patients with preexisting interstitial lung disease revealed that involvement of more than 10% of the lung field was the only independent predictive factor associated with the risk of acute extended radiation pneumonitis (odds ratio = 6.14; 95% confidence interval = 1.0-37.4); p = 0.038). CONCLUSIONS: Pretreatment computed tomography evaluations of the presence of and area size occupied by preexisting interstitial lung disease should be assessed for safer irradiation of areas involving the lung field.


Assuntos
Doenças Pulmonares Intersticiais/complicações , Neoplasias Pulmonares/complicações , Pneumonite por Radiação/etiologia , Doença Aguda , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Modelos Logísticos , Doenças Pulmonares Intersticiais/diagnóstico por imagem , Neoplasias Pulmonares/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Pneumonite por Radiação/diagnóstico por imagem , Radiografia Torácica , Estudos Retrospectivos , Tomografia Computadorizada por Raios X
13.
BMC Cancer ; 15: 589, 2015 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-26275617

RESUMO

BACKGROUND: Magnetic resonance imaging (MRI) enables a more sensitive detection of brain metastasis and stereotactic irradiation (SRI) efficiently controls brain metastasis. In limited-stage small cell lung cancer (LS-SCLC), prophylactic cranial irradiation (PCI) in patients with good responses to initial treatment is recommended based on the survival benefit shown in previous clinical trials. However, none of these trials evaluated PCI effects using the management of brain metastasis with MRI or SRI. This study aimed to determine the effects of MRI and SRI on the benefits of PCI in patients with LS-SCLC. METHODS: The clinical records of pathologically proven SCLC from January 2006 to June 2013 in facilities equipped with or had access to SRI in Japan were retrospectively reviewed. Patients with LS-SCLC and complete or good partial responses after initial treatment were included in the study and analyzed by the Kaplan-Meier method. RESULTS: Of 418 patients with SCLC, 124 met criteria and were divided into patients receiving PCI (PCI group; n = 29) and those without PCI (non-PCI groups; n = 95). At baseline, ratios of patients with stage III were significantly advantageous for the non-PCI group, although younger age and high ratios of complete response and MRI confirmed absence of brain metastasis were advantageous for the PCI group. Neither median survival times (25 vs. 34 months; p = 0.256) nor cumulative incidence of brain metastasis during 2 years (45.5 vs. 30.8%; p = 0.313) significantly differed between the two groups. Moreover, these factors did not significantly differ among patients with stage III disease (25 vs. 26 months; p = 0.680, 42.3 vs. 52.3%; p = 0.458, respectively). CONCLUSION: PCI may be less beneficial in patients with LS-SCLC if the management with MRI and SRI is available.


Assuntos
Neoplasias Encefálicas/cirurgia , Irradiação Craniana/métodos , Neoplasias Pulmonares/cirurgia , Imagem por Ressonância Magnética/métodos , Radiocirurgia/métodos , Carcinoma de Pequenas Células do Pulmão/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/secundário , Gerenciamento Clínico , Feminino , Humanos , Japão , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Carcinoma de Pequenas Células do Pulmão/patologia , Análise de Sobrevida , Resultado do Tratamento
14.
Radiother Oncol ; 110(3): 546-52, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24560766

RESUMO

PURPOSE: To seek for the possible factors influencing overall survival (OS) with radiotherapy (RT) for biliary tract cancer. MATERIALS AND METHODS: Data were collected retrospectively from RT database of 31 institutions in Japan. All patients underwent at least external beam RT. The factors influencing OS were investigated. RESULTS: Data of 498 patients were analyzed. Median OS of the 212 patients who underwent surgery was significantly better than that of the 286 patients without surgery (31 vs. 15 months, p<0.001). The OS for the R0 or R1 resection group was significantly longer than that for the R2 or non-surgery group, as well as for n0 compared to n1 (all p<0.001). Chemoradiotherapy (CRT), both sequential and concurrent, resulted in a better OS than RT alone for the n1 group (31 vs. 13 months, p<0.001), and marginally better for the R0/R1 group (p=0.065; p=0.054 for concurrent CRT). However, no such benefit was observed for the R2/non-surgical patients. Multivariate analysis identified performance status, clinical stage, and surgery as significant factors. CONCLUSION: Surgery, especially R0/R1 resection, seemed as the gold standard for treatment of biliary tract cancer including RT, even in the highly heterogeneous population obtained from the multicenter retrospective study. The possibility was shown that CRT yielded better survival benefit especially for n1 patients. We recommend that future prospective trials include an arm of adjuvant CRT at least for n1 and possibly R0/R1 patients.


Assuntos
Neoplasias do Sistema Biliar/radioterapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Sistema Biliar/mortalidade , Quimiorradioterapia , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
15.
PLoS One ; 8(11): e80397, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24260384

RESUMO

Glioblastoma stem cells (GSC) are a significant cell model for explaining brain tumor recurrence. However, mechanisms underlying their radiochemoresistance remain obscure. Here we show that most clonogenic cells in GSC cultures are sensitive to radiation treatment (RT) with or without temozolomide (TMZ). Only a few single cells survive treatment and regain their self-repopulating capacity. Cells re-populated from treatment-resistant GSC clones contain more clonogenic cells compared to those grown from treatment-sensitive GSC clones, and repeated treatment cycles rapidly enriched clonogenic survival. When compared to sensitive clones, resistant clones exhibited slower tumor development in animals. Upregulated genes identified in resistant clones via comparative expression microarray analysis characterized cells under metabolic stress, including blocked glucose uptake, impaired insulin/Akt signaling, enhanced lipid catabolism and oxidative stress, and suppressed growth and inflammation. Moreover, many upregulated genes highlighted maintenance and repair activities, including detoxifying lipid peroxidation products, activating lysosomal autophagy/ubiquitin-proteasome pathways, and enhancing telomere maintenance and DNA repair, closely resembling the anti-aging effects of caloric/glucose restriction (CR/GR), a nutritional intervention that is known to increase lifespan and stress resistance in model organisms. Although treatment-introduced genetic mutations were detected in resistant clones, all resistant and sensitive clones were subclassified to either proneural (PN) or mesenchymal (MES) glioblastoma subtype based on their expression profiles. Functional assays demonstrated the association of treatment resistance with energy stress, including reduced glucose uptake, fatty acid oxidation (FAO)-dependent ATP maintenance, elevated reactive oxygen species (ROS) production and autophagic activity, and increased AMPK activity and NAD(+) levels accompanied by upregulated mRNA levels of SIRT1/PGC-1α axis and DNA repair genes. These data support the view that treatment resistance may arise from quiescent GSC exhibiting a GR-like phenotype, and suggest that targeting stress response pathways of resistant GSC may provide a novel strategy in combination with standard treatment for glioblastoma.


Assuntos
Adaptação Fisiológica/genética , Resistencia a Medicamentos Antineoplásicos/genética , Glioblastoma/genética , Glioblastoma/metabolismo , Glucose/metabolismo , Células-Tronco/metabolismo , Estresse Fisiológico/genética , Linhagem Celular Tumoral , Reparo do DNA/genética , Dacarbazina/análogos & derivados , Dacarbazina/farmacologia , Expressão Gênica/genética , Glioblastoma/tratamento farmacológico , Glioblastoma/radioterapia , Humanos , Transdução de Sinais/genética , Temozolomida , Regulação para Cima/genética
16.
PLoS One ; 8(10): e77416, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24124617

RESUMO

Tumours defined as Ewing sarcoma (ES) constitute a group of highly malignant neoplasms that most often affect children and young adults in the first 2 decades of life. The EWS/Fli-1 fusion gene, a product of the translocation t(11;22) (q24; 12), is detected in 95% of ES patients. Recently, it was validated that cells emit a heterogeneous mixture of vesicular, organelle-like structures (microvesicles, MVs) into their surroundings including blood and body fluids, and that these MVs contain a selected set of tumor-related proteins and high levels of mRNAs and miRNAs. In this present study, we detected the Ewing sarcoma-specific EWS/Fli-1 mRNA in MVs from the culture medium of ES cell lines carrying t(11;22) (q24; 12). Also, we detected this fusion gene in approximately 40% of the blood samples from mice inoculated with xenografts of TC135 or A673 cells. These findings indicate the EWS/Fli-1 mRNA in MVs might be a new non-invasive diagnostic marker for specific cases of Ewing sarcoma.


Assuntos
Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Proteína Proto-Oncogênica c-fli-1/genética , Proteína Proto-Oncogênica c-fli-1/metabolismo , RNA Mensageiro/metabolismo , Proteína EWS de Ligação a RNA/genética , Proteína EWS de Ligação a RNA/metabolismo , Sarcoma de Ewing/genética , Sarcoma de Ewing/metabolismo , Vesículas Secretórias/metabolismo , Animais , Sequência de Bases , Transporte Biológico , Linhagem Celular Tumoral , Modelos Animais de Doenças , Espaço Extracelular/metabolismo , Xenoenxertos , Humanos , Camundongos , Proteínas de Fusão Oncogênica/química , Proteína Proto-Oncogênica c-fli-1/química , RNA Mensageiro/química , Proteína EWS de Ligação a RNA/química
17.
J Clin Invest ; 123(2): 600-10, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23281395

RESUMO

Clear cell sarcoma (CCS) is an aggressive soft tissue malignant tumor characterized by a unique t(12;22) translocation that leads to the expression of a chimeric EWS/ATF1 fusion gene. However, little is known about the mechanisms underlying the involvement of EWS/ATF1 in CCS development. In addition, the cellular origins of CCS have not been determined. Here, we generated EWS/ATF1-inducible mice and examined the effects of EWS/ATF1 expression in adult somatic cells. We found that forced expression of EWS/ATF1 resulted in the development of EWS/ATF1-dependent sarcomas in mice. The histology of EWS/ATF1-induced sarcomas resembled that of CCS, and EWS/ATF1-induced tumor cells expressed CCS markers, including S100, SOX10, and MITF. Lineage-tracing experiments indicated that neural crest-derived cells were subject to EWS/ATF1-driven transformation. EWS/ATF1 directly induced Fos in an ERK-independent manner. Treatment of human and EWS/ATF1-induced CCS tumor cells with FOS-targeted siRNA attenuated proliferation. These findings demonstrated that FOS mediates the growth of EWS/ATF1-associated sarcomas and suggest that FOS is a potential therapeutic target in human CCS.


Assuntos
Fator 1 Ativador da Transcrição/genética , Proteína EWS de Ligação a RNA/genética , Sarcoma de Células Claras/genética , Animais , Sequência de Bases , Linhagem Celular Tumoral , Linhagem da Célula/genética , Proliferação de Células , Expressão Gênica , Fusão Gênica , Genes fos , Humanos , Camundongos , Camundongos Transgênicos , Crista Neural/patologia , Proteínas de Fusão Oncogênica/genética , RNA Interferente Pequeno/genética , Sarcoma de Células Claras/etiologia , Sarcoma de Células Claras/patologia , Fatores de Transcrição/genética
18.
Shinrigaku Kenkyu ; 82(6): 547-53, 2012 Feb.
Artigo em Japonês | MEDLINE | ID: mdl-22514907

RESUMO

The purpose of this study was to improve the Japanese version of the Television Affinity Scale (TAS), and to examine the relationship between affinity for television and viewing behavior. Data was based on a random sample of 552 people in Hachioji City (Tokyo, Japan); the response rate was 55.2%. The results revealed the following: (a) the TAS 6-item version had sufficient reliability and validity, (b) the TAS provided information which could not be explained directly by demographic factors, and (c) affinity for television was positively correlated with unplanned and non-concentrated television viewing. These results are consistent with the findings of Erikawa, Yamada, Kawabata, and Numazaki (2007). In addition, the TAS scores correlated positively with entertainment program viewing. This is consistent with the findings of Rubin (1984) that television affinity correlated with ritualized television viewing. The implications of these results for contemporary television viewing are discussed.


Assuntos
Atitude , Televisão , Adulto , Idoso , Feminino , Hábitos , Humanos , Masculino , Pessoa de Meia-Idade , Distribuição Aleatória , Inquéritos e Questionários , Tóquio
19.
Circ Heart Fail ; 5(2): 274-85, 2012 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-22343033

RESUMO

BACKGROUND: We investigated the effects of asialoerythropoietin (asialoEPO), a nonerythrogenic erythropoietin derivative, on 3 murine models of heart failure with different etiologies. METHODS AND RESULTS: Doxorubicin (15 mg/kg) induced heart failure within 2 weeks (toxic cardiomyopathy). Treatment with asialoEPO (6.9 µg/kg) for 2 weeks thereafter attenuated the associated left ventricular dysfunction and dilatation. In addition, the asialoEPO-treated heart showed less myocardial fibrosis, inflammation, and oxidative damage, and diminished atrophic cardiomyocyte degeneration, which was accompanied by restored expression of GATA-4 and sarcomeric proteins. Mice with large 6-week-old myocardial infarctions exhibited marked left ventricular dysfunction with adverse remodeling (ischemic cardiomyopathy). AsialoEPO treatment for 4 weeks significantly mitigated progression of the dysfunction and remodeling and reduced myocardial fibrosis, inflammation, and oxidative damage. Finally, 25-week-old δ-sarcoglycan-deficient mice (genetic cardiomyopathy) were treated with asialoEPO for 5 weeks. AsialoEPO mitigated the progressive cardiac remodeling and dysfunction through cardiomyocyte hypertrophy, and upregulated expression of GATA-4 and sarcomeric proteins. AsialoEPO appears to act by altering the activity of the downstream erythropoietin receptor signals extracellular signal-regulated protein kinase, Akt, signal transducer, and activator of transcription 3 and 5 in a model-specific manner. CONCLUSIONS: The findings suggest that asialoEPO exerts broad cardioprotective effects through distinct mechanisms depending on the model, which are independent of the erythrogenic action. This compound may be promising for the treatment of heart failure of various etiologies.


Assuntos
Assialoglicoproteínas/uso terapêutico , Eritropoetina/análogos & derivados , Insuficiência Cardíaca/tratamento farmacológico , Função Ventricular Esquerda/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos , Animais , Assialoglicoproteínas/administração & dosagem , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Eritropoetina/administração & dosagem , Eritropoetina/uso terapêutico , Seguimentos , Insuficiência Cardíaca/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Resultado do Tratamento , Função Ventricular Esquerda/fisiologia
20.
Nihon Kokyuki Gakkai Zasshi ; 49(9): 692-6, 2011 Sep.
Artigo em Japonês | MEDLINE | ID: mdl-22073617

RESUMO

A 65-year-old man who had suffered from traumatic spinal cord injury had chronic lumbar pain. He had exacerbation of lumbar pain and intermittent fever and consulted several doctors, but the cause of the lumbar pain was unknown. An orthopedic specialist took an MRI. Spinal MRI showed increased signal intensity at the level of T10-11 and a mass in his right lower lung field, so he was referred to our hospital. Two transbronchial lung biopsy procedures failed to obtain malignant cells. CT guided biopsy showed fibrous and hyalinizing tissue contained plasma cells and lyphocytes. Staphylococcus aureus was cultured from the second bronchial lavage fluids of brush and blood cultures, so we began administration of ampicillin-sulbactam. Avoiding threatened or actual cord compression due to collapse resulting from spinal instability, posterior fusion with instrumentation was done through the back of his chest wall. At once, bone biopsy was done, and showed no malignant cells. As soon as antibacterial treatment was stopped after the operation, he had bloody sputa and fever. The antibacterial agent was resumed and the symptoms improved. The mass decreased in size and lumbar pain improved gradually, so we concluded the diagnosis was pyogenic spondylitis caused by S. aureus. After about 5 months of antibacterial treatment, the tumor substantially diminished.


Assuntos
Neoplasias da Medula Espinal/diagnóstico , Neoplasias da Medula Espinal/secundário , Espondilite/diagnóstico , Infecções Estafilocócicas/diagnóstico , Idoso , Antibacterianos/uso terapêutico , Diagnóstico Diferencial , Humanos , Neoplasias Pulmonares/patologia , Masculino , Espondilite/tratamento farmacológico , Infecções Estafilocócicas/tratamento farmacológico , Supuração
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