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1.
Ann Oncol ; 29(5): 1220-1226, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29438463

RESUMO

Background: Paclitaxel is currently only available as an intravenous (i.v.) formulation. DHP107 is a novel oral formulation of lipid ingredients and paclitaxel. DHP107 demonstrated comparable efficacy, safety, and pharmacokinetics to i.v. paclitaxel as a second-line therapy in patients with advanced gastric cancer (AGC). DREAM is a multicenter, open-label, prospective, randomized phase III study of patients with histologically/cytologically confirmed, unresectable/recurrent AGC after first-line therapy failure. Methods and materials: Patients were randomized 1 : 1 to DHP107 (200 mg/m2 orally twice daily days 1, 8, 15 every 4 weeks) or i.v. paclitaxel (175 mg/m2 day 1 every 3 weeks). Patients were stratified by Eastern Cooperative Oncology Group performance status, disease status, and prior treatment; response was assessed (Response Evaluation Criteria in Solid Tumors) every 6 weeks. Primary end point: non-inferiority of progression-free survival (PFS); secondary end points: overall response rate (ORR), overall survival (OS), and safety. For the efficacy analysis, sequential tests for non-inferiority were carried out, first with a non-inferiority margin of 1.48, then with a margin of 1.25. Results: Baseline characteristics were balanced in the 236 randomized patients (n = 118 per arm). Median PFS (per-protocol) was 3.0 (95% CI 1.7-4.0) months for DHP107 and 2.6 (95% CI 1.8-2.8) months for paclitaxel (hazard ratio [HR] = 0.85; 95% CI 0.64-1.13). A sensitivity analysis on PFS using independent central review showed similar results (HR = 0.93; 95% CI 0.70-1.24). Median OS (full analysis set) was 9.7 (95% CI 7.1 - 11.5) months for DHP107 versus 8.9 (95% CI 7.1-12.2) months for paclitaxel (HR = 1.04; 95% CI 0.76-1.41). ORR was 17.8% for DHP107 (CR 4.2%; PR 13.6%) versus 25.4% for paclitaxel (CR 3.4%; PR 22.0%). Nausea, vomiting, diarrhea, and mucositis were more common with DHP107; peripheral neuropathy was more common with paclitaxel. There were only few Grade≥3 adverse events, most commonly neutropenia (42% versus 53%); febrile neutropenia was reported infrequently (5.9% versus 2.5%). No hypersensitivity reactions occurred with DHP107 (paclitaxel 2.5%). Conclusions: DHP107 as a second-line treatment of AGC was non-inferior to paclitaxel for PFS; other efficacy and safety parameters were comparable. DHP107 is the first oral paclitaxel with proven efficacy/safety for the treatment of AGC. ClinicalTrials.gov: NCT01839773.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Recidiva Local de Neoplasia/tratamento farmacológico , Paclitaxel/administração & dosagem , Neoplasias Gástricas/tratamento farmacológico , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Intervalo Livre de Doença , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Critérios de Avaliação de Resposta em Tumores Sólidos , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Análise de Sobrevida
2.
Andrologia ; 50(3)2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29110315

RESUMO

NAD(P)H-quinone oxidoreductase 1 (NQO1) is a highly inducible flavoprotein known to involve in various cellular defence mechanisms. In this study, we explored whether NQO1 deletion affects hormone-induced prostatic hyperplasia. Testosterone propionate (3 mg/kg, IP) was injected into wild-type (WT) and NOQ1 knockout C57BL/6 mice (NQO1-/- ) for 14 consecutive days, and the samples were collected for biological and histochemical studies. The testosterone-treated NQO1-/- showed about 140% higher prostate weight than the testosterone-treated WT, with enhanced connective tissue and hyperplastic glands formations. However, increased dihydrotestosterone level after testosterone treatment was not significantly different between the WT and NQO1-/- . In contrast, the enhanced nuclear expression of proliferating cell nuclear antigen in NQO1-/- prostate confirmed aggravated prostatic hyperplasia in NQO1-/- . Moreover, the expression of heat shock protein (HSP) 90-α was markedly increased in the NQO1-/- , and this was supported by increased testosterone-induced nuclear androgen receptor expression in NQO1-silenced LNCaP cells. Testosterone-induced prostate-specific antigen expression was not reversed in NOQ1-silenced cells after finasteride treatment. Although the exact role of NQO1 in prostatic hyperplasia remains unclear, the hyperplasia exacerbation due to NQO1 deletion might be independent of type 2 5α-reductase and might be related to enhanced androgen receptor affinity due to enhanced HSP90-α expression.


Assuntos
Di-Hidrotestosterona/sangue , NAD(P)H Desidrogenase (Quinona)/genética , Próstata/metabolismo , Hiperplasia Prostática/genética , Testosterona/sangue , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/genética , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/metabolismo , Animais , Linhagem Celular Tumoral , Proteínas de Choque Térmico HSP90/genética , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Masculino , Camundongos , Camundongos Knockout , NAD(P)H Desidrogenase (Quinona)/metabolismo , Próstata/efeitos dos fármacos , Hiperplasia Prostática/induzido quimicamente , Hiperplasia Prostática/metabolismo , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Propionato de Testosterona
3.
Skin Res Technol ; 22(3): 276-83, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26346687

RESUMO

BACKGROUND: Dark circles refer to a symptom that present darkness under the eyes. Because of improvement in the quality of life, the dark circles have been recognized as one of major cosmetic concerns. However, it is not easy to classify the dark circles because they have various causes. METHODS: To select suitable instruments and detailed evaluation items, the dark circles were classified according to the causes through visual assessment, Wood's lamp test, and medical history survey for 100 subjects with dark circles. After the classification, were newly recruited for instrument conformity assessment. Through this, suitable instruments for dark circle evaluation were selected. We performed a randomized clinical trial for dark circles, a placebo-controlled double-blind study, using effective parameters of the instruments selected from the preliminary test. RESULTS: Dark circles of vascular type (35%) and mixed type (54%), a combination of pigmented and vascular types, were the most common. Twenty four subjects with the mixed type dark circles applied the test product (Vitamin C 3%, Vitamin A 0.1%, Vitamin E 0.5%) and placebo on randomized split-face for 8 weeks. The effective parameters (L*, a, M.I., E.I., quasi L*, quasi a* and dermal thickness) were measured during the study period. Result showed that the L* value of Chromameter(®) , Melanin index (M.I.) of Mexameter(®) and quasi L* value obtained by image analysis improved with statistical significance after applying the test product compared with the placebo product. CONCLUSION: We classified the dark circles according to the causes of the dark circles and verified the reliability of the parameter obtained by the instrument conformity assessment used in this study through the efficacy evaluation. Also based on this study, we were to suggest newly established methods which can be applied to the evaluation of efficacy of functional cosmetics for dark circles.


Assuntos
Colorimetria/métodos , Dermoscopia/métodos , Doenças Palpebrais/classificação , Doenças Palpebrais/diagnóstico , Pálpebras/anormalidades , Hiperpigmentação/classificação , Hiperpigmentação/diagnóstico , Anamnese/métodos , Exame Físico/métodos , Adulto , Diagnóstico Diferencial , Técnicas de Diagnóstico Oftalmológico , Método Duplo-Cego , Dermatoses Faciais/classificação , Dermatoses Faciais/diagnóstico , Feminino , Humanos , Pessoa de Meia-Idade , Variações Dependentes do Observador , Efeito Placebo , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Adulto Jovem
4.
Ann Oncol ; 26(10): 2097-101, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26216386

RESUMO

BACKGROUND: Five-weekly S-1 plus cisplatin (SP5) is one of the standard first-line regimens for advanced gastric cancer (GC), proven in a Japanese phase III study. To enhance the dose intensity of cisplatin, 3-weekly S-1 plus cisplatin (SP3) was developed. PATIENTS AND METHODS: This multicenter, randomized, open-label, phase III study evaluated whether SP3 (S-1 80 mg/m(2)/day on days 1-14 and cisplatin 60 mg/m(2) on day 1) was noninferior/superior to SP5 (S-1 80-120 mg/day on days 1-21 and cisplatin 60 mg/m(2) on day 1 or 8) in terms of progression-free survival (PFS). Chemotherapy-naive patients with metastatic, recurrent gastric or gastroesophageal junction adenocarcinoma were randomized 1 : 1 to receive either SP3 or SP5. The trial is registered at ClinicalTrials.gov (NCT00915382). RESULTS: Between February 2009 and January 2012, 625 patients were randomized at 42 sites in Korea and Japan. With a median follow-up duration of 32.4 months (range, 13.3-48.6 months) in surviving patients, SP3 was not only noninferior but also superior to SP5 in terms of PFS [median 5.5 versus 4.9 months; hazard ratio (HR) = 0.82; 95% confidence interval (CI) 0.68-0.99; P = 0.0418 for superiority). There was no difference in overall survival (OS) between the groups (median 14.1 versus 13.9 months; HR = 0.99; 95% CI 0.81-1.21; P = 0.9068). In patients with measurable disease, the response rates were 60% in the SP3 arm and 50% in the SP5 arm (P = 0.065). Both regimens were generally well tolerated, but grade 3 or higher anemia (19% versus 9%) and neutropenia (39% versus 9%) were more frequent in SP3. CONCLUSIONS: SP3 is superior to SP5 in terms of PFS. However, since the improvement in PFS was only slight and there was no difference in OS, both SP3 and SP5 can be recommended as first-line treatments for patients with advanced GC.


Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Gástricas/tratamento farmacológico , Adenocarcinoma/mortalidade , Adenocarcinoma/secundário , Cisplatino/administração & dosagem , Esquema de Medicação , Combinação de Medicamentos , Seguimentos , Humanos , Metástase Linfática , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Ácido Oxônico/administração & dosagem , Prognóstico , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Taxa de Sobrevida , Tegafur/administração & dosagem
5.
Ann Oncol ; 25(11): 2272-2277, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25149706

RESUMO

BACKGROUND: An exploratory translational analysis was conducted as part of a phase II study of dovitinib to assess the relevance of soluble serum proteins and circulating tumor (ct) DNA (ctDNA) as biomarkers in patients with tyrosine kinase inhibitor (TKI)-refractory gastrointestinal stromal tumors (GISTs). PATIENTS AND METHODS: Predose serum samples were collected from 30 patients on day 1 of cycle 1 and cycle 2. Serum levels of angiogenesis-related proteins were assessed by enzyme-linked immunosorbent assay, and Beads, emulsions, amplification, and magnetics (BEAMing) assays were carried out to detect mutations in serum ctDNA. RESULTS: Dovitinib increased vascular endothelial growth factor (VEGF)165 (1.26-fold, P = 0.006), VEGF-A (1.27-fold, P = 0.004), placental growth factor (6.0-fold, P = 0.002), fibroblast growth factor 23 (1.45-fold, P = 0.02), and interleukin 8 (1.75-fold, P = 0.04) levels, and decreased soluble vascular endothelial growth factor receptor (sVEGFR)-2 levels (0.8-fold, P = 0.001). The changes in sVEGFR-2 were significantly associated with metabolic response determined by positron emission tomography (P = 0.02) and progression-free survival (PFS; P = 0.02). Secondary kinase mutations were identified in the ctDNA of 11 patients (41%), and these patients all had mutations involving KIT exon 17. Patients with secondary KIT mutations had significantly worse overall survival {median, 5.5 months [95% confidence interval (CI) 3.8-7.2 months]} than those with no detectable secondary mutations [9.8 months (95% CI 9.6-10.0 months); hazard ratio = 2.7 (95% CI 1.0-7.3); P = 0.047]. CONCLUSIONS: Changes in sVEGFR-2 levels were associated with dovitinib-mediated antitumor activity. Genotyping of serum ctDNA with BEAMing is useful for the identification of resistant mutations potentially associated with poor prognosis in patients with GISTs.


Assuntos
Benzimidazóis/administração & dosagem , Biomarcadores Tumorais/sangue , Tumores do Estroma Gastrointestinal/sangue , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Quinolonas/administração & dosagem , Adulto , Idoso , DNA de Neoplasias/sangue , DNA de Neoplasias/genética , Intervalo Livre de Doença , Feminino , Tumores do Estroma Gastrointestinal/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Células Neoplásicas Circulantes/patologia , Inibidores de Proteínas Quinases/administração & dosagem , Proteínas Proto-Oncogênicas B-raf/sangue , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas c-kit/sangue , Proteínas Proto-Oncogênicas c-kit/genética , Receptor beta de Fator de Crescimento Derivado de Plaquetas/sangue , Receptor beta de Fator de Crescimento Derivado de Plaquetas/genética , Fator A de Crescimento do Endotélio Vascular/sangue , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/sangue
6.
Tissue Antigens ; 84(4): 398-404, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25155097

RESUMO

Lesions of Behçet's disease (BD) show vascular infiltrates of immune cells expressing integrins. ß2 integrins (CD11/CD18) play a major role in cell migration to the inflammatory lesion and also induce cytokine production. Thus, genetic polymorphisms of CD11/CD18 may be associated with the pathogenesis of BD. In this study, nine single nucleotide polymorphisms (SNPs) of the CD11a, CD11c, and CD18 were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and haplotype analysis in 305 BD patients and 266 healthy controls. The frequencies of genotype rs11574944 CC and haplotype rs11574944C-rs2230433G-rs8058823A in CD11a were significantly lower in BD patients. The frequencies of genotype rs2230429 CC, rs2929 GG, and haplotype rs2230429C-rs2929G in CD11c were higher in BD patients. The frequencies of genotype rs235326CC and haplotype rs2070946A-rs235326C-rs760456G-rs684G in CD18 were significantly higher in the BD patients than in the controls. Other SNPs in CD11a, CD11c, and CD18 gene were not significantly different. Therefore, the major genotype and haplotype of CD11a/CD18 may play a role in decreasing the susceptibility of BD, whereas the major genotype and haplotype of CD11c/CD18 may play a role in increasing the susceptibility of BD.


Assuntos
Síndrome de Behçet/genética , Antígeno CD11a/genética , Antígeno CD11c/genética , Antígenos CD18/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Povo Asiático , Frequência do Gene , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , República da Coreia
7.
Skin Res Technol ; 20(4): 422-8, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24506419

RESUMO

BACKGROUND: Long-term exposure to sunlight changes skin features like amount of facial wrinkling and skin elasticity, which is useful in estimating skin health and age-related changes. Skin elasticity is evaluated by quantitative methods such as the noninvasive suction device Cutometer(®) , which is widely used to evaluate regional body-elasticity differences and correlate these findings with the results of other instrumental data. Few field studies have been done with the Ballistometer(®) device, another noninvasive method for measuring skin elasticity. METHOD: In this study, we measured the skin elasticity of each subject's forehead, cheek, and volar forearm using two devices with different means of obtaining quantitative measurements - Ballistometer(®) (Diastron Ltd.) and Cutometer(®) (CK electronics). RESULTS: The results from testing with the Ballistometer(®) and Cutometer(®) devices showed that the degree of skin elasticity of the volar forearm is greater than those found on the cheek and forehead. The parameters measured by the Ballistometer(®) showed high correlation patterns. On the cheek skin, the correlation coefficient between Ballisto-parameters and R parameters (R0, R3, R8) was higher than other skin sites. CONCLUSION: Taken together, R parameters measured by the Cutometer(®) device have been widely distributed in the evaluation of skin elasticity in research and cosmetics. Although the methodologies are different, the Ballistometer(®) device is also a useful tool to evaluate skin elasticity.


Assuntos
Módulo de Elasticidade/fisiologia , Testes de Dureza/instrumentação , Manometria/instrumentação , Estimulação Física/instrumentação , Fenômenos Fisiológicos da Pele , Adulto , Desenho de Equipamento , Análise de Falha de Equipamento , Feminino , Humanos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Estresse Mecânico
8.
Ann Oncol ; 24(6): 1567-73, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23406728

RESUMO

BACKGROUND: PEP02 is a novel highly stable liposomal nanocarrier formulation of irinotecan. This randomized phase II study evaluated the efficacy and safety of single agent PEP02 compared with irinotecan or docetaxel in the second-line treatment of advanced oesophago-gastric (OG) cancer. PATIENTS AND METHODS: Patients with locally advanced/metastatic disease who had failed one prior chemotherapy regimen were randomly assigned to PEP02 120 mg/m(2), irinotecan 300 mg/m(2) or docetaxel (Taxotere) 75 mg/m(2) every 3 weeks. The primary end point was objective response rate (ORR). Simon's two-stage design was used and the ORR of interest was 20% (α = 0.05, type II error ß = 0.10, null hypothesis of ORR was 5%). RESULTS: Forty-four patients per arm received treatment, and 124 were assessable for response. The ORR statistical threshold for the first stage was reached in all arms. In the intent-to-treat (ITT) population, ORRs were 13.6% (6/44), 6.8% (3/44) and 15.9% (7/44) in the PEP02, irinotecan and docetaxel arms, respectively. The median progression-free survival (PFS) and overall survival were similar between the trial arms. Commonest grade 3-4 adverse event reported was diarrhoea in the PEP02 and irinotecan groups (27.3% versus 18.2%). CONCLUSION: The ORR associated with PEP02 was comparable with docetaxel and numerically greater than that of irinotecan. PEP02 warrants further evaluation in the advanced gastric cancer setting.


Assuntos
Adenocarcinoma/tratamento farmacológico , Camptotecina/análogos & derivados , Portadores de Fármacos/administração & dosagem , Neoplasias Esofágicas/tratamento farmacológico , Junção Esofagogástrica/patologia , Neoplasias Gástricas/tratamento farmacológico , Taxoides/administração & dosagem , Adenocarcinoma/diagnóstico , Adenocarcinoma/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Camptotecina/administração & dosagem , Docetaxel , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/mortalidade , Junção Esofagogástrica/efeitos dos fármacos , Feminino , Humanos , Irinotecano , Masculino , Pessoa de Meia-Idade , Nanocápsulas/administração & dosagem , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/mortalidade , Taxa de Sobrevida/tendências
9.
Ann Oncol ; 24(2): 489-494, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23110809

RESUMO

BACKGROUND: We evaluated whether complementary and alternative medicine (CAM) use influenced outcomes [survival and health-related quality of life (HRQOL)] of cancer patients whose condition had just been judged terminal. PATIENTS AND METHODS: From July 2005 to October 2006, we conducted a prospective cohort study of 481 terminally ill cancer patients at 11 university hospitals and the National Cancer Center in Korea. We assessed how the use of CAM affected HRQOL and survival. RESULTS: In a follow-up of 481 patients and 163.8 person-years, we identified 466 deceased cases. On multivariate analyses, CAM users did not have better survival compared with nonusers [adjusted hazard ratio (aHR), 0.91; 95% confidence interval (CI) 0.74-1.10]. Among mind-body interventions, prayer showed significantly worse survival (aHR, 1.56; 95% CI, 1.00-2.43). Clinically, CAM users reported significantly worse cognitive functioning (-11.6 versus -1.3; P < 0.05) and fatigue (9.9 versus -1.0; P < 0.05) than nonusers. Compared with nonusers in subgroup analysis, users of alternative medical treatments, prayer, vitamin supplements, mushrooms, or rice and cereal reported clinically significant worse changes in some HRQOL subscales. CONCLUSION: While CAM did not provide any definite survival benefit, CAM users reported clinically significant worse HRQOLs.


Assuntos
Terapias Complementares , Neoplasias/terapia , Qualidade de Vida , Doente Terminal , Idoso , Estudos de Coortes , Terapias Complementares/psicologia , Feminino , Nível de Saúde , Humanos , Masculino , Neoplasias/mortalidade , Neoplasias/psicologia , Estudos Prospectivos , Inquéritos e Questionários , Taxa de Sobrevida , Resultado do Tratamento
10.
Osteoarthritis Cartilage ; 21(12): 2013-20, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24120491

RESUMO

OBJECTIVE: Many osteoarthritis (OA) models have been developed in mice to understand OA progression and evaluate new OA therapies. However, the individual variation of the joint lesions remains a critical problem in most of the current OA models. We established an OA model in C57BL/6 mice that is more reproducible and amenable to therapeutic intervention by controlling their movement. DESIGN: OA was induced in 9-week-old C57BL/6 mice by destabilizing the medial meniscus. The mice were then raised in the standard cage for free movement or in a confined cage customized to restrict movement. Mice in the confined cage were subjected to no exercise or exercise of 400, 800, and 1200 m/day. RESULTS: OA lesions of mice in the confined cage were more severe in the exercise group and showed much less variation. However, the patterns of OA lesions over time were quite different depending on the amount of daily exercise; the patterns increased linearly until 8 weeks in 400 m/day exercise group, but showed plateauing after 4 weeks in 800 m/day and 1200 m/day groups. The validity of our novel OA model with movement control was proven by successfully discriminating the therapeutic effect of hyaluronic acid (HA) in histological scores, while the OA model using standard caging showed a statistically insignificant difference. CONCLUSION: The mouse OA model using the confine cage and enforced periodic exercise of mice is more reproducible and reliable than standard caging methods.


Assuntos
Artrite Experimental/patologia , Cartilagem Articular/patologia , Modelos Animais de Doenças , Meniscos Tibiais/cirurgia , Camundongos , Osteoartrite do Joelho/patologia , Animais , Progressão da Doença , Instabilidade Articular , Masculino , Camundongos Endogâmicos C57BL , Condicionamento Físico Animal/métodos , Reprodutibilidade dos Testes
11.
Invest New Drugs ; 31(6): 1547-58, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24091982

RESUMO

BACKGROUND: We evaluated the maximum tolerated dose (MTD) and safety of sunitinib plus capecitabine/cisplatin (XP) or capecitabine/oxaliplatin (XELOX) in Korean patients with advanced gastric cancer (GC). METHODS: Sunitinib (37.5 or 25 mg/day) was administered on a 2-week-on/1-week-off schedule with chemotherapy. Assessments included dose-limiting toxicity (DLT), safety, pharmacokinetics, and antitumor activity. RESULTS: Twenty-eight patients received sunitinib/XP; 48 received sunitinib/XELOX. The MTDs were: sunitinib 25 mg/day, cisplatin 80 mg/m(2), and capecitabine 1,000 mg/m(2); sunitinib 37.5 mg/day, oxaliplatin 110 mg/m(2), and capecitabine 800 mg/m(2); and sunitinib 25 mg/day, oxaliplatin 110 mg/m(2), and capecitabine 1,000 mg/m(2). DLTs at the MTDs comprised grade (G) 4 febrile neutropenia plus G3 diarrhea (n = 1; sunitinib/XP), dose delays due to hematologic toxicity (n = 2; both sunitinib/XP), G3 bleeding (menorrhagia; n = 1; sunitinib/XELOX), and G3 increased alanine aminotransferase levels (n = 1; sunitinib/XELOX). There was a high frequency of G3/4 hematologic adverse events observed with both treatment regimens, particularly with sunitinib/XP. Frequent non-hematologic, G3/4 adverse events were nausea, stomatitis, and hypophosphatemia with sunitinib/XP and hypophosphatemia and pulmonary embolism with sunitinib/XELOX. No drug-drug interactions were apparent. At the MTDs, median progression-free survival was 6.4 months and 5.5-8.0 months for sunitinib/XP and sunitinib/XELOX, respectively; and the objective response rate was 46.7% and 43.5-45.5% for sunitinib/XP and sunitinib/XELOX, respectively. CONCLUSIONS: At the MTD, sunitinib/XELOX had an acceptable safety profile in patients with advanced GC.


Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Gástricas/tratamento farmacológico , Adenocarcinoma/sangue , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Capecitabina , Cisplatino/administração & dosagem , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Esquema de Medicação , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/análogos & derivados , Humanos , Indóis/administração & dosagem , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Compostos Organoplatínicos/administração & dosagem , Oxaliplatina , Pirróis/administração & dosagem , Neoplasias Gástricas/sangue , Sunitinibe
12.
Clin Exp Dermatol ; 38(7): 758-67, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23581888

RESUMO

BACKGROUND: Alopecia areata (AA) is characterized by rapid and complete hair loss in one or multiple areas of the scalp. Stress is an important triggering factor in AA. AIM: To identify the inhibitory effect of tianeptine on catagen induction in C57BL/6 mice with AA-like lesions induced by ultrasonic wave stress (UWS). METHODS: The mice were divided into four groups. Group 1 received oral tianeptine before and after UWS; group 2 received oral tianeptine only after UWS; group 3 was given UWS treatment only; and group 4 (negative control group) was not given any treatment. Phototrichigraphy and dermatoscopy were used for assessment. Histological analysis was performed using haematoxylin and eosin, toluidine blue, Masson trichrome and Verhoeff-van Gieson stains. Immunohistochemical analysis was also performed. The level of apoptosis and expression of neuropeptides in the skin were assessed by terminal deoxynucleotidyl transferase dUTP nick end labelling and immunofluorescence assays. RESULTS: Mice in group 1 had an increased rate of hair growth and greater hair-shaft thickness compared with mice in groups 2 and 3. In addition, mice in group 1 had a higher number of anagen hair follicles, increased synthesis of collagen and elastic fibres, decreased mast-cell degranulation, reduction in cell apoptosis in hair follicles, and recovery of vitamin D receptor expression. Expression of neuropeptides (substance P, calcitonin gene-related peptide) was not altered. CONCLUSIONS: Tianeptine might play a role in suppressing catagen induction in a stress-induced AA mouse model.


Assuntos
Alopecia em Áreas/tratamento farmacológico , Antidepressivos Tricíclicos/uso terapêutico , Ciclo Celular/efeitos dos fármacos , Estresse Psicológico/tratamento farmacológico , Tiazepinas/uso terapêutico , Alopecia em Áreas/psicologia , Animais , Antidepressivos Tricíclicos/farmacologia , Modelos Animais de Doenças , Feminino , Folículo Piloso/efeitos dos fármacos , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos C57BL , Estresse Psicológico/complicações , Tiazepinas/farmacologia
13.
Anim Genet ; 44(6): 750-3, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23718263

RESUMO

The akirin 2 gene, located on chromosome 9 in cattle, was previously reported to be associated with nuclear factor-kappa B (NF-κB), involved in immune reactions and marbling of meat. To determine whether a single nucleotide polymorphism (SNP) in akirin 2 is associated with economically important traits of Korean native cattle, the c.*188G>A SNP DNA marker in the 3'-UTR region of akirin 2 was analyzed for its association with carcass weight, longissimus muscle area and marbling. The c.*188G>A SNP was genotyped by polymerase chain reaction restriction fragment length polymorphism, and the frequency of the AA, AG, and GG genotypes were 6.82%, 71.29% and 21.88% respectively. This SNP was significantly associated with longissimus muscle area (Bonferroni corrected P < 0.05), and marbling score (Bonferroni corrected P < 0.01). These results suggest that the c.*188G>A SNP of akirin 2 might be useful as a DNA marker for longissimus muscle area and marbling scores in Korean native cattle.


Assuntos
Bovinos/genética , Carne/análise , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética , Proteínas Repressoras/genética , Animais , Sequência de Bases , Bovinos/fisiologia , Primers do DNA/genética , Etiquetas de Sequências Expressas , Frequência do Gene , Genótipo , Modelos Lineares , Lipídeos/análise , Lipídeos/genética , Dados de Sequência Molecular , Músculo Esquelético/química , NF-kappa B/genética , República da Coreia , Análise de Sequência de DNA/veterinária
14.
Tissue Antigens ; 79(5): 333-9, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22428754

RESUMO

Matrix metalloproteinases (MMPs) induce leukocyte migration into inflammation sites that lead to either promotion or repression of inflammation by activating or inactivating cytokines. An increased level of MMP-9 and a decreased level of MMP-2 have been observed in Behçet's disease (BD). This study was performed to analyze the relationship between MMP-2, -9, -12 and the tissue inhibitor of metalloproteinase-2 (TIMP-2) promoter polymorphisms in developing BD. The expression of MMP-2 and -9 was also evaluated in the skin of BD. The MMPs and TIMP-2 polymorphisms were confirmed by using polymerase chain reaction-restriction fragment length polymorphism in 251 BD and 312 controls. Cutaneous expression of MMP-2 and -9 in 17 BD patients with erythema nodosum (EN) or EN-like lesion was compared with 14 patients with idiopathic EN by immunohistochemical stains. The frequency of MMP-2-1575*G/*G and MMP-2-735*C/*C genotypes was shown to be lower in BD, whereas MMP-9-1562*C/*C was significantly higher in BD compared with the controls. The frequency of common haplotype MMP-2-1575*G -735*C was significantly lower in BD patients than in controls (P = 0.0046, permutation P = 0.009). No significant differences were observed between BD and controls in the allele and genotype frequencies of MMP-12-82A>G or TIMP-2-418G>C polymorphisms. The tissue expression of MMP-2, shown by immunohistochemistry, was significantly lower in BD compared with the controls. However, the expression of MMP-9 was significantly higher in BD. These results suggest that MMP-2 and -9 could each modulate the development of BD in opposite directions. Major genotypes of the MMP-2-1575*G/*G and MMP-2-735*C/*C and the common MMP-2-1575*G -735*C haplotype may provide some protection against development of BD, while MMP-9-1562*C/*C may promote the disease. The reciprocal expression of MMP-2 and -9 in the skin tissue of BD was also confirmed.


Assuntos
Síndrome de Behçet/genética , Eritema Nodoso/genética , Metaloproteinase 12 da Matriz/genética , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 9 da Matriz/genética , Inibidor Tecidual de Metaloproteinase-2/genética , Adolescente , Adulto , Idoso , Alelos , Povo Asiático/genética , Síndrome de Behçet/complicações , Síndrome de Behçet/patologia , Estudos de Casos e Controles , Eritema Nodoso/complicações , Eritema Nodoso/patologia , Feminino , Genótipo , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Polimorfismo Genético , Polimorfismo de Fragmento de Restrição , Regiões Promotoras Genéticas , República da Coreia , Pele/metabolismo , Pele/patologia
15.
Invest New Drugs ; 30(6): 2377-83, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22270258

RESUMO

PURPOSE: To evaluated the efficacy and safety of sorafenib in patients with advanced gastrointestinal stromal tumors (GIST) who failed to previous standard treatments. EXPERIMENTAL DESIGN: Thirty-one patients with measurable metastatic GIST who failed both imatinib and sunitinib were accrued. Sorafenib was administered orally at 400 mg twice daily until disease progression or development of intolerance. The primary endpoint was disease control rate (response + stable disease, DCR) at 24 weeks. RESULTS: Sorafenib was well tolerated, with hand-foot skin reaction, fatigue, hypertension, and abdominal pain being the most frequent adverse events. The relative dose intensity of sorafenib during the first 6 months was >80%. Four patients achieved partial response (response rate 13%, 95% CI 1-25%), and 16 (52%) had stable disease. DCR at 24 weeks was measured as 36% (95% CI 19-52%). Median progression-free and overall survivals were 4.9 and 9.7 months, respectively. Progression-free survival of patients with prior use of nilotinib (P = .0085) and with primary genotypes other than KIT exon 11 mutation (P = .0341) was significantly shorter than that of patients without. CONCLUSIONS: Sorafenib showed antitumor activity in this population of imatinib and sunitinib pretreated GIST. With sorafenib, about one third of patients can maintain disease control for more than 24 weeks.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Gastrointestinais/tratamento farmacológico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Niacinamida/análogos & derivados , Compostos de Fenilureia/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Adulto , Idoso , Povo Asiático , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Neoplasias Gastrointestinais/genética , Tumores do Estroma Gastrointestinal/genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Niacinamida/uso terapêutico , Proteínas Proto-Oncogênicas c-kit/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Sorafenibe , Resultado do Tratamento
16.
Endoscopy ; 44(9): 807-12, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22752892

RESUMO

BACKGROUND AND STUDY AIM: Chemotherapy has been suggested to affect the outcome of pyloric stent placement. This study aimed to investigate the association between the response to chemotherapy and pyloric stent outcome. PATIENTS AND METHODS: Data from 113 patients with inoperable gastric cancer who received chemotherapy after pyloric stent placement at the National Cancer Center hospital were analyzed retrospectively. Chemotherapy response was assessed using the Response Evaluation Criteria in Solid Tumors. A Cox proportional hazards model was used to evaluate the effect of chemotherapy response on the complications of stents. RESULTS: The stent migration rate was 15.9% (18/113) and the re-stenosis rate was 30.1% (34/113). The response rates to chemotherapy were higher in the first-line group than in the salvage chemotherapy group (second-line or more) (44.8% [26/58] vs. 3.6% [2/55], respectively; P < 0.001). The proportion of patients with long time-to-progression (> 8 weeks) was also higher in the first-line than the salvage chemotherapy group (81.0% [47 /58] vs. 61.8% [34 /55], respectively; P = 0.036). Although, the response to chemotherapy was not associated with stent migration or re-stenosis, a long time-to-progression (adjusted hazard ratio [aHR] = 0.29, 95% confidence interval [CI] 0.13-0.67) and first-line chemotherapy (aHR = 0.45, 95%CI 0.22-0.93) were protective factors against re-stenosis in the multivariate analysis. In patients who received first-line chemotherapy, the median duration of patency of covered and uncovered stents was 20 weeks (95%CI 11-29) and 33 weeks (95 %CI 18-48), respectively (P = 0.317). CONCLUSIONS: A long time-to-progression and first-line chemotherapy were significant protective factors against re-stenosis. In chemotherapy-naïve gastric cancer patients with pyloric obstruction, placement of an uncovered stent followed by chemotherapy can be considered to increase stent patency.


Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos/uso terapêutico , Obstrução da Saída Gástrica/terapia , Stents , Neoplasias Gástricas/tratamento farmacológico , Adenocarcinoma/complicações , Adulto , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Intervalo Livre de Doença , Feminino , Obstrução da Saída Gástrica/etiologia , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Modelos de Riscos Proporcionais , Falha de Prótese , Recidiva , Estudos Retrospectivos , Fatores de Risco , Terapia de Salvação , Neoplasias Gástricas/complicações , Fatores de Tempo
17.
Br J Cancer ; 104(7): 1126-34, 2011 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-21364592

RESUMO

BACKGROUND: We evaluated the association between polymorphisms of cytochrome P450 2A6 (CYP2A6)/excision repair cross-complementation group 1 (ERCC1)/X-ray repair cross-complementing group 1(XRCC1) and treatment outcomes of metastatic gastric cancer (MGC) patients treated with S-1/cisplatin. METHODS: Among MGC patients (n=108), who received S-1 (40 mg m(-2) b.i.d., days 1-14) and cisplatin (60 mg m(-2), day 1) every 3 weeks, we analysed the wild-type allele (W) and variants (V) of CYP2A6 (*4, *7, *9, *10), and the polymorphisms of ERCC1 (rs11615, rs3212986) and XRCC1 (rs25487). RESULTS: Patients having fewer CYP2A6 variants had better response rates (W/W vs W/V other than *1/*4 vs V/V or *1/*4=66.7 vs 58.3 vs 32.3%; P=0.008), time to progression (TTP) (7.2 vs 6.1 vs 3.5 months, P=0.021), and overall survival (23.2 vs 15.4 vs 12.0 months, P=0.004). ERCC1 19442C>A (rs3212986) was also associated with response rate (C/C, 46.7% vs C/A, 55.3% vs A/A, 87.5%) (P=0.048) and TTP (4.4 vs 7.6 vs 7.9 months) (P=0.012). Patients carrying both risk genotypes of CYP2A6 (V/V or 1/*4) and ERCC1 19442C>A (C/C) vs those carrying none showed an adjusted odds ratio of 0.113 (P=0.004) for response, and adjusted hazard ratios of 3.748 (P=0.0001) for TTP and 2.961 (P=0.006) for death. CONCLUSION: Polymorphisms of CYP2A6 and ERCC1 19442C>A correlated with the efficacy of S-1/cisplatin.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Hidrocarboneto de Aril Hidroxilases/genética , Cisplatino/uso terapêutico , Proteínas de Ligação a DNA/genética , Endonucleases/genética , Ácido Oxônico/uso terapêutico , Polimorfismo Genético , Neoplasias Gástricas/tratamento farmacológico , Tegafur/uso terapêutico , Adulto , Idoso , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Citocromo P-450 CYP2A6 , Combinação de Medicamentos , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Ácido Oxônico/administração & dosagem , Ácido Oxônico/efeitos adversos , Neoplasias Gástricas/genética , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Tegafur/administração & dosagem , Tegafur/efeitos adversos , Proteína 1 Complementadora Cruzada de Reparo de Raio-X
18.
Ann Oncol ; 22(4): 890-896, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20860988

RESUMO

BACKGROUND: The aim of this study was to investigate the efficacy and safety of S-1/irinotecan/oxaliplatin (TIROX) in metastatic gastric cancer (MGC) and the association between treatment outcome and uridine diphosphate-glucuronosyltransferase (UGT) 1A polymorphisms. PATIENTS AND METHODS: Patients with previously untreated MGC received S-1 40 mg/m(2) b.i.d. on days 1-14 and irinotecan 150 mg/m(2) plus oxaliplatin 85 mg/m(2) on day 1 every 3 weeks. RESULTS: Forty-four patients were enrolled. In intent-to-treat analysis, the objective response rate was 75%, including the complete response (CR) rate of 14%. The median time to progression and overall survival was 10.2 and 17.6 months, respectively. Ten (26%) of the 39 patients with primary gastric tumor showed biopsy-confirmed gastric CR. Grade 3/4 neutropenia developed in 66% of patients and grade 3 febrile neutropenia in 16%. The most common grade 3 nonhematologic toxic effects were abdominal pain (18%), anorexia (16%), and diarrhea (14%). UGT1A polymorphisms were associated with significantly higher incidence of grade 4 leukopenia (UGT1A1*6), neutropenia (UGT1A1*6, UGT1A6*2, and UGT1A7*3), grade 3/4 febrile neutropenia (UGT1A1*6), and grade 3 abdominal pain (UGT1A1*6). CONCLUSIONS: The TIROX regimen induced marked tumor reduction and promising survival with a manageable toxicity profile in MGC patients. UGT1A genotype may be predictive of TIROX toxicity.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Camptotecina/análogos & derivados , Glucuronosiltransferase/genética , Compostos Organoplatínicos/uso terapêutico , Ácido Oxônico/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Tegafur/uso terapêutico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Camptotecina/administração & dosagem , Camptotecina/efeitos adversos , Camptotecina/uso terapêutico , Combinação de Medicamentos , Feminino , Humanos , Irinotecano , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Compostos Organoplatínicos/administração & dosagem , Compostos Organoplatínicos/efeitos adversos , Oxaliplatina , Ácido Oxônico/administração & dosagem , Ácido Oxônico/efeitos adversos , Polimorfismo Genético , Tegafur/administração & dosagem , Tegafur/efeitos adversos , Resultado do Tratamento
19.
Osteoarthritis Cartilage ; 19(12): 1440-8, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21843651

RESUMO

OBJECTIVE: Bone marrow stimulation (BMS) has been regarded as a first line procedure for repair of articular cartilage. However, repaired cartilage from BMS is known to be unlike that of hyaline cartilage and its inner endurance is not guaranteed. The reason presumably came from a shortage of cartilage-forming cells in blood clots derived by BMS. In order to increase repairable cellularity, the feasibility of autologous bone marrow-derived buffy coat transplantation in repair of large full-thickness cartilage defects was investigated in this study. METHODS: Rabbits were divided into four groups: the defect remained untreated as a negative control; performance of BMS only (BMS group); BMS followed by supplementation of autologous bone marrow buffy coat (Buffy coat group); transplantation of autologous osteochondral transplantation (AOTS) as a positive control. RESULTS: Repair of cartilage defects in the Buffy coat group in a rabbit model was more effective than BMS alone and similar to AOTS. Gross findings, histological analysis, histological scoring, immunohistochemistry, and chemical assay demonstrated that supplementation of autologous bone marrow buffy coat after BMS arthroplasty effectively repaired cartilage defects in a rabbit model, and was more effective than BMS arthroplasty alone. CONCLUSION: Supplementation of autologous bone marrow-derived buffy coat in cases of BMS could be a useful clinical protocol for cartilage repair.


Assuntos
Buffy Coat/transplante , Células da Medula Óssea/fisiologia , Cartilagem Articular/lesões , Animais , Cartilagem Articular/metabolismo , Cartilagem Articular/patologia , Centrifugação com Gradiente de Concentração , Colágeno Tipo II/metabolismo , Ensaio de Unidades Formadoras de Colônias , Modelos Animais de Doenças , Matriz Extracelular/transplante , Estudos de Viabilidade , Glicosaminoglicanos/metabolismo , Células-Tronco Mesenquimais/fisiologia , Coelhos
20.
Br J Cancer ; 100(2): 298-304, 2009 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-19127259

RESUMO

This prospective study was conducted with the Korean Cancer Study Group to evaluate the efficacy and safety of cetuximab combined with modified FOLFOX6 (mFOLFOX6) as first-line treatment in recurrent or metastatic gastric cancer and to identify potential predictive biomarkers. Patients received cetuximab 400 mg m(-2) at week 1 and 250 mg m(-2) weekly thereafter until disease progression. Oxaliplatin (100 mg m(-2)) and leucovorin (100 mg m(-2)) were administered as a 2-h infusion followed by a 46-h continuous infusion of 5-fluorouracil (2400 mg m(-2)) every 2 weeks for a maximum of 12 cycles. Biomarkers potentially associated with efficacy were analysed. Among 38 evaluable patients, confirmed response rate (RR) was 50.0% (95% CI 34.1-65.9). Median time-to-progression (TTP) was 5.5 months (95% CI 4.5-6.5) and overall survival (OS) 9.9 months. Eleven patients having tumour EGFR expression by immunohistochemistry with low serum EGF and TGF-alpha levels showed a 100% RR compared to 37.0% in the remaining 27 patients (P<0.001). Moreover, ligand level increased when disease progressed in seven out of eight patients with EGFR expression and low baseline ligand level. No patient exhibited EGFR amplification or K-ras mutations. Gastric cancer patients with EGFR expression and low ligand levels had better outcomes with cetuximab/mFOLFOX6 treatment.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/análise , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Gástricas/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Humanizados , Cetuximab , Feminino , Fluoruracila/administração & dosagem , Humanos , Leucovorina/administração & dosagem , Neoplasias Hepáticas/química , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/tratamento farmacológico , Estadiamento de Neoplasias , Compostos Organoplatínicos/administração & dosagem , Oxaliplatina , Neoplasias Peritoneais/química , Neoplasias Peritoneais/secundário , Prognóstico , Estudos Prospectivos , Neoplasias Gástricas/química , Neoplasias Gástricas/patologia , Taxa de Sobrevida , Resultado do Tratamento
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