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1.
Ann Oncol ; 32(11): 1434-1441, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34391895

RESUMO

BACKGROUND: The severity of oxaliplatin (L-OHP)-induced peripheral sensory neuropathy (PSN) exhibits substantial interpatient variability, and some patients suffer from long-term, persisting PSN. To identify single-nucleotide polymorphisms (SNPs) predicting L-OHP-induced PSN using a genome-wide association study (GWAS) approach. PATIENTS AND METHODS: A large prospective GWAS including 1379 patients with stage II/III colon cancer who received L-OHP-based adjuvant chemotherapy (mFOLFOX6/CAPOX) under the phase II (JOIN/JFMC41) or the phase III (ACHIVE/JFMC47) trial. Firstly, GWAS comparison of worst grade PSN (grade 0/1 versus 2/3) was carried out. Next, to minimize the impact of ambiguity in PSN grading, extreme PSN phenotypes were selected and analyzed by GWAS. SNPs that could predict time to recovery from PSN were also evaluated. In addition, SNPs associated with L-OHP-induced allergic reactions (AR) and time to disease recurrence were explored. RESULTS: No SNPs exceeded the genome-wide significance (P < 5.0 × 10-8) in either GWAS comparison of worst grade PSN, extreme PSN phenotypes, or time to recovery from PSN. An association study focusing on AR or time to disease recurrence also failed to reveal any significant SNPs. CONCLUSION: Our results highlight the challenges of utilizing SNPs for predicting susceptibility to L-OHP-induced PSN in daily clinical practice.


Assuntos
Neoplasias do Colo , Estudo de Associação Genômica Ampla , Protocolos de Quimioterapia Combinada Antineoplásica , Quimioterapia Adjuvante , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/genética , Fluoruracila/uso terapêutico , Humanos , Recidiva Local de Neoplasia , Oxaliplatina/efeitos adversos , Estudos Prospectivos
2.
Ann Oncol ; 27(6): 1143-1148, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27069012

RESUMO

BACKGROUND: Peripheral sensory neuropathy (PSN) is a dose-limiting toxicity of oxaliplatin-based chemotherapy. Several genetic markers have been shown to predict oxaliplatin-induced PSN; however, results remain to be validated in a large-scale and prospective pharmacogenomics study. PATIENTS AND METHODS: Among 882 patients enrolled in the JFMC41-1001-C2 (JOIN trial), which was designed to investigate the tolerability of adjuvant-modified FOLFOX6 (mFOLFOX6) in Japanese Patients with stage II or III colon cancers undergoing curative resection, 465 patients were eligible for this pharmacogenomics analysis. Twelve single-nucleotide polymorphisms (SNPs) were selected based on published data. The effect of each genotype on time to PSN onset was evaluated in all patients (n = 465) using the Cox proportional hazard model. For the association analysis between severity of PSN and 12 SNP markers, 84 patients who failed to complete 12 cycles of mFOLFOX6 from grade 0/1 PSN group were excluded because the termination of the protocol treatment had been caused by reasons other than PSN. RESULTS: Comparison of grade 0/1 PSN with grade 2/3 PSN or grade 3 PSN showed no significant associations with any of the 12 SNP markers after adjustment for total dose of oxaliplatin. Time-to-onset analysis also failed to reveal any significant differences. CONCLUSIONS: Our large-scale and prospective pharmacogenomics study of Japanese patients receiving protocol treatment of adjuvant mFOLFOX6 could not verify a role for any of the 12 SNP markers reported as being significantly associated with PSN. Considering the OR observed in this study (range: 0.76-1.89), further evaluation of these 12 SNP markers in the context of L-OHP-induced PSN is unlikely to be clinically informative.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias do Colo/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/genética , Farmacogenética , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Quimioterapia Adjuvante/efeitos adversos , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Feminino , Fluoruracila/efeitos adversos , Humanos , Japão , Leucovorina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Compostos Organoplatínicos/administração & dosagem , Compostos Organoplatínicos/efeitos adversos , Oxaliplatina , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/patologia , Polimorfismo de Nucleotídeo Único/genética
4.
Surg Today ; 30(12): 1100-6, 2000.
Artigo em Inglês | MEDLINE | ID: mdl-11193742

RESUMO

Even though angiogenesis inhibitor is thought to be one of the promising agents in tumor dormancy therapy, its optimal administration is still unknown. Therefore, the efficient protocol using TNP-470 was examined regarding its treatment affect against spontaneous liver metastases of colon tumors in the rabbit. A spontaneous liver metastases model was established in the rabbit by the inoculation of VX-2 tumors into the subserosal space of the colon. The therapeutic effect of TNP-470 was then investigated by monitoring both the number of metastatic nodules in the liver and the microvessel density (MVD) in the tumor by immunohistochemical staining using anti-CD31 monoclonal antibody. TNP-470 did not show any effect on the primary tumor. It was able to reduce the metastatic spread to liver when it was administered at the microscopic metastatic stage. Treatment at this stage, however, was not able to sufficiently control the disease. These results indicated that TNP-470 could efficiently cause the tumor to enter into a dormant state by inhibiting angiogenesis when it was used at the initial stage of the metastatic process in the liver. Regarding its clinical application, TNP-470 might be useful for preventing the metachronous liver metastases of colorectal cancer when it is administered as adjuvant therapy after curative surgery.


Assuntos
Inibidores da Angiogênese/farmacologia , Neoplasias do Colo/patologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/secundário , Sesquiterpenos/farmacologia , Inibidores da Angiogênese/administração & dosagem , Animais , Cicloexanos , Feminino , Infusões Intravenosas , Neoplasias Hepáticas/irrigação sanguínea , Neovascularização Patológica/tratamento farmacológico , O-(Cloroacetilcarbamoil)fumagilol , Coelhos , Sesquiterpenos/administração & dosagem
7.
Lancet ; 343(8906): 1122-6, 1994 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-7910230

RESUMO

In Japan the standard adjuvant treatment after resection of gastric cancer is intravenous mitomycin plus oral fluorouracil. We have assessed the efficacy of protein-bound polysaccharide (PSK) in addition to standard chemotherapy in patients who had undergone curative gastrectomy at 46 institutions in central Japan. 262 patients were randomly assigned standard treatment alone or with PSK. The minimum follow-up time was 5 years (range 5-7 years). PSK improved both the 5-year disease-free rate (70.7 vs 59.4% in standard treatment group, p = 0.047) and 5-year survival (73.0 vs 60.0%, p = 0.044). The two regimens had only slight toxic effects, consisting of nausea, leucopenia, and liver function impairment, and there were no significant differences between the groups. The treatments were clinically well tolerated and compliance was good. Addition of PSK to adjuvant chemotherapy with mitomycin and fluorouracil is beneficial as treatment after curative gastrectomy.


Assuntos
Adjuvantes Imunológicos/uso terapêutico , Antibióticos Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Gastrectomia , Proteoglicanas/uso terapêutico , Neoplasias Gástricas/terapia , Administração Oral , Adulto , Idoso , Terapia Combinada , Feminino , Fluoruracila/administração & dosagem , Humanos , Injeções Intravenosas , Leucopenia/induzido quimicamente , Leucopenia/epidemiologia , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Mitomicinas/administração & dosagem , Náusea/induzido quimicamente , Náusea/epidemiologia , Estadiamento de Neoplasias , Cooperação do Paciente , Modelos de Riscos Proporcionais , Neoplasias Gástricas/sangue , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Taxa de Sobrevida
8.
Cardiovasc Intervent Radiol ; 16(4): 209-13, 1993.
Artigo em Inglês | MEDLINE | ID: mdl-8402781

RESUMO

This retrospective study examined the computed tomography (CT) criteria for judging the effectiveness of transcatheter arterial Lipiodol-chemoembolization (Lp-chemo-TAE) in 35 cases with hepatocellular carcinoma (HCC). Massive necrosis, defined as involving 97% or more of the HCC nodule, was observed in 15 cases after Lp-chemo-TAE, whereas nonmassive necrosis, defined as involving < or = 96% of the HCC nodule, was observed in the remaining 20 cases. In 12 of 15 cases (80%) with massive necrosis, uniform dense retention of Lipiodol (Lp) was observed throughout the HCC nodule on CT images 3-4 weeks after Lp-chemo-TAE as opposed to only one (5%) of 20 cases with nonmassive necrosis (p < 0.01). Eight of nine cases (89%) with massive necrosis had tumor attenuation values of 365 Hounsfield units (HU) or greater on CT images 3-4 weeks after embolization, as opposed to only four (27%) of 15 cases with nonmassive necrosis (p < 0.01). We conclude that the effectiveness of the Lp-chemo-TAE can be judged on CT from the degree and duration of Lp retention in the HCC nodule and the measurement of the attenuation value of the HCC nodule.


Assuntos
Carcinoma Hepatocelular/terapia , Quimioembolização Terapêutica , Óleo Iodado/administração & dosagem , Neoplasias Hepáticas/terapia , Fígado/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/epidemiologia , Epirubicina/administração & dosagem , Feminino , Humanos , Fígado/patologia , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/epidemiologia , Masculino , Pessoa de Meia-Idade , Mitomicina/administração & dosagem , Necrose , Estudos Retrospectivos
9.
Gan To Kagaku Ryoho ; 20(1): 137-40, 1993 Jan.
Artigo em Japonês | MEDLINE | ID: mdl-8422178

RESUMO

Cisplatin, mitomycin C and 5-fluorouracil were given a 55-year-old woman for an unresectable gastric cancer, and successful radical gastrectomy was performed. Postoperative adjuvant immunochemotherapy using UFT and PSK was continued for about 4 years and 4 months. Pancytopenia was observed at 5 years after the treatment and then marked leucocytosis was noted. She also showed complications of general fatigue, appetite loss etc. A secondary acute leukemia associated with eosinophilia was diagnosed by peripheral blood examinations, showing WBC, 122,400: blast, 37.5 % and eosinophil, 41%. Results also showed atypia and pseudo-Pelger nuclear abnormality of eosinophil, high positive stain of cell myelogenic cell surface marker, many numeral and structural abnormalities of chromosomal analysis, etc. From the above results, it was suggested that the leukemia might be induced by previously performed chemotherapy. The patient died about 2 months following its onset.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cisplatino/efeitos adversos , Gastrectomia , Leucemia Mieloide Aguda/induzido quimicamente , Segunda Neoplasia Primária , Neoplasias Gástricas/tratamento farmacológico , Feminino , Fluoruracila/administração & dosagem , Humanos , Pessoa de Meia-Idade , Mitomicina/administração & dosagem , Proteoglicanas/administração & dosagem , Neoplasias Gástricas/cirurgia , Tegafur/administração & dosagem , Uracila/administração & dosagem
10.
Gan To Kagaku Ryoho ; 16(8 Pt 1): 2563-76, 1989 Aug.
Artigo em Japonês | MEDLINE | ID: mdl-2505682

RESUMO

To evaluate the efficacy of PSK for adjuvant immuno-chemotherapy in patients who had undergone radical gastrectomy, a randomized controlled trial has been in progress in collaboration with 46 institutions in the Chubu district of Japan. A total of 262 patients were registered for this trial during the two years from July 1985 to June 1987 with a centralized registration system, and were allocated into the 5-FU+PSK group (Group P) and 5-FU alone group (Group C) by the minimization method following the random permuted blocks method. Between the two groups, the parameters of sex, age, serosal invasion (S), lymph-node metastasis (N), and the combination of S . N factor levels were distributed without significant differences. An induction treatment with MMC 6 mg/m2 was given to all patients following curative gastrectomy and on the 7th post-operative day. Two weeks after surgery, Group P received alternately PSK 3 g/day for 4 week and 5-FU 150 mg/day for 4 weeks as one course, and 10 courses were given. Group C received 5-FU alone for 4 weeks using alternate rest interval for 4 weeks. Since both experimental and clinical studies suggested that alternate treatments using PSK and anticancer agents were effective, treatment in this trial alternated PSK and 5-FU. A final follow-up study will be completed in June 1992, when all patients shall have survived more than 5 years after surgery. The administration of 5-FU was completed by January. 1989, but PSK has been administered to group P. The period from 18 to 42 months after surgery was reached in all eligible patients (253) at the end of December 1988. The disease-free survival curves and overall survival curves of group P were significantly (p = 0.018 and p = 0.045,) better than those of group C.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Fluoruracila/administração & dosagem , Proteoglicanas/administração & dosagem , Neoplasias Gástricas/terapia , Idoso , Ensaios Clínicos como Assunto , Terapia Combinada , Esquema de Medicação , Feminino , Fluoruracila/uso terapêutico , Seguimentos , Gastrectomia , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Mitomicina , Mitomicinas/administração & dosagem , Estudos Multicêntricos como Assunto , Distribuição Aleatória , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/cirurgia
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