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1.
Ann Oncol ; 32(3): 368-374, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33278599

RESUMO

BACKGROUND: Adjuvant chemotherapy and chemoradiotherapy are some of the standards of care for gastric cancer (GC). The Adjuvant chemoRadioTherapy In Stomach Tumors (ARTIST) 2 trial compares two adjuvant chemotherapy regimens and chemoradiotherapy in patients with D2-resected, stage II or III, node-positive GC. PATIENTS AND METHODS: The ARTIST 2 compared, in a 1:1:1 ratio, three adjuvant regimens: oral S-1 (40-60 mg twice daily 4 weeks on/2 weeks off) for 1 year, S-1 (2 weeks on/1 week off) plus oxaliplatin 130 mg/m2 every 3 weeks (SOX) for 6 months, and SOX plus chemoradiotherapy 45 Gy (SOXRT). Randomization was stratified according to surgery type (total or subtotal gastrectomy), pathologic stage (II or III), and Lauren histologic classification (diffuse or intestinal/mixed). The primary endpoint was disease-free survival (DFS) at 3 years; a reduction of 33% in the hazard ratio (HR) for DFS with SOX or SOXRT, when compared with S-1, was considered clinically meaningful. The trial is registered at clinicaltrials.gov (NCT0176146). RESULTS: A total of 546 patients were recruited between February 2013 and January 2018 with 182, 181, and 183 patients in the S-1, SOX, and SOXRT arms, respectively. Median follow-up period was 47 months, with 178 DFS events observed. Estimated 3-year DFS rates were 64.8%, 74.3%, and 72.8% in the S-1, SOX, and SOXRT arms, respectively. HR for DFS in the control arm (S-1) was shorter than that in the SOX and SOXRT arms: S-1 versus SOX, 0.692 (P = 0.042) and S-1 versus SOXRT, 0.724 (P = 0.074). No difference in DFS was found between SOX and SOXRT (HR 0.971; P = 0.879). Adverse events were as anticipated in each arm, and were generally well-tolerated and manageable. CONCLUSIONS: In patients with curatively D2-resected, stage II/III, node-positive GC, adjuvant SOX or SOXRT was effective in prolonging DFS, when compared with S-1 monotherapy. The addition of radiotherapy to SOX did not significantly reduce the rate of recurrence after D2 gastrectomy.


Assuntos
Neoplasias Gástricas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Capecitabina/uso terapêutico , Quimioterapia Adjuvante , Intervalo Livre de Doença , Fluoruracila/uso terapêutico , Humanos , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Oxaliplatina/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia
2.
Br J Cancer ; 91(1): 11-7, 2004 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-15162146

RESUMO

The risk of locoregional recurrence in resected gastric adenocarcinoma is high, but the benefit of adjuvant treatment remains controversial. In particular, after extended lymph node dissection, the role of radiotherapy is questionable. Since 1995, we started a clinical protocol of adjuvant chemoradiotherapy after D2 gastrectomy and analysed the patterns of failure for 291 patients. Adjuvant chemotherapy consisted of five cycles of fluorouracil and leucovorin, and concurrent radiotherapy was given with 4500 cGy from the second cycle of chemotherapy. With a median follow-up of 48 months, 114 patients (39%) showed any type of failure, and the local and regional failures were seen in 7% (20 out of 291) and 12% (35 out of 291), respectively. When the recurrent site was analysed with respect to the radiation field, in-field recurrence was 16% and represented 35% of all recurrences. Our results suggest that adjuvant chemoradiotherapy has a potential effect on reducing locoregional recurrence. Moreover, low locoregional recurrence rates could give a clue as to which subset of patients could be helped by radiotherapy after D2 gastrectomy. However, in order to draw a conclusion on the role of adjuvant radiotherapy, a randomised study is needed.


Assuntos
Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/radioterapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Gastrectomia , Recidiva Local de Neoplasia , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/radioterapia , Adenocarcinoma/mortalidade , Adenocarcinoma/cirurgia , Idoso , Quimioterapia Adjuvante , Intervalo Livre de Doença , Feminino , Fluoruracila/administração & dosagem , Seguimentos , Humanos , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Radioterapia Adjuvante , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/cirurgia , Taxa de Sobrevida , Falha de Tratamento
3.
Ann Oncol ; 14(9): 1373-7, 2003 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-12954575

RESUMO

BACKGROUND: We report the results of postoperative chemoradiotherapy after curative resection in gastric cancer patients. PATIENTS AND METHODS: Patients with gastric cancer staged IB to IV(M0) were treated with chemoradiotherapy after curative resection with extensive (D2) lymph node dissection. Nodal metastases were observed in 261 (90%) patients. The chemotherapy consisted of fluorouracil 400 mg/m(2) plus leucovorin 20 mg/m(2) for 5 days, followed by 4500 cGy of radiotherapy for 5 weeks with fluorouracil and leucovorin on the first 4 days and the last 3 days of radiotherapy. Two 5-day cycles of chemotherapy were given 4 weeks after the completion of radiotherapy. RESULTS: Of 290 patients accrued, 229 (79%) patients completed chemoradiotherapy as planned. With a median follow-up of 49 months, 114 (34%) patients have relapsed: 33 (29%) locoregional relapses, 76 (67%) peritoneal relapses and 41 (36%) distant metastases. The 5-year overall and relapse-free survivals were 60% and 57%, respectively. Tolerance was acceptable, the main toxicity being neutropenia. CONCLUSIONS: This postoperative chemoradiotherapy after curative resection of gastric cancer was feasible, with acceptable toxicities. Whether this adjuvant therapy in gastric cancer patients that have undergone a D2 lymph node dissection impacts on survival or reduces the incidence of relapses remains to be studied.


Assuntos
Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/radioterapia , Fluoruracila/uso terapêutico , Leucovorina/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/radioterapia , Adenocarcinoma/mortalidade , Adenocarcinoma/cirurgia , Adulto , Idoso , Quimioterapia Adjuvante/efeitos adversos , Terapia Combinada/efeitos adversos , Fluoruracila/efeitos adversos , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Cuidados Pós-Operatórios , Prognóstico , Radioterapia Adjuvante/efeitos adversos , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/cirurgia , Resultado do Tratamento
4.
FASEB J ; 15(11): 2022-4, 2001 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-11511526

RESUMO

Our previous study showed that tea polyphenols inhibited MAP kinase and AP-1 activities in mouse epidermal JB6 cells and the corresponding H-ras-transformed cell line 30.7b Ras 12. The present study investigated the mechanisms of this inhibition. The cells were incubated with (-)-epigallocatechin-3-gallate (EGCG) or theaflavin-3,3'-digallate (TFdiG) (20 mM) for different times, and the cell lysate was analyzed by immunoblotting. EGCG treatment decreased the levels of phospho-Erk1/2 and -MEK1/2 time-dependently (by 60% at 60 min). TFdiG lowered their levels by 38%-50% at 15 min. TFdiG effectively decreased total Raf-1 protein levels, most likely through lysosomal degradation. EGCG did not affect protein levels or the activity of Raf-1 significantly but decreased its association with MEK1 as determined by co-immunoprecipitation. In addition, EGCG and TFdiG (10 mM) inhibited the phosphorylation of Elk-1 by isolated phospho-Erk1/2 in vitro. This inhibition of Erk1/2 activity is Elk-1 concentration-dependent and ATP concentration-independent, which suggests that EGCG and TFdiG interfere with the binding of the protein substrate to the kinase. The presently demonstrated specific mechanisms of inhibition of MAP kinases by EGCG and TFdiG may help us to understand the effects of tea consumption on cancer, inflammatory diseases, and cardiovascular diseases.


Assuntos
Biflavonoides , Catequina/farmacologia , Proteínas de Ligação a DNA , Flavonoides , Ácido Gálico/farmacologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Transdução de Sinais , Fatores de Transcrição , Trifosfato de Adenosina/metabolismo , Catálise , Catequina/análogos & derivados , Linhagem Celular , Ácido Gálico/análogos & derivados , MAP Quinase Quinase 1 , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Fenóis/metabolismo , Fosforilação , Polímeros/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-raf/metabolismo , Transdução de Sinais/efeitos dos fármacos , Especificidade por Substrato , Chá , Proteínas Elk-1 do Domínio ets
5.
J Surg Res ; 73(1): 90-4, 1997 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-9441799

RESUMO

BACKGROUND: Improved organ preservation is essential for the success of small bowel transplantation. Small bowel is usually preserved in UW (University of Wisconsin) solution which does not contain glutamine (Gln), the principal fuel for the enterocyte. We hypothesized that Gln-supplemented UW would improve mucosal function and structure of cold preserved small intestine. MATERIALS AND METHODS: Jejunum (40 cm) was harvested from Lewis rats and preserved for 18 hr at 4 degrees C in saline; UW solution only; UW with 1, 2, or 4% Gln; and UW containing 1, 2, or 4% isonitrogenous balanced nonessential amino acids (NEAA). 14C glucose transport, mucosal protein, mucosal maltase and alkaline phosphatase, jejunal villous height, and histologic damage were measured. RESULTS: UW with 2% Gln significantly increased glucose transport and mucosal protein when compared to the 2% NEAA and UW-only groups. Two percent Gln significantly decreased histologic damage of jejunum following cold preservation. Increasing Gln to 4% did not significantly increase its efficacy when compared to the UW with 2% Gln group. There were no significant differences in the activities of mucosal maltase and alkaline phosphatase among the various treatment groups. CONCLUSIONS: The addition of Gln, optimally provided at a concentration of 2%, to UW solution may protect the preserved small bowel segments from cold ischemic injury and improve mucosal function.


Assuntos
Glutamina/farmacologia , Intestino Delgado/fisiologia , Intestino Delgado/transplante , Preservação de Órgãos , Fosfatase Alcalina/metabolismo , Animais , Transporte Biológico , Temperatura Baixa , Glucose/metabolismo , Mucosa Intestinal/anatomia & histologia , Mucosa Intestinal/fisiologia , Intestino Delgado/anatomia & histologia , Jejuno/anatomia & histologia , Jejuno/fisiologia , Masculino , Tamanho do Órgão , Proteínas/metabolismo , Ratos , Ratos Endogâmicos Lew , alfa-Glucosidases/metabolismo
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