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1.
Anticancer Res ; 41(9): 4505-4513, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34475076

RESUMO

BACKGROUND: The tumor vascular microenvironment has an important role in tumor progression and metastasis. The objective of this study was to assess the significance of metastatic hepatic tumor vascular microenvironment in relation to the response to systemic fluorouracil-based chemotherapy [folinic acid/fluorouracil/oxaliplatin (FOLFOX) or folinic acid/fluorouracil/irinotecan (FOLFIRI)]. PATIENTS AND METHODS: A total of 48 consecutive patients with colorectal cancer (CRC) with hepatic metastasis were retrospectively reviewed, and factors such as metastatic tumor vascular microenvironment, chemotherapy response and hepatic resection, were analyzed. Tumor angiogenesis was microscopically evaluated by microvessel density (MVD) in sections stained immunochemically with antibody to CD34 in patients with hepatic resection. Angiogenesis in the tumor microenvironment in association with ring enhancement (RE) on computed tomography (CT) was also examined. RESULTS: Microscopic examination revealed that peripheral RE on CT of the metastatic tumor was associated with tumor angiogenesis by MVD. The overall response rate after six courses of first-line chemotherapy for liver metastasis with RE on CT was 64% (23/36), whereas the response rate for those without RE was 25% (3/12), which was significantly lower, although the survival of patients with RE-positive and RE-negative tumors did not differ significantly. CONCLUSION: Peripheral RE of metastatic hepatic tumor on CT was associated with angiogenesis in the tumor microenvironment and higher chemotherapy response.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/secundário , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD34/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Camptotecina/análogos & derivados , Camptotecina/farmacologia , Camptotecina/uso terapêutico , Neoplasias Colorretais/diagnóstico por imagem , Neoplasias Colorretais/metabolismo , Angiografia por Tomografia Computadorizada , Feminino , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Humanos , Leucovorina/farmacologia , Leucovorina/uso terapêutico , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/metabolismo , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/farmacologia , Compostos Organoplatínicos/uso terapêutico , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento , Microambiente Tumoral/efeitos dos fármacos
2.
Int J Surg Case Rep ; 76: 161-165, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33032048

RESUMO

BACKGROUND: Combination of choledochocele and extra-hepatic duct duplication is an extremely rare congenital abnormality. CASE PRESENTATION: The patient was an 81-year-old Japanese man. He visited the emergency room for severe abdominal colic pain. He was diagnosed with severe pancreatitis with cholelithiasis and treated conservatively by percutaneous trans-hepatic gallbladder drainage (PTGBD) for 4 months. Thereafter, he was transferred to our institute and cholangiography was performed via the PTGBD tube, revealing cholecysto- and choledocho-lithiasis. The cystic-duct joined the right hepatic duct with extra-hepatic bile duct duplication and the terminal bile duct flowed into the cystic papilla of Vater. The main pancreatic duct also joined into the cystic papilla. These observations confirmed choledochocele with extra-hepatic bile duct duplication. Surgical exploration was performed, and hepatico-jejunostomy with hepatic-ductplasty and cholecystectomy with choledocholithotomy were carried out. He was discharged and his course was uneventful. CONCLUSION: A very rare combined case of choledochocele with bile duct duplication, which would escalate the pancreatitis and cholangitis, was successfully treated. Their pathogeneses in relation to pancreaticobiliary maljunction is discussed.

3.
Gastric Cancer ; 16(4): 571-80, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23187882

RESUMO

BACKGROUND: Trastuzumab has been recently approved for clinical use to treat HER2-expressing advanced gastric cancer, and anti-HER2-targeting therapy has become a promising option for gastric cancer. Lapatinib is a dual tyrosine kinase inhibitor targeting EGFR and HER2. The aim of the present study was to explore the utility of lapatinib for gastric cancer, with a particular focus on trastuzumab-mediated antibody-dependent cellular cytotoxicity (ADCC). METHODS: Nine gastric cancer cell lines were evaluated for the effects of lapatinib on the cell-surface accumulation of HER2 and analyzed for their additional effects on trastuzumab-mediated ADCC. Also, HER2 signaling with Western blot, proliferative function with the MTT assay, and apoptosis-inducing activity with 7ADD/Annexin-V were investigated when a panel of gastric cancer cell lines was treated with lapatinib. RESULTS: Lapatinib inhibited HER2 signaling and cell proliferation in the panel of gastric cancer cell lines. Lapatinib also induced the accumulation of HER2 on the cell surface, resulting in the enhancement of trastuzumab-mediated ADCC of gastric cancer. CONCLUSIONS: Lapatinib exhibits inhibitory activity in gastric cancer cells, and the combination of lapatinib with trastuzumab may be a promising treatment strategy for gastric cancer patients.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Citotoxicidade Celular Dependente de Anticorpos/efeitos dos fármacos , Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Quinazolinas/farmacologia , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia , Apoptose/efeitos dos fármacos , Western Blotting , Sinergismo Farmacológico , Citometria de Fluxo , Humanos , Lapatinib , Receptor ErbB-2/metabolismo , Trastuzumab , Células Tumorais Cultivadas
4.
Oncoimmunology ; 1(7): 1104-1110, 2012 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-23170258

RESUMO

HER2 is a promising target for immunotherapeutic interventions with T cell-based approaches since it is amplified and overexpressed in 20-30% of breast cancers. However, several previous studies including ours showed that HER2-overexpressing tumors may escape cytotoxic T lymphocyte-mediated lysis by downregulating MHC Class I and components of the antigen-processing machinery. The aims of the present study were to analyze the relationship between HER2 and MHC Class I expression and to elucidate the mechanisms underlying MHC Class I downregulation in breast cancer. We explored expression of HER2, MHC Class I, PTEN, Ki67, estrogen and progesterone expression in 70 breast cancer patients by immunohistochemistry (IHC) and analyzed their correlation. We also explored the components of the signal transduction pathway that are involved in the regulation of MHC Class I expression using small-interfering RNAs targeting HER2 as well as an inhibitor of HER2 signaling. HER2 expression in breast cancers correlated inversely with MHC Class I expression analyzed by IHC. HER2 depletion by small-interfering RNAs resulted in MHC Class I upregulation. Moreover, MHC Class I expression on breast cancer cell lines was upregulated by PD98059, an inhibitor of mitogen-associated protein kinases, in a dose-dependent manner. Thus, agents that target the MAPK signaling pathway may increase MHC Class I expression in breast cancer cells.

5.
Anticancer Res ; 31(9): 2999-3005, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21868551

RESUMO

BACKGROUND: Although it was previously reported that lapatinib combined with Herceptin improved the progression-free survival rate compared with lapatinib alone for patients with Herceptin-refractory HER2-positive metastatic breast cancer, the mechanism is purported to be an antiproliferative effect relating to the synergism of these two agents. MATERIALS AND METHODS: We evaluated how lapatinib interacts with Herceptin in HER2-positive breast cancer, with a particular focus on Herceptin-mediated antibody-dependent cellular cytotoxicity (ADCC). RESULTS: In an in vitro assay, lapatinib induced HER2 expression at the cell surface of HER2-positive breast cancer cell lines, leading to the enhancement of Herceptin-mediated ADCC. Furthermore, we present a case report in which a second Herceptin treatment following lapatinib resulted in the marked shrinkage of multiple metastatic tumors in HER2-positive breast cancer. CONCLUSION: Lapatinib may have the potential to convert Herceptin-refractory to Herceptin-sensitive tumors in HER2-positive breast cancer by up-regulation of the cell surface expression of HER2.


Assuntos
Anticorpos Monoclonais/farmacologia , Citotoxicidade Celular Dependente de Anticorpos/imunologia , Genes erbB-2 , Quinazolinas/farmacologia , Regulação para Cima , Anticorpos Monoclonais Humanizados , Western Blotting , Sinergismo Farmacológico , Feminino , Citometria de Fluxo , Humanos , Lapatinib , Pessoa de Meia-Idade , Trastuzumab
6.
Nutrition ; 27(2): 146-52, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21215924

RESUMO

OBJECTIVE: Although randomized clinical trials have shown that immunonutrition results in the improvement of postoperative complications, the detailed mechanisms of its immunomodulation are still unclear. In the present study, we investigated if such immunonutrition could affect T-cell and natural killer (NK) cell functions, with particular focus on type 17 helper T (Th17) cells and NK cell-activating markers, in patients with esophageal and gastric cancer and in healthy volunteers. METHODS: Patients (n = 22) and healthy volunteers (n = 10) were orally administered an immunonutritional diet (Impact, 750 mL/d) in addition to a conventional diet for 5 d. The expression of NK cell-activation markers (NKG2D, CD16, CD107a, NKp30, NKp44, and NKp46), frequency of CD56(dim) NK, Th17, and regulatory T cells, and trastuzumab-mediated antibody-dependent cell-mediated cytotoxicity were analyzed before and after immunonutrition. RESULTS: Immunonutrition significantly enhanced antibody-dependent cell-mediated cytotoxic activity as an NK cell function, paralleling the upregulated expression of NKG2D and CD16 and increased frequency of CD56(dim) NK cells. Furthermore, the immunonutrition significantly increased the frequency of Th17 cells. CONCLUSION: Immunonutrition modulates NK and T-cell-mediated immunity.


Assuntos
Dieta/métodos , Imunidade Celular , Células Matadoras Naturais/metabolismo , Estado Nutricional , Células Th17/imunologia , Adenocarcinoma/dietoterapia , Adenocarcinoma/imunologia , Administração Oral , Idoso , Estudos de Casos e Controles , Linhagem Celular Tumoral , Neoplasias Esofágicas/dietoterapia , Neoplasias Esofágicas/imunologia , Feminino , Humanos , Células Matadoras Naturais/imunologia , Ativação Linfocitária/imunologia , Masculino , Pessoa de Meia-Idade , Neoplasias Gástricas/dietoterapia , Neoplasias Gástricas/imunologia , Linfócitos T Reguladores/metabolismo
7.
Int J Cancer ; 129(10): 2408-16, 2011 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-21207425

RESUMO

Lapatinib is a dual tyrosine kinase inhibitor of the EGFR and HER2 tyrosine kinase domains. EGFR is expressed in 33.3% and HER2 in 30.3% of esophageal squamous cell carcinomas (ESCCs). To explore the potential utility of Lapatinib for therapy of ESCC patients, we evaluated the effect of Lapatinib on a panel of ESCC cell lines. EGFR and HER2 expression by the cell lines was established, and the effects of Lapatinib on inhibition of the phosphorylation of HER2, antiproliferative effect, apoptosis-inducing activity and accumulation of HER2 and EGFR on cell surface were evaluated. Additionally, the combined effect of Lapatinib together with Herceptin or Cetuximab on cell-mediated cytotoxicity was evaluated. Lapatinib inhibited HER2 phosphorylation in HER2-overexpressing, HER2 gene amplification positive ESCC cell line. Lapatinib also inhibited cell proliferation, induced apoptosis and caused the surface accumulation of HER2 and EGFR in ESCC cell lines. Addition of Lapatinib increased Herceptin-mediated antibody-dependent cell-mediated cytotoxicity by 15-25% with three ESCC target cell lines. Similarly, Cetuximab-mediated antibody-dependent cell-mediated cytotoxicity also increased by 15-30% in two ESCC cell lines on addition of Lapatinib. Cumulatively, the data indicate that Lapatinib has activity in EGFR- and/or HER2-expressing ESCC cells, and the combination therapy of Lapatinib and Cetuximab/Herceptin is a promising strategy in ESCC.


Assuntos
Citotoxicidade Celular Dependente de Anticorpos/efeitos dos fármacos , Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Receptores ErbB/genética , Neoplasias Esofágicas/genética , Genes erbB-2 , Neoplasias de Células Escamosas/genética , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/farmacologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Receptores ErbB/metabolismo , Humanos , Lapatinib , Neoplasias de Células Escamosas/metabolismo , Fosforilação
8.
Int J Clin Oncol ; 14(3): 245-8, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19593617

RESUMO

We herein report the complete remission of multiple recurrent hepatocellular carcinomas (HCCs) by the oral administration of tegafur/uracil (UFT) alone. A 56-year-old Japanese man with two huge HCCs was admitted and underwent hepatic resection. Intraoperative ultrasonography revealed that the tumor thrombus extended to the inferior vena cava (IVC) with a small tumor in the left hepatic lobe. Right trisectionectomy of the liver, removal of the tumor thrombus in the IVC, and partial resection of the left lobe were performed. Microscopic examination revealed that the larger tumor was moderately to poorly differentiated HCC and the smaller tumor was well-differentiated HCC. The small tumor in the left lobe was diagnosed as an intrahepatic metastasis of the larger tumor. Two months after the surgery, computed tomography (CT) revealed multiple HCC recurrences in the remnant liver, but complete remission was achieved by the administration of UFT alone. To clarify the reason for the good response of the recurrent HCC to UFT, the mRNA expression level of several fluoropyrimidine metabolism enzymes was measured in resected specimens. A lower expression of thymidine phosphorylase (TP) might explain the good response to UFT. The patient is alive without intra- or extrahepatic recurrence more than 6 years after the hepatic resection.


Assuntos
Carcinoma Hepatocelular/terapia , Hepatectomia , Neoplasias Hepáticas/terapia , RNA Mensageiro/análise , Veia Cava Inferior/patologia , Administração Oral , Carcinoma Hepatocelular/enzimologia , Quimioembolização Terapêutica , Terapia Combinada , Di-Hidrouracila Desidrogenase (NADP)/genética , Humanos , Neoplasias Hepáticas/enzimologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Orotato Fosforribosiltransferase/genética , Tegafur/administração & dosagem , Timidina Fosforilase/genética , Timidilato Sintase/genética , Uracila/administração & dosagem
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