RESUMO
BACKGROUND/AIMS: We aimed to clarify whether cyclooxygenase-2 (COX-2) and microsomal prostaglandin E synthase-1 (mPGES-1) genotypes were associated with certain histological findings and endoscopical appearances based on Kyoto classification. METHODS: We enrolled 285 Helicobacter pylori-infected gastritis patients. Genotypes of COX-2 1195, COX-2 1290, mPGES-1, interleukin-1ß (IL-1ß) 511 and tumour necrosis factor-α (TNF-α) 308 were analyzed. Genotyping was performed by polymerase chain reaction. Endoscopic appearances and histological assessment were determined by using Kyoto classification, operative link on gastritic intestinal metaplasia assessment and the updated Sydney system. RESULTS: There was a significant (p = 0.027) relationship between the IL-1ß 511 C-carrier and histological gastric inflammation in H. pylori-infected gastritis patients. There was a significant (p = 0.009) correlation between the COX-2 1195 G-carrier genotype and histological intestinal metaplasia in the gastric antrum of H. pylori-infected gastritis patients and gastric xanthoma (p = 0.027). The COX-2 1195 G-carrier genotype was also significantly (p = 0.038) associated with the score of endoscopic intestinal metaplasia based on Kyoto classification. The mPGES-1 genotype was significantly (p = 0.002) associated with endoscopic swelling of area. CONCLUSION: Our results suggest that in Japan, there exists a significant correlation between the COX-2 1195 G-carrier genotype and intestinal metaplasia in histological and endoscopic findings based on Kyoto classification in H. pylori-infected gastric mucosa.
Assuntos
Ciclo-Oxigenase 2/genética , Mucosa Gástrica/patologia , Gastrite/genética , Infecções por Helicobacter/genética , Lesões Pré-Cancerosas/genética , Antro Pilórico/patologia , Xantomatose/genética , Idoso , Feminino , Mucosa Gástrica/diagnóstico por imagem , Mucosa Gástrica/microbiologia , Gastrite/diagnóstico por imagem , Gastrite/microbiologia , Gastrite/patologia , Gastroscopia , Genótipo , Técnicas de Genotipagem/métodos , Infecções por Helicobacter/diagnóstico por imagem , Infecções por Helicobacter/microbiologia , Infecções por Helicobacter/patologia , Helicobacter pylori/isolamento & purificação , Humanos , Interleucina-1beta/genética , Japão , Masculino , Metaplasia/diagnóstico por imagem , Metaplasia/genética , Metaplasia/microbiologia , Metaplasia/patologia , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Lesões Pré-Cancerosas/diagnóstico por imagem , Lesões Pré-Cancerosas/microbiologia , Lesões Pré-Cancerosas/patologia , Prostaglandina-E Sintases/genética , Antro Pilórico/diagnóstico por imagem , Antro Pilórico/microbiologia , Xantomatose/microbiologia , Xantomatose/patologiaRESUMO
BACKGROUND: Recent updated guidelines of the Japanese Society of Gastroenterology recommend the use of a single dose of antiplatelet agents in patients undergoing endoscopic submucosal dissection (ESD). However, the postoperative bleeding risk after gastric ESD associated with the continuation or interruption of antithrombotic therapy remains controversial. We aimed to evaluate whether certain factors including interrupted antithrombotic therapy could affect early and delayed post-ESD bleeding risk. METHODS: Three hundred sixty-four patients with gastric neoplasms were treated with ESD at our hospital between October 2005 and December 2012. Seventy-four patients with interrupted antithrombotic therapy were undertaken with ESD. Early and delayed postoperative bleeding patterns were estimated. Various clinical characteristics such as gender, age, tumor location, tumor size, ESD procedure time, platelet count, and comorbidity were evaluated. RESULTS: There was a significant difference (p = 0.042) in the ESD procedure time between the patients with postoperative bleeding and those without it. There was no significant difference in postoperative bleeding between the patients on antithrombotic therapy and not on it. Moreover, interrupted antithrombotic therapy and platelet count were significantly (p = 0.0461 and p = 0.0059, respectively) associated with early postoperative bleeding in multivariate analysis. In addition, in univariate analysis, ESD procedure time was significantly (p = 0.041) associated with delayed postoperative bleeding. CONCLUSIONS: Antithrombotic therapy and prolonged ESD procedure time were significantly associated with early and delayed postoperative bleeding, respectively.
Assuntos
Ressecção Endoscópica de Mucosa/efeitos adversos , Hemorragia Gastrointestinal/epidemiologia , Neoplasias Gastrointestinais/cirurgia , Inibidores da Agregação Plaquetária/efeitos adversos , Hemorragia Pós-Operatória/epidemiologia , Tromboembolia/prevenção & controle , Idoso , Aspirina/efeitos adversos , Aspirina/normas , Feminino , Mucosa Gástrica/cirurgia , Hemorragia Gastrointestinal/sangue , Hemorragia Gastrointestinal/etiologia , Neoplasias Gastrointestinais/sangue , Gastroscopia/efeitos adversos , Humanos , Mucosa Intestinal/cirurgia , Masculino , Pessoa de Meia-Idade , Duração da Cirurgia , Inibidores da Agregação Plaquetária/normas , Contagem de Plaquetas , Hemorragia Pós-Operatória/sangue , Hemorragia Pós-Operatória/etiologia , Período Pós-Operatório , Guias de Prática Clínica como Assunto , Estudos Retrospectivos , Fatores de Risco , Fatores de TempoRESUMO
An 81-year-old man was admitted with upper abdominal pain and weight loss. Esophagogastroduodenoscopy revealed a large tumor located from the gastric angle to the body. Histological analysis of a biopsy revealed a moderately differentiated adenocarcinoma. Computed tomography revealed metastases in the liver and lung and the patient was subsequently diagnosed with metastatic advanced gastric cancer. He was treated with chemotherapy using S-1 (80 mg/m2) and cisplatin (CDDP) (60 mg/m2). Twenty-two months after chemotherapy, the gastric tumor, and the nodules in the liver and lung, had disappeared. We subsequently diagnosed a clinical complete response. The patient was treated with further S-1 monotherapy for 7 months after complete response assessment. He has lived for more than 7 years since the initial diagnosis without recurrence. Chemotherapy using S-1 and CDDP may be a potent strategy for improving survival in elderly patients with advanced gastric cancer.
Assuntos
Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia , Idoso de 80 Anos ou mais , Endoscopia do Sistema Digestório , Seguimentos , Humanos , Masculino , Metástase Neoplásica , Neoplasias Gástricas/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Resultado do TratamentoRESUMO
We report a case of lymph node metastasis of intrahepatic bile duct cancer that was successfully treated using chemotherapy and radiation therapy.A man in his 70s underwent hepatic resection for intrahepatic bile duct cancer, and abdominal CT 1 year 8 months after surgery revealed lymph node swelling(25mm in diameter)along the common hepatic artery.He was diagnosed with lymph node metastasis and began to receive chemotherapy.We administered gemcitabine(GEM), cisplatin, and S-1 for 6 months, and GEM and S-1 for 1 year 4 further months as combination therapy.One year 10 months after the start of chemotherapy, the size of the lymph node decreased to 13 mm.However, as FDG uptake was seen on FDG-PET, radiation targeted to the lymph node was applied(50 Gy/25 Fr).After completion of radiation therapy, the lymph node has not regrown even in the absence of treatment, and the patient survives 6 years after the primary operation(4 years 4 months since the start of chemotherapy for recurrence).This case suggested that multidisciplinary therapy might be useful for lymph node metastasis of intrahepatic bile duct cancer.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias dos Ductos Biliares/terapia , Ductos Biliares Intra-Hepáticos/patologia , Idoso , Neoplasias dos Ductos Biliares/patologia , Ductos Biliares Intra-Hepáticos/cirurgia , Terapia Combinada , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Combinação de Medicamentos , Humanos , Metástase Linfática , Masculino , Ácido Oxônico/administração & dosagem , Recidiva , Tegafur/administração & dosagem , Resultado do Tratamento , GencitabinaRESUMO
BACKGROUND: In Japanese routine clinical practice, endoscopy is generally carried out without sedation. The present study aimed to identify the factors essential for appropriate selection of transnasal esophagogastroduodenoscopy (TN-EGD) as an alternative to unsedated transoral esophagogastroduodenoscopy (TO-EGD). PATIENTS AND METHODS: Subjects in this prospective cohort study comprised consecutive outpatients who underwent EGD at a single center. Factors predicting TO-EGD-induced distress were evaluated on a visual analog scale (VAS) and analyzed. Patients were classified into a two-layered system on the basis of these predictive factors, and the severity of distress between the TN-EGD and TO-EGD groups was compared using VAS and the change in the rate-pressure product as subjective and objective indices, respectively. RESULTS: In total, 728 outpatients (390 male, 338 female; mean age, 63.1 ± 0.5 years; TO-EGD group, 630; TN-EGD group, 98)met the inclusion criteria. Multivariate logistic regression analysis confirmed that age <65 years (P < 0.01; odds ratio [OR], 1.69; 95% confidence interval [CI], 1.14-2.52), gender (female; P < 0.01; OR,1.97; 95% CI, 1.34-2.91), marital status (single; P < 0.01; OR, 1.96; 95% CI, 1.18-3.27), and anxiety towards TO-EGD (P < 0.001; OR, 3.62; 95% CI, 2.44-5.37) were independently associated with intolerance. Both indices were significantly higher in the TO-EGD subgroup than in the TN-EGD subgroup in the high predictive class, but not in the low predictive class. CONCLUSION: Predictive factors for detecting intolerance to unsedated TO-EGD may be useful to appropriately select patients who transpose unsedated TO-EGD to TN-EGD.
Assuntos
Endoscopia Gastrointestinal/métodos , Gastroenteropatias/terapia , Cirurgia Endoscópica por Orifício Natural/métodos , Medição da Dor/métodos , Dor/classificação , Feminino , Seguimentos , Gastroenteropatias/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Boca , Nariz , Satisfação do Paciente , Estudos Prospectivos , Inquéritos e QuestionáriosRESUMO
BACKGROUND AND AIM: Little is known about the clinical significance of treatment for endoscopically determined peptic ulcers (EPU), incidentally detected as surrogate endpoints for non-steroidal anti-inflammatory drugs (NSAIDs)-associated ulcers complication, such as overt bleeding and perforation. Even uncomplicated-EPU without overt bleeding signs when antithrombotic agents (AT) were cotherapied may be of potential bleeding sites. The aim of the present study was to evaluate whether microcytic anemia, implying potential bleeding, is associated with NSAIDs-associated EPU or cotherapies with AT. METHODS: Two hundred and thirty-eight outpatients with rheumatoid arthritis under long-term NSAIDs therapies underwent upper endoscopy and were divided into the following four groups according to the pattern (presence: + or absence: -) of AT cotherapy/EPU, respectively: A, -/- (n = 165); B, -/+ (n = 44); C, +/- (n = 25); and D, +/+ (n = 4). RESULTS: EPU were found in 48 of the 238 studied patients (20.2%). After significant interactions among four groups hadstatistically been identified, hemoglobin (Hb) and mean corpuscular volume (MCV) as biomarkers for potential bleeding were compared between the groups.Hb and MCV were significantly lower in the D group than in the A,B, or C groups (Hb: P < 0.01, respectively; P < 0.05, MCV; P < 0.01 or P < 0.05, respectively). CONCLUSIONS: Patients with NSAIDs-associated EPU and AT cotherapy indicated significantly more severe microcytic anemia pattern than those without EPU or AT cotherapy, despite no evidence of overt bleeding. Even uncomplicated-EPU without overt bleeding when ATs were cotherapied may be of potential bleeding sites.
Assuntos
Fibrinolíticos/uso terapêutico , Gastroscopia , Úlcera Péptica Hemorrágica/tratamento farmacológico , Análise de Variância , Anti-Inflamatórios não Esteroides/efeitos adversos , Ensaio de Imunoadsorção Enzimática , Feminino , Infecções por Helicobacter/diagnóstico , Helicobacter pylori , Humanos , Masculino , Pessoa de Meia-Idade , Úlcera Péptica Hemorrágica/induzido quimicamente , Estudos RetrospectivosRESUMO
BACKGROUND: Endoscopic submucosal dissection (ESD) is more invasive than other common endoscopic procedures and may increase the risk for deep vein thrombosis (DVT)/pulmonary embolism. The incidence of DVT/pulmonary embolism after ESD has not been adequately studied. OBJECTIVE: To evaluate DVT incidence and disease-specific features of D-dimer levels in ESD patients. DESIGN: Prospective cohort study. SETTING: Single academic center. PATIENTS: This study involved 60 patients with superficial gastric neoplasms indicated for ESD. INTERVENTION: For all patients who underwent ESD, ultrasonography of the lower limbs was performed to detect DVT the day after ESD. D-dimer levels were measured 3 times: before ESD, immediately after ESD, and the day after ESD. MAIN OUTCOME MEASUREMENTS: DVT incidence after ESD. RESULTS: The DVT incidence was 10.0% (6/60). At all 3 time points, D-dimer measurements were higher in patients with DVT than in patients without DVT. According to receiver operating characteristic curve analysis, the resulting cut-off value of the D-dimer level the day after ESD was 1.9 µg/mL (sensitivity 83.3%; specificity 79.6%) for ESD patients, with superior association to pre-ESD or immediately after ESD. In univariate analyses, high D-dimer levels the day after ESD and the presence of comorbidities were significantly associated with DVT development. LIMITATIONS: Single center and small number of patients. CONCLUSION: ESD procedures have a moderate risk for venous thromboembolism. In patients undergoing ESD, D-dimer levels, especially on the day after ESD, may have specific features associated with DVT development.
Assuntos
Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Gastroscopia/efeitos adversos , Embolia Pulmonar/etiologia , Neoplasias Gástricas/cirurgia , Trombose Venosa/etiologia , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Embolia Pulmonar/diagnóstico , Embolia Pulmonar/diagnóstico por imagem , Curva ROC , Ultrassonografia , Trombose Venosa/diagnóstico , Trombose Venosa/diagnóstico por imagemRESUMO
Low-dose aspirin (L-ASA) has been increasingly used for primary or secondary prevention of cardiovascular events, and has the advantages of both low cost and long duration of antiplatelet action. But, an increment of L-ASA prescription has become an object of public concern for gastrointestinal events through its antiplatelet action and cyclooxygenase inhibitory action. Although knowledge about endoscopic characteristics of L-ASA associated ulcers is limited, the ulcers have common distinctive feature that sudden gastrointestinal bleedings or latently advanced-anemia are often the earliest symptom because aspirin-induced ulcers often exist without symptoms of dyspepsia. Endoscopic characteristics of L-ASA associated ulcers seem to be required further investigation, including the impact of the severity of gastritis and corpus atrophy by Helicobacter pylori infection on the endoscopic characteristics.
Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Aspirina/efeitos adversos , Endoscopia Gastrointestinal , Úlcera Péptica/induzido quimicamente , Úlcera Péptica/patologia , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Rheumatoid arthritis (RA) patients are at increased risk of peptic ulcers (PU) induced by nonsteroidal antiinflammatory drugs (NSAIDs). However, the impact of potential drug interactions on the development of PU has yet to be determined in a daily clinical setting. The aim was to estimate the clinical important interactions for PU presented by comedication in Japanese RA outpatients on long-term NSAID treatment. METHODS: This retrospective cohort study enrolled 196 consecutive RA outpatients on NSAID medication for at least 3 months. Potential risk factors for endoscopic PU were analyzed in RA outpatients on longterm NSAID treatment. RESULTS: PU incidence was 31% with bisphosphonate co-therapy and 17% without the co-therapy. PU incidence was only 5% in subjects with proton pump inhibitors (PPI) or prostaglandin E1 analogues (PG) co-therapy, 14% with histamine-H(2) receptor antagonists(H2RA) co-therapy, and 27% without anti-ulcer agents. In multivariate logistic regression analysis, bisphosphonate co-therapy remained a significant risk factor for PU (OR, 2.29; 95% CI, 1.09-4.81). Other risk factors for ulcer development were advanced age (greater than 60 years) and smoking (OR, 2.58; 95% CI, 1.03-6.49 and OR, 2.71; 95% CI, 1.13-5.53, respectively.) Factors that significantly reduced the incidence of PU were H2RA or PPI/PG cotherapies (OR, 0.29; 95% CI, 0.12-0.68.). CONCLUSIONS: Bisphosphonate co-therapy as well as advanced age and smoking was found to be a significant risk factor in PU, while co-therapies of standard-dose H2RA or PPI/PG proved effective in preventing PU in Japanese RA patients on long-term NSAID treatment.
Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Artrite Reumatoide/tratamento farmacológico , Conservadores da Densidade Óssea/administração & dosagem , Difosfonatos/administração & dosagem , Úlcera Péptica/epidemiologia , Idoso , Estudos de Coortes , Esquema de Medicação , Endoscopia do Sistema Digestório , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Úlcera Péptica/diagnóstico , Polimedicação , Estudos Retrospectivos , Fatores de RiscoRESUMO
BACKGROUND AND AIMS: The aim of this study was to see whether administration of celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, could prevent the development of gastric cancer via inhibition of apurinic/apyrimidinic endonuclease-1 (APE-1) expression induced by Helicobacter pylori infection. METHODS: 70 Mongolian gerbils were divided into 6 groups. Group 1 gerbils served as controls (n = 6). Ten gerbils were given N-methyl-N-nitrosourea (MNU), 30 ppm, 5 times biweekly (group 2). Short-term H. pylori infection was induced in 6 gerbils which were sacrificed 8 weeks after H. pylori infection (group 3). Long-term H. pylori infection was induced in 6 other gerbils which were sacrificed 44 weeks after H. pylori infection (group 4). Twenty gerbils were given MNU pretreatment 5 times biweekly and long-term H. pylori infection (group 5). In addition, after H. pylori inoculation, group 6 gerbils also received celecoxib with their diet for 26 weeks. APE-1 expression alone or with COX-2 in gastric tissues was evaluated by Western blot and immunohistological analysis. Myeloperoxidase (MPO) activity and thiobarbituric-acid-reactive substance (TBARS) levels were also evaluated. RESULTS: APE-1 was localized in gastric epithelial cells and mesenchymal cells including macrophages in H. pylori-infected gerbils. The numbers of APE-1-positive cells in group 4 and 5 were significantly increased compared to those of group 3. Celecoxib treatment significantly reduced MPO activity, TBARS levels and the incidence of gastric cancer. APE-1 and IkappaBalpha phosphorylation levels were significantly increased in MNU-pretreated H. pylori-infected gerbils compared to those in MNU-only gerbils. Celecoxib significantly reduced APE-1 and IkappaBalpha phosphorylation levels in MNU-pretreated H. pylori-infected gerbils. COX-2 and APE-1 were coexpressed in the macrophages of H. pylori-infected gerbils. CONCLUSION: Celecoxib prevented gastric cancer in MNU-pretreated H. pylori-infected gerbils with a reduction in APE-1 expression thereby suggesting the implication of APE-1 in gastric carcinogenesis in this model.
Assuntos
Inibidores de Ciclo-Oxigenase/administração & dosagem , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/biossíntese , Expressão Gênica/efeitos dos fármacos , Infecções por Helicobacter/metabolismo , Pirazóis/administração & dosagem , Neoplasias Gástricas/prevenção & controle , Sulfonamidas/administração & dosagem , Animais , Celecoxib , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/genética , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Gerbillinae , Infecções por Helicobacter/complicações , Masculino , Neoplasias Gástricas/etiologiaRESUMO
BACKGROUND AND AIM: Apurinic/apyrimidinic endonuclease-1 (APE-1) is a key enzyme in DNA base excision repair (BER), linked to cancer chemosensitivity. However, little is known about the localization of APE-1 in Helicobacter pylori-infected gastric mucosa or its role in the development of gastric cancer. To investigate the role of APE-1 in the development of gastric cancer, we examined APE-1 expression and localization in cultured cells and gastric biopsies from patients with H. pylori-infected gastritis or gastric adenoma, and from surgically resected gastric cancer. METHODS: APE-1 mRNA and protein expression were determined in H. pylori (CagA+) water-extract protein (HPWEP)-stimulated MKN-28 cells, gastric adenocarcinoma cell-line (AGS) cells, and human peripheral macrophages by real-time polymerase chain reaction and Western blot analysis. APE-1 expression and 8-OHdG as a measure of oxidative DNA damage were evaluated by immunostaining. Localization of APE-1 and IkappaBalpha phosphorylation in gastric adenoma and gastric cancer tissues were evaluated by single- and double-label immunohistochemistry. RESULTS: In studies in vitro, HPWEP-stimulation significantly increased APE-1 mRNA expression levels in both MKN-28 cells and human peripheral macrophages. Hypo/reoxygenation treatment significantly increased APE-1 protein expression in HPWEP-stimulated MKN-28 cells. HPWEP stimulation significantly increased both APE-1 expression and IkappaBalpha phosphorylation levels in MKN-28 and AGS cells. In human tissues, APE-1 expression in H. pylori-infected gastritis without goblet cell metaplasia was significantly increased as compared to that in tissues from uninfected subjects. Eradication therapy significantly reduced both APE-1 and 8-OHdG expression levels in the gastric mucosa. APE-1 expression was mainly localized in epithelial cells within gastric adenoma and in mesenchymal cells of gastric cancer tissues. APE-1 expression in gastric cancer tissues was significantly reduced compared to that in H. pylori-infected gastric adenoma, while 8-OHdG index and IkappaBalpha phosphorylation levels did not differ between these two neoplastic tissue types. Co-localization of APE-1 and IkappaBalpha phosphorylation was observed not in gastric cancer cells but in gastric adenoma cells. CONCLUSION: H. pylori infection is associated with increased APE-1 expression in human cell lines and in gastric tissues from subjects with gastritis and gastric adenomas. The observed distinct expression patterns of APE-1 and 8-OHdG in gastric adenoma and gastric cancer tissues may provide insight into the progression of these conditions and warrants further investigation.
Assuntos
DNA Liase (Sítios Apurínicos ou Apirimidínicos)/metabolismo , Gastrite/enzimologia , Gastrite/microbiologia , Infecções por Helicobacter/enzimologia , Helicobacter pylori , Neoplasias Gástricas/enzimologia , Neoplasias Gástricas/microbiologia , Adenoma/enzimologia , Adenoma/genética , Adenoma/microbiologia , Adulto , Idoso , Células Cultivadas , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/genética , Feminino , Mucosa Gástrica/metabolismo , Mucosa Gástrica/microbiologia , Gastrite/genética , Infecções por Helicobacter/genética , Infecções por Helicobacter/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/metabolismo , Neoplasias Gástricas/genéticaRESUMO
BACKGROUND: Recent studies have reported that expression of monocyte chemoattractant protein 1 (MCP-1) and its receptor (CCR2) and CD40 ligation on mesenchymal cells play important roles in tumor development. Cyclooxygenase 2 (COX-2) has also been shown to contribute to tumor angiogenesis. We examined the interaction between MCP-1 and CD40 ligation in mesenchymal cells in gastric cancer to determine the effect of these factors on vascular endothelial growth factor (VEGF) production via upregulation of COX-2 expression. METHODS: COX-2, prostaglandin E2 (PGE2), and VEGF production were evaluated in CD40 ligand (CD40L)-stimulated macrophages. CD40L and MCP-1 mRNA levels in gastric cancer tissues were evaluated by real-time polymerase chain reaction (PCR). Localizations of MCP-1, CD40L, CD34, CD40, and CCR2 in 34 gastric cancer tissue specimens were evaluated by single-or double-label immunohistochemistry. RESULTS: COX-2 expression levels were significantly higher in CD40L-stimulated macrophages and correlated with increased PGE2 and VEGF production. Addition of MCP-1 to CD40L-stimulated macrophages had a synergistic effect on COX-2 expression and subsequent PGE2 and VEGF production. CD40L and MCP-1 mRNA levels were significantly higher in poorly differentiated gastric cancers than in H. pylori-infected gastritis patients. High microvessel density was significantly associated with MCP-1 and CCR2 scores and lymph node metastasis. CONCLUSIONS: MCP-1 and CD40L had a synergistic effect on COX-2 expression and subsequent VEGF production in gastric cancer.
Assuntos
Ligante de CD40/metabolismo , Quimiocina CCL2/metabolismo , Ciclo-Oxigenase 2/metabolismo , Neoplasias Gástricas/patologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Adenocarcinoma/patologia , Adulto , Idoso , Ciclo-Oxigenase 2/genética , Feminino , Gastrite/microbiologia , Gastrite/patologia , Humanos , Imuno-Histoquímica , Metástase Linfática , Macrófagos/metabolismo , Masculino , Mesoderma/citologia , Mesoderma/patologia , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , RNA Mensageiro/metabolismo , Receptores CCR2/metabolismo , Regulação para CimaRESUMO
Recent studies have reported that expression of MCP-1 and its receptor, CCR2; and CD40-CD40 ligand (CD40L) interaction on mesenchymal cells play important roles in tumor development. Studies have also connected MCP-1, CCR2, and CD40L to COX-2 expression. The aim of this study was to examine the effect of MCP-1/CCR2 and CD40-CD40L interaction on COX-2 and VEGF expression in endothelial cells. We also investigated the localization of these proteins in gastric cancer tissue. COX-2 and CCR2 levels were evaluated in CD40L-stimulated HUVECs by Western blot and real-time PCR. VEGF secreted in the culture media was quantified by ELISA. Localizations of MCP-1, CD40L, CD34, CD40 and CCR2 in 34 gastric cancer tissue specimens were evaluated by immunohistochemistry. CD40-CD40L interaction-induced COX-2 production and subsequently, upregulated COX-2 production contributed to elevated VEGF and CCR2 levels in CD40L-stimulated HUVECs. CD40L-stimulated VEGF production was COX-2 but not COX-1 dependent. RS-102895, a CCR2-specific antagonist, significantly reduced VEGF production in CD40L- and MCP-1-stimulated HUVECs. MCP-1 had a synergistic effect on COX-2, CCR2 and VEGF levels in CD40L-stimulated HUVECs. In gastric cancer tissue, there was significant correlation between microvessel density and scores for CD40L, MCP-1 and CCR2 protein expression. Thus, MCP-1 had a synergistic effect on COX-2 and CCR2 protein expression in CD40L-stimulated HUVECs and thereby stimulated VEGF production in these cells.
Assuntos
Benzoxazinas/metabolismo , Ligante de CD40/metabolismo , Quimiocina CCL2/metabolismo , Ciclo-Oxigenase 2/metabolismo , Células Endoteliais/metabolismo , Regulação da Expressão Gênica , Piperidinas/metabolismo , Receptores CCR2/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Antígenos CD40/metabolismo , Linhagem Celular , Meios de Cultivo Condicionados , Ciclo-Oxigenase 2/genética , Células Endoteliais/citologia , Humanos , Microcirculação , Receptores CCR2/antagonistas & inibidores , Receptores CCR2/genética , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologiaRESUMO
BACKGROUND: Recent studies have shown that CD40, a key player in angiogenesis and tubular formation, is an extracellular receptor of the heat shock protein 70 (HSP70)-peptide complex in endothelial cells. The aim of the present study was to determine the effect of extracellular HSP70 treatment on CD40L-suppressed apoptosis and CD40L-induced tubular formation in human umbilical vein endothelial cells (HUVEC). METHODS: The apoptotic index of CD40L-stimulated HUVEC with or without recombinant human HSP70 was evaluated using terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling assay analysis. Binding of HSP70-peptide complex to CD40 on HUVEC was determined by double-labeling immunofluorescence methods. To evaluate the biological activity of CD40 engagement pretreated with rhHSP70 (0.5, 1 and 3 ng/mL), the extent of new capillary-like networking structure (tubular formation) formation in HUVEC was counted using an Olympus digital camera. Vascular invasion into MNK-28 cell clusters was assessed by counting the number of tubular structures extending from the HUVEC into growth factor-depleted Matrigel. Scores for CD34, HSP70 and CD40L expression levels in gastric cancer tissues were determined by immunostaining. RESULTS: CD40L stimulation inhibited vincristine-induced apoptosis of HUVEC in a dose-dependent manner. Extracellular HSP70 treatment significantly blocked the inhibition of apoptosis by CD40L in HUVEC exposed to vincristine. HSP70-peptide complex bound to CD40 on HUVEC. Extracellular HSP70 treatment also significantly reduced CD40L-induced tubular formation in a dose-dependent manner. HSP70 treatment also suppressed invasive tubular formation into MKN-28 cells clusters by CD40L-activated HUVEC. There was a significant relationship between CD40L expression levels and microvessel density; however, the relationship between HSP70 expression level and microvessel density in gastric cancer tissues was not significant. CONCLUSIONS: Extracellular HSP70 treatment blocks CD40L inhibition of apoptosis and CD40L induction of tubular formation in HUVEC.
Assuntos
Apoptose , Antígenos CD40/metabolismo , Ligante de CD40/metabolismo , Células Endoteliais/metabolismo , Proteínas de Choque Térmico HSP70/metabolismo , Neovascularização Fisiológica , Antígenos CD34/análise , Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular , Células Cultivadas , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/patologia , Humanos , Microvasos/química , Microvasos/patologia , Proteínas Recombinantes/metabolismo , Neoplasias Gástricas/irrigação sanguínea , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Vincristina/farmacologiaRESUMO
Studies have linked microsomal prostaglandin E synthase (mPGES)-1 with gastric cancer. The purpose of this study was to determine mPGES-1, mPGES-2, and cytosolic PGES (cPGES) expression in gastric cancer and to evaluate the correlation between mPGES-1 and mPGES-2 expression and clinicopathological factors and cyclooxygenase-2 expression. PGES protein expression was examined by Western blot in gastric cancer cell lines and in biopsy samples from patients with gastric cancer. mPGES-1, mPGES-2, and cPGES protein localizations were examined immunohistochemically in 129 archival gastric cancer surgical resections. mPGES-1 protein expression was found in gastric cancer biopsies and cancer cell lines with differentiated or undifferentiated adenocarcinoma. There was no mPGES-1 expression in nonneoplastic biopsies. All cell lines and tissue samples expressed mPGES-2 and cPGES. Immunohistochemical analysis showed cancer cells expressed mPGES-1 in 47% of cases. mPGES-2 immunoreactivity was seen both in nonneoplastic glandular epithelium and cancer cells; however, cancer cell immunoreactivity was significantly more pronounced in 29% of cases. cPGES expression was constitutive both in nonneoplastic and neoplastic tissues, with no significant variation among cases. mPGES-1 and mPGES-2 expression correlated with cyclooxygenase-2 expression. mPGES-1 and mPGES-2 expression, and tumor-node-metastasis stage had independent prognostic significance under multivariate analysis in patients with gastric cancer overall and in patients with differentiated cancers. However, only tumor-node-metastasis stage and mPGES-2 expression retained independent prognostic significance in patients with poorly differentiated cancers. mPGES-1 and mPGES-2 correlate with clinicopathological factors and may be valuable prognostic factors in gastric cancer.
Assuntos
Adenocarcinoma/enzimologia , Oxirredutases Intramoleculares/biossíntese , Neoplasias Gástricas/enzimologia , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Idoso , Western Blotting , Ciclo-Oxigenase 2/biossíntese , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Metástase Linfática/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Prostaglandina-E Sintases , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologiaRESUMO
BACKGROUND/AIM: The aim of this study was to see whether administration of celecoxib, a selective COX-2 inhibitor, prior to the appearance of intestinal metaplasia could prevent the development of gastric cancer in Helicobacter pylori-infected Mongolian gerbils. METHODS: Fifty-two Mongolian gerbils were divided into 3 groups and given 5 biweekly doses of N-methyl-N-nitrosourea (MNU; 30 ppm). At week 12, group 2 (n = 20) and group 3 (n = 22) gerbils were then given an injection of H. pylori, while group 1 controls (n = 10) received Brucella broth alone. In addition, 7 weeks after H. pylori inoculation, at week 19, group 3 gerbils also received a 36-week administration course of celecoxib (1,500 ppm) in their diet. The incidence of gastric adenocarcinoma was determined at week 54 by histological analysis. COX-2 and Cdx2 protein expression and COX activity were evaluated for each group. The extent of intestinal metaplasia, Cdx2 and MUC2 expression, and the apoptotic index were evaluated semi-quantitatively by immunohistochemistry. RESULTS: The incidence of gastric adenocarcinoma was: group 1, 0% (0/10); group 2, 65% (13/20), and group 3, 23% (5/22; p < 0.05). Continuous celecoxib administration significantly reduced COX activity and COX-2 protein expression, Cdx2 and MUC2 protein immunoreactivity, and the extent of Alcian blue periodic acid-Schiff-positive intestinal metaplasia in H. pylori-infected gerbils. Celecoxib also induced apoptosis in these gerbils. Significant inhibition of Cdx2 expression in group 3 gerbils was also shown by Western blot analysis. CONCLUSIONS: Prior to the first appearance of intestinal metaplasia, timely administration of celecoxib prevents gastric cancer occurrence by disrupting the progression of intestinal metaplasia into gastric carcinoma through its inhibition of Cdx2 expression in MNU-pretreated H. pylori-infected Mongolian gerbils.
Assuntos
Biomarcadores Tumorais/análise , Infecções por Helicobacter/patologia , Proteínas de Homeodomínio/metabolismo , Lesões Pré-Cancerosas/patologia , Pirazóis/farmacologia , Neoplasias Gástricas/prevenção & controle , Sulfonamidas/farmacologia , Animais , Biópsia por Agulha , Fator de Transcrição CDX2 , Celecoxib , Modelos Animais de Doenças , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/patologia , Regulação Neoplásica da Expressão Gênica , Gerbillinae , Helicobacter pylori/patogenicidade , Proteínas de Homeodomínio/efeitos dos fármacos , Proteínas de Homeodomínio/genética , Imuno-Histoquímica , Masculino , Probabilidade , Distribuição Aleatória , Valores de Referência , Medição de Risco , Sensibilidade e Especificidade , Neoplasias Gástricas/microbiologia , Neoplasias Gástricas/patologiaRESUMO
A 54-year-old man was admitted to our hospital with the symptoms of palpitation, dyspnea, and tarry stool. Upper gastroduodenal endoscopy revealed submucosal lesions with vascular ectasia in the second part of the duodenum. Dynamic computed tomography (CT) detected a hypervascular lesion in the pancreatic head and the duodenum. Selective angiography showed proliferation of a vascular network and early filling of the portal vein at the early arterial phase. With a diagnosis of pancreatic arteriovenous malformation (AVM), we performed pylorus-preserving pancreaticoduodenectomy. At laparotomy, localized and meandering vessels were seen on the surface of the head of the pancreas. Histological examination showed dilated tortuous vessels accompanied by severed elastic fibers in the vessel media and blood clot formation. The incidence of pancreatic AVM remains extremely low, and recurrent gastrointestinal bleeding is a frequent complication. To prevent recurrent bleeding and progressive portal hypertension, surgery may be the definitive management of symptomatic AVM.
Assuntos
Malformações Arteriovenosas/complicações , Duodeno/irrigação sanguínea , Hemorragia Gastrointestinal/etiologia , Pâncreas/irrigação sanguínea , Malformações Arteriovenosas/diagnóstico , Malformações Arteriovenosas/cirurgia , Hemorragia Gastrointestinal/prevenção & controle , Humanos , Hipertensão Portal/etiologia , Hipertensão Portal/prevenção & controle , Masculino , Pessoa de Meia-Idade , Pancreaticoduodenectomia/métodos , Prevenção SecundáriaRESUMO
We have previously shown that the cyclooxygenase (COX)-2/PGE2 pathway plays a key role in VEGF production in gastric fibroblasts. Recent studies have identified three PGE synthase (PGES) isozymes: cytosolic PGES (cPGES) and microsomal PGES (mPGES)-1 and -2, but little is known regarding the expression and roles of these enzymes in gastric fibroblasts. Thus we examined IL-1beta-stimulated mPGES-1 and cPGES mRNA and protein expression in gastric fibroblasts by quantitative PCR and Western blot analysis, respectively, and studied both their relationship to COX-1 and -2 and their roles in PGE2 and VEGF production in vitro. IL-1beta stimulated increases in both COX-2 and mPGES-1 mRNA and protein expression levels. However, COX-2 mRNA and protein expression were more rapidly induced than mPGES-1 mRNA and protein expression. Furthermore, MK-886, a nonselective mPGES-1 inhibitor, failed to inhibit IL-1beta-induced PGE2 release at the 8-h time point, while totally inhibiting PGE2 at the later stage. However, MK-886 did inhibit IL-1beta-stimulated PGES activity in vitro by 86.8%. N-(2-cyclohexyloxy-4-nitrophenyl)-methanesulfonamide (NS-398), a selective COX-2 inhibitor, totally inhibited PGE2 production at both the 8-h and 24-h time points, suggesting that COX-2-dependent PGE2 generation does not depend on mPGES-1 activity at the early stage. In contrast, NS-398 did not inhibit VEGF production at 8 h, and only partially at 24 h, whereas MK-886 totally inhibited VEGF production at each time point. These results suggest that IL-1beta-induced mPGES-1 protein expression preferentially coupled with COX-2 protein at late stages of PGE2 production and that IL-1beta-stimulated VEGF production was totally dependent on membrane-associated proteins involved in eicosanoid and glutathione metabolism (MAPEG) superfamily proteins, which includes mPGES-1, but was partially dependent on the COX-2/PGE2 pathway.
Assuntos
Dinoprostona/biossíntese , Fibroblastos/enzimologia , Microssomos/enzimologia , Prostaglandina-Endoperóxido Sintases/metabolismo , Linhagem Celular , Ciclo-Oxigenase 1 , Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase/farmacologia , Citosol/enzimologia , Expressão Gênica , Humanos , Indóis/farmacologia , Interleucina-1/farmacologia , Proteínas de Membrana , Nitrobenzenos/farmacologia , Pirazóis/farmacologia , Estômago/citologia , Estômago/fisiologia , Sulfonamidas/farmacologia , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Recently, three different prostaglandin E2 synthases have been identified: microsomal prostaglandin E synthase (mPGES)-1, cytosolic PGES (cPGES), and mPGES-2; however, their role and connection to cyclooxygenase (COX)-2 in the gastric ulcer repair process remain unknown. Therefore, we examined mPGES-1, cPGES, and mPGES-2 expression and localization in the stomach in vitro and in vivo. Tissues were obtained from Helicobacter pylori (H. pylori)-infected patients and consisted of surgical resections of gastric ulcers, or biopsies of gastric ulcers or gastritis. mPGES-1 mRNA and protein expression levels were examined by real-time polymerase chain reaction (PCR) and Western blot analysis, respectively. mPGES-1, cPGES, and mPGES-2 localization were analyzed immunohistochemically. Induction of PGES expression in response to interleukin (IL)-1beta was examined in vitro in the cultured human gastric fibroblast line Hs262.St. Real-time PCR analysis of mPGES-1 mRNA expression in biopsy samples showed significantly higher expression levels in open than in closed gastric ulcer tissue. Western blot analysis showed mPGES-1 protein expression limited to open ulcer tissue, while mPGES-2 and cPGES immunoreactivities were seen in both open and closed ulcer tissue. Immunohistochemical analysis showed strong mPGES-1 expression in fibroblasts and macrophages of the ulcer bed, paralleling COX-2 expression. cPGES and mPGES-2 expression levels were seen in both fibroblasts of the ulcer bed and in epithelial cells. Furthermore, stronger cPGES and mPGES-2 immunoreactivities were seen in scattered mast cell-like cells and neuroendocrine-like cells, respectively. Induction of mPGES-1 expression in response to IL-1beta was seen in cultured gastric fibroblasts in vitro, and double immunostaining showed mPGES-1 coexpression with COX-2 in fibroblasts of the ulcer bed in vivo. In conclusion, mPGES-1, cPGES, and mPGES-2 are all expressed in gastric ulcer tissue, but only mPGES-1 parallels COX-2 expression in mesenchymal and inflammatory cells of the ulcer bed, suggesting a key role for this enzyme in the ulcer repair process.
Assuntos
Gastrite/enzimologia , Oxirredutases Intramoleculares/metabolismo , Isoenzimas/metabolismo , Microssomos/enzimologia , Úlcera Gástrica/enzimologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Western Blotting , Linhagem Celular , Ciclo-Oxigenase 2 , Citosol/enzimologia , Indução Enzimática/efeitos dos fármacos , Feminino , Fibroblastos/enzimologia , Gastrite/microbiologia , Infecções por Helicobacter/enzimologia , Helicobacter pylori/enzimologia , Humanos , Imuno-Histoquímica , Interleucina-1/farmacologia , Macrófagos/metabolismo , Masculino , Proteínas de Membrana , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Prostaglandina-E Sintases , Prostaglandina-Endoperóxido Sintases/metabolismo , RNA Mensageiro/metabolismo , Úlcera Gástrica/microbiologia , Úlcera Gástrica/cirurgiaRESUMO
OBJECTIVES: One of the counter-effects of Helicobacter pylori eradication therapy is subsequent obesity. Ghrelin is a recently discovered growth hormone releasing peptide. This endogenous secretagogue increases appetite and facilitates fat storage. The majority of circulating ghrelin is produced in the gastric mucosa. Therefore, we aimed at investigating changes in ghrelin immunoreactivity in gastric mucosa tissues of patients infected with H. pylori. METHODS: Sixty-one patients with H. pylori infection (25 cases each of duodenal and gastric ulcer, and 11 cases of gastritis) and 22 healthy controls without H. pylori infection were included in the study. H. pylori-infected patients received standard proton pump-based triple therapy followed by histological examination and (13)C-urea breath test to confirm H. pylori eradication. H. pylori was eradicated in 50 out of 61 patients. Biopsy specimens were obtained from antrum and corpus before and 3 months following eradication. Ghrelin expression was evaluated immunohistochemically with an anti-ghrelin antibody, and the number of ghrelin-positive cells determined per 1 mm(2) of the lamina propria mucosa. RESULTS: There was no relationship between ghrelin immunoreactivity and body weight or body mass index for healthy controls. The number of ghrelin-positive cells was significantly lower for H. pylori-infected patients than for healthy controls. However, the ghrelin-positive cell number increased significantly following H. pylori eradication without significant change in severity of atrophy. CONCLUSIONS: These data indicated that H. pylori infection affected ghrelin expression. After H. pylori eradication, gastric tissue ghrelin concentration increased significantly. This could lead to the increased appetite and weight gain seen following H. pylori eradication.