RESUMO
BACKGROUND: Oral semaglutide in older subjects with type 2 diabetes was as effective as in younger subjects, according to phase 3 clinical trials. However, its efficacy can be limited in very aged population, due to the presence of impaired cognitive function and the complex instructions for its use. Here, we investigated its efficacy and safety by further age bracket in older subjects in real-world. METHODS: We retrospectively studied subjects > 65 years of age with type 2 diabetes who started oral semaglutide treatment. The primary outcome was the change in glycated hemoglobin (HbA1c) over 6 months. Adverse events and cognitive function were evaluated using the Common Terminology Criteria for Adverse Events (CTCAE) and the Hasegawa Dementia Rating Scale-revised (HDS-R). The achievement rate of glycemic targets was evaluated based on the age, health status of subjects and their use of anti-diabetic agents which can cause hypoglycemia, with additional analysis between two subgroups; early (65-74) versus late (≥ 75) older. Furthermore, we evaluated the relationships between their improvements in HbA1c and the baseline characteristics of the subjects, including their cognitive function and insulin secretory capacity. RESULTS: We studied the efficacy of the drug in 24 subjects. Their HbA1c and body weight significantly decreased (- 13.1 ± 7.5 mmol/mol and - 3.0 ± 2.4 kg, respectively; P < 0.01). Although cognitive function was lower in the late older group (r = -0.57, P < 0.01), changes in HbA1c showed no difference between the two subgroups (P = 0.66) and it correlated with the insulin secretory capacity rather than cognitive function (r = -0.49, P < 0.05). Glycemic targets were more likely to be achieved (P < 0.01), but HbA1c excessively decreased in late older subjects who were also using insulin or an insulin secretagogue. The frequency of adverse events was similar to that in the clinical trial, whereas discontinuation of medication were more frequent among the late older subjects (Early; n = 2, Late; n = 4). CONCLUSIONS: Oral semaglutide improves the glycemic control of older subjects, but it might be a risk for potential hypoglycemia and discontinuation because of adverse events in subjects of ≥ 75 years. Attention should be paid to insulin secretory capacity and concomitant medications rather than concern about adherence.
Assuntos
Diabetes Mellitus Tipo 2 , Peptídeos Semelhantes ao Glucagon , Hemoglobinas Glicadas , Hipoglicemiantes , Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Masculino , Feminino , Estudos Retrospectivos , Idoso , Peptídeos Semelhantes ao Glucagon/administração & dosagem , Peptídeos Semelhantes ao Glucagon/uso terapêutico , Peptídeos Semelhantes ao Glucagon/efeitos adversos , Hipoglicemiantes/uso terapêutico , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/efeitos adversos , Hemoglobinas Glicadas/análise , Idoso de 80 Anos ou mais , Administração Oral , Glicemia/análise , Glicemia/efeitos dos fármacos , Resultado do Tratamento , Hipoglicemia/induzido quimicamente , Seguimentos , Cognição/efeitos dos fármacosRESUMO
BACKGROUND AND AIMS: Acute graft-versus-host disease (GVHD) is a major complication after allogeneic hematopoietic stem cell transplantation, which often targets gastrointestinal (GI) tract. Osteopontin (OPN) plays an important physiological role in the efficient development of Th1 immune responses and cell survival by inhibiting apoptosis. The role of OPN in acute GI-GVHD is poorly understood. In the present study, we investigated the role of OPN in donor T cells in the pathogenicity of acute GI-GVHD. METHODS: OPN knockout (KO) mice and C57BL/6 (B6) mice were used as donors, and (C57BL/6 × DBA/2) F1 (BDF1) mice were used as allograft recipients. Mice with acute GI-GVHD were divided into three groups: the control group (BDF1âBDF1), B6 group (B6âBDF1), and OPN-KO group (OPN-KOâBDF1). Bone marrow cells and spleen cells from donors were transplanted to lethally irradiated recipients. Clinical GVHD scores were assessed daily. Recipients were euthanized on day 7 after transplantation, and colons and small intestines were collected for various analyses. RESULTS: The clinical GVHD score in the OPN-KO group was significantly increased compared with the B6 and control groups. We observed a difference in the severity of colonic GVHD between the OPN-KO group and B6 group, but not small intestinal-GVHD between these groups. Interferon-γ, Tumor necrosis factor-α, Interleukin-17A, and Interleukin-18 gene expression in the OPN-KO group was differed between the colon and small intestine. Flow cytometric analysis revealed that the fluorescence intensity of splenic and colonic CD8 T cells expressing Fas Ligand was increased in the OPN-KO group compared with the B6 group. CONCLUSION: We demonstrated that the importance of OPN in T cells in the onset of acute GI-GVHD involves regulating apoptosis of the intestinal cell via the Fas-Fas Ligand pathway.
Assuntos
Apoptose/imunologia , Células Epiteliais/imunologia , Gastroenteropatias/imunologia , Doença Enxerto-Hospedeiro/imunologia , Osteopontina/imunologia , Doença Aguda , Aloenxertos , Animais , Apoptose/genética , Transplante de Medula Óssea/efeitos adversos , Transplante de Medula Óssea/métodos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Citocinas/genética , Citocinas/imunologia , Citocinas/metabolismo , Proteína Ligante Fas/genética , Proteína Ligante Fas/imunologia , Proteína Ligante Fas/metabolismo , Citometria de Fluxo , Gastroenteropatias/genética , Gastroenteropatias/metabolismo , Expressão Gênica/imunologia , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/genética , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Contagem de Linfócitos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Camundongos Knockout , Microscopia de Fluorescência , Osteopontina/genética , Osteopontina/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Índice de Gravidade de DoençaRESUMO
BACKGROUND: Methods for the artificial three-dimensional (3D) culture of mouse and human small-intestinal and large-intestinal stem cells have been established with CD24+ or Paneth cell niches. In contrast, no studies have established stable 3D culture for rat colon stem cells. In this study, we established an advanced method for efficient rat colonic stem cell culture. METHODS: Using various tissue homogenates, we investigated the colonic organoid forming capacity under the TMDU protocol immediately adjacent to Ootani's 3D culture assembly in the same culture dish. Next, we examined whether the supernatant from the colon could be replaced by a colon homogenate. Finally, we identified the bioactive substances that were indispensable for efficient organoid culture using protein purification by three-step column chromatography and proteomic analysis with a quantitative nanoflow liquid chromatography-tandem mass spectrometry (LC-MS/MS). RESULTS: By combining Ootani's method with the TMDU protocol, we established a refined culture method for Lewis rat colon organoids, which we refer to as the modified TMDU protocol. Furthermore, we confirmed that PGE2 and galection-4 promoted rat colonic organoid formation. CONCLUSIONS: We established efficient rat colonic stem cell cultures in vitro. This success will contribute to the study of rat intestinal-disease models.
Assuntos
Colo/citologia , Técnicas de Cultura de Órgãos/métodos , Organoides/citologia , Organoides/crescimento & desenvolvimento , Animais , Células Cultivadas , Colo/crescimento & desenvolvimento , Ratos , Células-Tronco/citologiaRESUMO
Mutation in K-RAS (K-RAS-MT) plays important roles in both cancer progression and resistance to anti-epidermal growth factor receptor (EGFR) therapy in gastrointestinal tumors. Insulin-like growth factor-1 receptor (IGF-1R) signaling is required for carcinogenicity and progression of many tumors as well. We have previously shown successful therapy for gastrointestinal cancer cell lines bearing a K-RAS mutation using an anti-IGF-1R monoclonal antibody. In this study, we sought to evaluate effects of forced K-RAS-MT expression on gastrointestinal cancer cell lines representing a possible second resistance mechanism for anti-EGFR therapy and IGF-1R-targeted therapy for these transfectants. We made stable transfectants of K-RAS-MT in two gastrointestinal cancer cell lines, colorectal RKO and pancreatic BxPC-3. We assessed the effect of forced expression of K-RAS-MT on proliferation, apoptosis, migration, and invasion in gastrointestinal cancer cells. Then we assessed anti-tumor effects of dominant negative IGF-1R (IGF-1R/dn) and an IGF-1R inhibitor, picropodophyllin, on the K-RAS-MT transfectants. Overexpression of K-RAS-MT in gastrointestinal cancer cell lines led to more aggressive phenotypes, with increased proliferation, decreased apoptosis, and increased motility and invasion. IGF-1R blockade suppressed cell growth, colony formation, migration, and invasion, and up-regulated chemotherapy-induced apoptosis of gastrointestinal cancer cells, even when K-RAS-MT was over-expressed. IGF-1R blockade inhibited the Akt pathway more than the extracellular signal-regulated kinase (ERK) pathway in the K-RAS-MT transfectants. IGF-1R/dn, moreover, inhibited the growth of murine xenografts expressing K-RAS-MT. Thus, K-RAS-MT might be important for progressive phonotype observed in gastrointestinal cancers. IGF-1R decoy is a candidate molecular therapeutic approach for gastrointestinal cancers even if K-RAS is mutated. © 2016 Wiley Periodicals, Inc.
Assuntos
Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/patologia , Trato Gastrointestinal/patologia , Mutação , Proteínas Proto-Oncogênicas p21(ras)/genética , Receptor IGF Tipo 1/metabolismo , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/metabolismo , Trato Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/metabolismo , Genes ras , Humanos , Camundongos , Terapia de Alvo Molecular , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Invasividade Neoplásica/prevenção & controle , Podofilotoxina/análogos & derivados , Podofilotoxina/farmacologia , Receptor IGF Tipo 1/antagonistas & inibidores , Receptor IGF Tipo 1/genética , Transdução de Sinais/efeitos dos fármacos , Regulação para CimaRESUMO
BACKGROUND: Percutaneous endoscopic gastrostomy (PEG) is the most common method of enteral nutrition in patients who require long-term tube feeding. According to meta-analyses, administration of systemic prophylactic antibiotics for PEG reduces peristomal infection. However, with several recent developments in the procedure and instruments, the risk of infection might have been reduced. The aim of this study was to evaluate the use of systemic antibiotic prophylaxis for a modified introducer method of PEG. METHODS: This prospective, randomized, double-blind trial assessed 278 patients undergoing PEG for inclusion. Ninety-one patients with an indication for PEG who gave informed consent to participate were randomized. Forty-six patients received prophylactic ampicillin and 45 patients received a placebo. A modified introducer method of PEG using a Seldinger PEG kit was performed. The primary outcome was the occurrence of clinically evident wound infection within 3 days after PEG. RESULTS: Wound infection within 3 days was observed in none in the prophylaxis group and in 1 patient in the control group (P=0.4945). There was no significant difference between 2 groups in the other parameters, including peristomal infection within 7 days, overall infection, white blood cell counts, C-reactive protein level, and successive rate of finishing antibiotics. CONCLUSIONS: For wound infection within 3 days, noninferiority of the placebo group to the antibiotics group was preliminarily suggested with our criteria, but not for peristomal infection within 7 days. More strict criteria for noninferiority should be examined in a further large sample study.
Assuntos
Ampicilina/administração & dosagem , Antibioticoprofilaxia , Nutrição Enteral , Estenose Esofágica/cirurgia , Idoso , Método Duplo-Cego , Feminino , Gastroscopia/métodos , Gastrostomia/métodos , Humanos , Japão , Masculino , Complicações Pós-Operatórias , Estudos Prospectivos , Infecção da Ferida Cirúrgica , Resultado do TratamentoRESUMO
BACKGROUND: Intratumoral human epidermal growth factor receptor 2 (HER2) heterogeneity of gastric cancer can be an obstacle to accurate HER2 assessment. Serum HER2, concentrations of the HER2 extracellular domain shed into the bloodstream, has a potential to compensate HER2 immunohistochemistry (IHC) but has not been scrutinized in gastric cancer. This study sought to explore the clinical utility of serum HER2 in gastric cancer. METHODS: We performed a prospective multicenter trial (SHERLOCK trial) involving patients with all-stage gastric or gastro-esophageal junction cancer. Serum HER2 was measured using direct chemiluminescence while tissue HER2 status was determined using IHC and fluorescent in situ hybridization. For stage IV cases, concordance between local and central laboratories in tissue HER2 assessment was also evaluated. RESULTS: Of 224 patients enrolled, both tissue HER2 status and serum HER2 levels were successfully determined in 212 patients and 21% (45/212) were tissue HER2-positive. Serum HER2 levels, ranged from 4.5 to 148.0 ng/ml (median 10.3), correlated with tissue HER2 status (p = 0.003). At a cut-off level of 28.0 ng/ml determined by receiver operating characteristics analysis, sensitivity, specificity, positive and negative predictive values of serum HER2 were 22.6%, 100%, 100% and 82.3%, respectively. All nine cases with elevated serum HER2 were tissue HER2-positive stage IV cases. Among 61 stage IV cases, the agreement rate for IHC scoring between the local and the central laboratories was 82% and tissue HER2 judgment was conflicting in five (8.2%) cases. Of these five cases, four were confirmed as false-negative and two of these four patients demonstrated elevated serum HER2. CONCLUSIONS: Serum HER2 levels correlated with tissue HER2 status in gastric cancer. Although the low sensitivity is a drawback, serum HER2 might be a useful adjunct tool to detect tissue HER2 false-negative gastric cancer.
Assuntos
Biomarcadores/análise , Receptor ErbB-2/metabolismo , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Amplificação de Genes , Humanos , Técnicas Imunoenzimáticas , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias , Prognóstico , Estudos Prospectivos , Curva ROC , Receptor ErbB-2/genética , Neoplasias Gástricas/genéticaAssuntos
Íleus , Obstrução Intestinal , Feminino , Humanos , Íleus/diagnóstico por imagem , Íleus/etiologia , Japão , Pessoa de Meia-IdadeRESUMO
UNLABELLED: Although mesenchymal stem cells (MSCs) have been implicated in hepatic injury, the mechanism through which they contribute to diabetic liver disease has not been clarified. In this study, we investigated the effects of MSC therapy on diabetic liver damage with a focus on the role of bone-marrow-derived cells (BMDCs), which infiltrate the liver, and elucidated the mechanism mediating this process. Rat bone-marrow (BM)-derived MSCs were administered to high-fat diet (HFD)-induced type 2 diabetic mice and streptozotocin (STZ)-induced insulin-deficient diabetic mice. MSC-conditioned medium (MSC-CM) was also administered to examine the trophic effects of MSCs on liver damage. Therapeutic effects of MSCs were analyzed by assessing serum liver enzyme levels and histological findings. Kinetic and molecular profiles of BMDCs in the liver were evaluated using BM-chimeric mice. Curative effects of MSC and MSC-CM therapies were similar because both ameliorated the aggravation of aspartate aminotransferase and alanine aminotransferase at 8 weeks of treatment, despite persistent hyperlipidemia and hyperinsulinemia in HFD-diabetic mice and persistent hyperglycemia in STZ-diabetic mice. Furthermore, both therapies suppressed the abnormal infiltration of BMDCs into the liver, reversed excessive expression of proinflammatory cytokines in parenchymal cells, and regulated proliferation and survival signaling in the liver in both HFD- and STZ-diabetic mice. In addition to inducing hepatocyte regeneration in STZ-diabetic mice, both therapies also prevented excessive lipid accumulation and apoptosis of hepatocytes and reversed insulin resistance (IR) in HFD-diabetic mice. CONCLUSION: MSC therapy is a powerful tool for repairing diabetic hepatocyte damage by inhibiting inflammatory reactions induced by BMDCs and IR. These effects are likely the result of humoral factors derived from MSCs.
Assuntos
Células da Medula Óssea/fisiologia , Diabetes Mellitus Experimental/terapia , Fígado/patologia , Transplante de Células-Tronco Mesenquimais , Animais , Apoptose , Comunicação Celular , Diferenciação Celular , Linhagem da Célula , Movimento Celular , Citocinas/análise , Diabetes Mellitus Experimental/patologia , Dieta Hiperlipídica , Resistência à Insulina , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Ratos , EstreptozocinaRESUMO
The role of mesenchymal stem cells (MSCs) in tumorigenesis remains controversial. Therefore, our goal was to determine whether exogenous MSCs possess intrinsic antineoplastic or proneoplastic properties in azoxymethane (AOM)-induced carcinogenesis. Three in vivo models were studied: an AOM/dextran sulfate sodium colitis-associated carcinoma model, an aberrant crypt foci model, and a model to assess the acute apoptotic response of a genotoxic carcinogen (AARGC). We also performed in vitro coculture experiments. As a result, we found that MSCs partially canceled AOM-induced tumor initiation but not tumor promotion. Moreover, MSCs inhibited the AARGC in colonic epithelial cells because of the removal of O(6)-methylguanine (O(6) MeG) adducts through O(6) MeG-DNA methyltransferase activation. Furthermore, MSCs broadly affected the cell-cycle machinery, potentially leading to G1 arrest in vivo. Coculture of IEC-6 rat intestinal cells with MSCs not only arrested the cell cycle at the G1 phase, but also induced apoptosis. The anti-carcinogenetic properties of MSCs in vitro required transforming growth factor (TGF)-ß signaling because such properties were completely abrogated by absorption of TGF-ß under indirect coculture conditions. MSCs inhibited AOM-induced tumor initiation by preventing the initiating cells from sustaining DNA insults and subsequently inducing G1 arrest in the initiated cells that escaped from the AARGC. Furthermore, tumor initiation perturbed by MSCs might potentially dysregulate WNT and TGF-ß-Smad signaling pathways in subsequent tumorigenesis. Obtaining a better understanding of MSC functions in colon carcinogenesis is essential before commencing the broader clinical application of promising MSC-based therapies for cancer-prone patients with inflammatory bowel disease.
Assuntos
Azoximetano/toxicidade , Carcinógenos/toxicidade , Neoplasias do Colo/metabolismo , Células-Tronco Mesenquimais/metabolismo , Neoplasias Experimentais/metabolismo , Animais , Células Cultivadas , Técnicas de Cocultura , Neoplasias do Colo/induzido quimicamente , Neoplasias do Colo/patologia , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Células-Tronco Mesenquimais/patologia , Neoplasias Experimentais/induzido quimicamente , Neoplasias Experimentais/patologia , Ratos , Ratos Endogâmicos Lew , Fator de Crescimento Transformador beta/metabolismo , Via de Sinalização Wnt/efeitos dos fármacosRESUMO
BACKGROUND: Esophageal stenosis following endoscopic submucosal dissection (ESD) is a serious adverse event that makes subsequent management more difficult. METHODS: This parallel, randomized, controlled, open-label study was designed to examine whether local steroid injection is an effective prophylactic treatment for esophageal stenoses following extensive ESD. This single center trial was conducted at the Keiyukai Hospital, a tertiary care center for gastrointestinal disease in Japan [University Hospital Medical Network Clinical Trial Registry (UMIN-CTR) on 15 September 2011 (UMIN000006327)]. Thirty-two patients with mucosal defects involving ≥75% of the esophageal circumference were randomized to receive a single dose of triamcinolone acetonide injections (n = 16) or be treated conventionally (n = 16). The primary outcome was the frequency of stricture requiring endoscopic dilatation; the surrogate primary endpoint was the number of dilatation sessions needed. Secondary outcomes included adverse event rates, the minimum diameter of the stenotic area and the duration of the course of dilatation treatments. RESULTS: The frequency of stricture was not significantly different between the groups because of insufficient statistical power, but the number of dilatation sessions required was significantly less in the steroid group (6.1 sessions [95% confidence interval, CI 2.8-9.4] versus 12.5 [95% CI 7.1-17.9] sessions in the control group; P = 0.04). The perforation rate was similar in both groups. The minimum diameter of stenotic lumens was significantly greater in the treatment group than controls (11.0 mm versus 7.1 mm, respectively; P = 0.01). The perforation rate was not significantly different between the groups (1.0% versus 0.5% in the treatment and control group, respectively). Steroid injection was effective in cases of mucosal defects encompassing the entire esophageal circumference. CONCLUSIONS: Prophylactic endoscopic steroid injection appears to be a safe means of relieving the severity of esophageal stenoses following extensive ESD.
Assuntos
Anti-Inflamatórios/uso terapêutico , Carcinoma de Células Escamosas/cirurgia , Neoplasias Esofágicas/cirurgia , Estenose Esofágica/prevenção & controle , Triancinolona Acetonida/uso terapêutico , Idoso , Anti-Inflamatórios/administração & dosagem , Dilatação , Dissecação/efeitos adversos , Perfuração Esofágica/etiologia , Estenose Esofágica/etiologia , Estenose Esofágica/terapia , Esofagoscopia , Feminino , Humanos , Injeções Intralesionais , Masculino , Pessoa de Meia-Idade , Mucosa/cirurgia , Triancinolona Acetonida/administração & dosagemRESUMO
BACKGROUND & AIMS: Crohn's disease is an inflammatory bowel disease induced by multiple genetic and environmental factors. Genome-wide association studies have identified genetic factors that affect the risk for Crohn's disease in European populations, but information from other ethnic groups is scarce. We therefore investigated genetic factors associated with Crohn's disease in the Japanese population. METHODS: We performed a genome-wide association study with 372 individuals with Crohn's disease (cases) and 3389 controls, all from the Japanese population. To confirm identified associations, we performed a replication study with an independent panel of 1151 Crohn's disease cases and 15,800 controls. We also performed an association analysis using genome-wide genotype imputation in the discovery cohort. RESULTS: We confirmed associations of Crohn's disease with variants in MHC (rs7765379, P = 2.11 × 10(-59)), TNFSF15 (rs6478106, P = 3.87 × 10(-45)), and STAT3 (rs9891119, P = 2.24 × 10(-14)). We identified 2 new susceptibility loci: on chromosome 4p14 (rs1487630, P = 2.40 × 10(-11); odds ratio, 1.33), and in the SLC25A15-ELF1-WBP4 region on 13q14 (rs7329174 in ELF1, P = 5.12 × 10(-9); odds ratio, 1.27). CONCLUSIONS: In a genome-wide association study, we identified 2 new susceptibility loci for Crohn's disease in a Japanese population. These findings could increase our understanding of the pathogenesis of Crohn's disease.
Assuntos
Doença de Crohn/genética , Loci Gênicos/genética , Predisposição Genética para Doença/epidemiologia , Estudo de Associação Genômica Ampla/métodos , Adulto , Distribuição por Idade , Idoso , Povo Asiático/genética , Estudos de Casos e Controles , Doença de Crohn/epidemiologia , Feminino , Regulação da Expressão Gênica , Genótipo , Humanos , Incidência , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Razão de Chances , Polimorfismo de Nucleotídeo Único , Valores de Referência , Distribuição por SexoRESUMO
Insulin-like growth factor-I receptor (IGF-IR) signaling is required for carcinogenicity and tumor development, and this pathway has not been well studied in human esophageal carcinomas. Esophageal cancer is one of the human cancers with the worst prognosis and has two main histologies: squamous cell carcinomas (ESCC) and adenocarcinoma (EAC). Previously, we have reported that detection of the IGF axis may be useful for the prediction of recurrence and poor prognosis of ESCC. We have also shown the successful therapy for several gastrointestinal cancers using recombinant adenoviruses expressing dominant negative IGF-IR (ad-IGF-IR/dn). The aim of this study is to develop potential targeted therapeutics to IGF-IR and to assess the effect of IGF-IR blockade in both of these types of esophageal cancer. We determined immunohistochemical expression of IGF-IR in a tissue microarray. We then assessed the effect of IGF-IR blockade on signal transduction, proliferation, apoptosis, and motility. Ad-IGF-IR/dn, a tyrosine kinase inhibitor, BMS-536924, and adenovirus expressing shRNA for IGF-IR were used. IGF-IR expression was common in both tumor types but not in normal tissues. IGF-IR was detected in metastatic sites at similar levels compared to the primary site. IGF-IR inhibition suppressed proliferation and colony formation in both cancers. IGF-IR blockades up-regulated both stress- and chemotherapy-induced apoptosis and reduced migration. Although IGF-IR/dn blocked ligand-induced activation of Akt-1 mainly, BMS-536924 effectively blocked both activation of Akt and MAPK. The IGF axis might play a key role in tumor progression of esophageal carcinomas. The IGF-IR targeting strategies might thus be useful anticancer therapeutics for human esophageal malignancies.
Assuntos
Adenocarcinoma/genética , Carcinoma de Células Escamosas/genética , Neoplasias Esofágicas/genética , Fator de Crescimento Insulin-Like I/genética , Terapia de Alvo Molecular , Receptor IGF Tipo 1/genética , Adenocarcinoma/patologia , Adenocarcinoma/terapia , Adenoviridae , Carcinogênese , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/terapia , Linhagem Celular Tumoral , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/terapia , Carcinoma de Células Escamosas do Esôfago , Regulação Neoplásica da Expressão Gênica , Humanos , Fator de Crescimento Insulin-Like I/antagonistas & inibidores , Fator de Crescimento Insulin-Like I/biossíntese , Prognóstico , Receptor IGF Tipo 1/biossíntese , Transdução de Sinais/genéticaRESUMO
BACKGROUND: Recent studies have suggested that narrow band imaging (NBI) is useful for detecting superficial pharyngeal cancer. Nevertheless, pharyngeal observation is not a routine practice during upper gastrointestinal (GI) endoscopy. Two aims of this study were to evaluate the feasibility of pharyngeal observation during upper GI endoscopy and to determine the prevalence of pharyngeal cancer in asymptomatic high-risk patients. METHODS: Fifty-year-old or older asymptomatic males with smoking and drinking habits were prospectively recruited as a pharyngeal cancer high-risk group. A total of 224 high-risk patients underwent pharyngeal observation using NBI before conventional upper GI endoscopy. The feasibility of pharyngeal examination without sedation was assessed by a questionnaire for the first 60 participants. RESULTS: The median time for pharyngeal observation was 1.7 min. The questionnaire demonstrated 88% of participants thought the pharyngeal examination acceptable. The NBI examination identified 5 superficial pharyngeal cancers (2 Tis and 3 T1) in 224 high-risk patients; the prevalence of pharyngeal cancer in this group was 2.2%. Three of the 5 patients had a concurrent or past history of esophageal squamous cell carcinoma (ESCC). CONCLUSIONS: Pharyngeal observation using NBI during upper GI endoscopy is well tolerated and recommended for all high-risk patients, particularly those with a history of ESCC. Basel.
Assuntos
Carcinoma de Células Escamosas/epidemiologia , Detecção Precoce de Câncer/métodos , Endoscopia Gastrointestinal , Neoplasias Esofágicas/epidemiologia , Imagem de Banda Estreita , Neoplasias Faríngeas/diagnóstico , Neoplasias Faríngeas/epidemiologia , Vigilância da População/métodos , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Consumo de Bebidas Alcoólicas , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Primárias Múltiplas/epidemiologia , Segunda Neoplasia Primária/epidemiologia , Satisfação do Paciente , Neoplasias Faríngeas/complicações , Prevalência , Estudos Prospectivos , Fatores de Risco , Fumar , Inquéritos e QuestionáriosRESUMO
Insulin-like growth factor (IGF)-I receptor (IGF-IR) signaling is required for carcinogenicity and progression of several cancers but the function of this pathway and its utility as a therapeutic target have not been studied comprehensively in biliary tract carcinomas (BTC). We investigated the immunohistochemical expression of elements of the IGF axis, matrilysin, overexpression of p53 and the methylation status of the IGFBP-3 promoter in 80 surgically resected BTC. We also assessed the effect of IGF-IR blockade on signal transduction, proliferation and survival in three BTC cell lines using a new tyrosine kinase inhibitor, BMS-536924, and dominant negative IGF-IR (IGF-IR/dn). The effects of IGF-IR blockade was also studied in nude mouse xenograft models. IGF-I was expressed in 60% and IGF-II in 50% of tumors. High expression was associated with tumor size. IGF-IR was expressed in 69% of the cases and was associated with advanced stage and matrilysin expression. Hypermethylation of the IGFBP-3 promoter was detected in 41% of BTC and was inversely correlated with p53 expression. BMS-536924 blocked autophosphorylation of IGF-IR and both Akt and ERK activation by both IGF-I and insulin. BMS-536924 suppressed proliferation and tumorigenicity in vitro in a dose-dependent fashion. This inhibitor upregulated chemotherapy-induced apoptosis in a dose-dependent fashion. Moreover, IGF-IR blockade was effective against tumors in mice. IGF-IR might identify a subset of BTC with a particularly aggressive phenotype and is a candidate therapeutic target in this disease. BMS-536924 might have significant therapeutic utility.
Assuntos
Neoplasias do Sistema Biliar/metabolismo , Neoplasias do Sistema Biliar/patologia , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Inibidores de Proteínas Quinases/farmacologia , Receptores de Somatomedina/metabolismo , Animais , Apoptose/efeitos dos fármacos , Benzimidazóis/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular , Metilação de DNA , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Insulina/metabolismo , Metaloproteinase 7 da Matriz/biossíntese , Camundongos , Camundongos Nus , Proteína Oncogênica v-akt/metabolismo , Regiões Promotoras Genéticas , Proteínas Tirosina Quinases/antagonistas & inibidores , Piridonas/farmacologia , Receptores de Somatomedina/biossíntese , Transdução de Sinais , Somatomedinas/biossíntese , Proteína Supressora de Tumor p53/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Ménétrier's disease (MD) is a rare, acquired, premalignant disorder of the stomach characterized by enlarged gastric folds with foveolar hyperplasia, the phenotype of antralization of gastric glands, hypochlorhydria and hypoproteinemia. The etiology of MD is unknown, but both increased signaling by transforming growth factor-α and infection with Helicobacter pylori (H. pylori) have been implicated. Here, a case involving 70-year-old man who lost weight after developing anorexia and diarrhea is reported. He was diagnosed as MD without H. pylori infection, and in spite of intensive care, he died 40 days after admission. An autopsy confirmed MD. Immunohistochemistry revealed overexpression of transforming growth factor-α in the foveolar region of the gastric mucosa. The autopsy also distinguished this H. pylori-negative MD from hyperplastic polyp of the stomach, which is important in clarifying the entity of H. pylori-negative MD.
Assuntos
Mucosa Gástrica/metabolismo , Gastrite Hipertrófica/etiologia , Fator de Crescimento Transformador alfa/metabolismo , Idoso , Ciclo-Oxigenase 2/metabolismo , Dilatação Patológica , Endossonografia , Evolução Fatal , Mucosa Gástrica/patologia , Gastrite Hipertrófica/epidemiologia , Gastrite Hipertrófica/metabolismo , Gastrite Hipertrófica/terapia , Infecções por Helicobacter/epidemiologia , Helicobacter pylori , Humanos , Imuno-Histoquímica , Insuflação , Masculino , Transdução de Sinais/fisiologiaRESUMO
BACKGROUND: Insulin-like growth factor (IGF)-I receptor (IGF-IR) signaling is required for tumorigenicity and tumor progression of gastrointestinal cancers. The authors previously reported the success of therapy for gastrointestinal cancers using adenoviruses that expressed dominant-negative IGF-IR (IGF-IR/dn). In addition, it has been demonstrated that IGF-IR signaling affects vascular endothelial growth factor (VEGF) expression in some other types of tumors. The objective of the current study was to evaluate this interaction by studying the roles of IGF-IR in tumor angiogenesis and lymphangiogenesis and their implications for targeted therapy in gastric cancer. METHODS: The impact of IGF signals on the expression of VEGF-A and VEGF-C in a human gastric cancer cell, MKN45, and vascular formation were assessed. The effects of IGF-IR/dn with or without bevacizumab on angiogenesis, lymphangiogenesis, and tumor suppression in mouse xenografts were assessed. RESULTS: IGFs induced the expression of VEGF ligands and up-regulated in vitro vascular vessel formation. IGF-IR/dn reduced VEGF expression, reduced the activation of both protein kinase B (Akt) and mitogen-activated protein kinase (MAPK), and reduced vascular formation, indicating that IGF-IR/dn inhibited tumor growth in mice by inhibiting both angiogenesis and lymphangiogenesis. However, IGF-IR/dn did not affect either blood sugar or body weight in these mice. The combination of IGF-IR/dn and bevacizumab was highly effective against these xenograft tumors, and only this combination resulted in the complete regression of 43% of tumors, reduced the expression of VEGF, and induced apoptosis. CONCLUSIONS: The current results indicated that IGF-IR is involved in angiogenesis and lymphangiogenesis through the modulation of VEGF ligand expression in the gastric cancer cell line MKN45. Targeting IGF-IR in combination with agents that block the VEGF pathway may have therapeutic utility for gastric cancer therapy.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Neovascularização Patológica/tratamento farmacológico , Receptor IGF Tipo 1/antagonistas & inibidores , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/metabolismo , Animais , Anticorpos Monoclonais Humanizados , Bevacizumab , Linhagem Celular Tumoral , Feminino , Humanos , Linfangiogênese/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Receptor IGF Tipo 1/fisiologia , Transdução de Sinais , Neoplasias Gástricas/irrigação sanguínea , Fator A de Crescimento do Endotélio Vascular/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Recent advances in our understanding of the genetic mutations associated with melanoma have led to the classification of distinct melanoma subtypes. A number of reports have consistently demonstrated that mucosal and acral melanomas more commonly harbor KIT-activating mutations than do other subtypes. Success in treating gastrointestinal stromal tumors with imatinib has led to speculation that KIT-mutated melanoma might also be effectively managed using this approach. A 78-year-old woman presented with a 4-month history of rectal bleeding. A colonoscopy revealed a black polypoid mass, 30 mm in diameter, originating near the dentate line, and a biopsy revealed malignant melanoma. Computed tomography showed multiple liver and lung metastases. A KIT mutation analysis showed the L576P mutation in exon 11. The patient did not want to undergo chemotherapy including a tyrosine-kinase inhibitor, so palliative radiotherapy for rectal symptoms was performed, but the patient died 4 months later due to disease progression. We describe the first case of anorectal melanoma with a KIT-activating mutation in Japan and summarize findings from the literature regarding the efficacy of KIT kinase inhibitors on this melanoma subtype.
Assuntos
Neoplasias do Ânus/genética , Neoplasias do Ânus/patologia , Melanoma/genética , Melanoma/patologia , Proteínas Proto-Oncogênicas c-kit/genética , Neoplasias Retais/genética , Neoplasias Retais/patologia , Idoso , Neoplasias do Ânus/radioterapia , Feminino , Humanos , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/secundário , Melanoma/radioterapia , Cuidados Paliativos , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-kit/antagonistas & inibidores , Neoplasias Retais/radioterapiaRESUMO
BACKGROUND: S-1, an oral fluoropyrimidine, is one of the standard chemotherapeutic agents for the treatment of metastatic gastric cancer(MGC). However, the most effective second-line regimen after failure of treatment with first-line agents such as S-1 is yet to be determined. The aim of this study was to investigate the various second-line chemotherapy regimens in MGC patients. METHODS: We retrospectively studied patients with MGC who received second-line treatment after failure of the first-line S-1 or S-1/cisplatin treatment. The overall survival times with each second-line regimen were determined using the Kaplan-Meier method, and the effect on overall survival was analyzed using Cox regression analysis. RESULTS: The median survival time for all patients was 14. 2 months(95% confidence interval(CI): 12. 88-15. 43 months)with a 1-year survival rate of 60. 4%. Kaplan-Meier analysis revealed that the second-line regimens containing irinotecan significantly improved the median survival time as compared to regimens without irinotecan(median survival time: 16. 5 and 13. 8 months, respectively). Cox regression analysis showed that irinotecan-containing regimens were associated with improved overall survival(hazard ratio: 0. 165; 95% CI: 0. 041-0. 665). CONCLUSION: The use of irinotecan-containing regimens as second-line chemotherapy after failure of first-line S-1 therapy may be beneficial for MGC patients.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Camptotecina/análogos & derivados , Resistencia a Medicamentos Antineoplásicos , Terapia de Salvação , Neoplasias Gástricas/tratamento farmacológico , Idoso , Camptotecina/administração & dosagem , Camptotecina/uso terapêutico , Cisplatino/administração & dosagem , Cisplatino/uso terapêutico , Combinação de Medicamentos , Feminino , Humanos , Irinotecano , Masculino , Metástase Neoplásica , Ácido Oxônico/administração & dosagem , Ácido Oxônico/uso terapêutico , Estudos Retrospectivos , Neoplasias Gástricas/patologia , Tegafur/administração & dosagem , Tegafur/uso terapêuticoRESUMO
Thus far, there have been limited case reports on immunoglobulin G4-related autoimmune hepatitis (IgG4-AIH), and its clinical features have not been elucidated. We herein report a rare case of IgG4-AIH simultaneously concomitant with autoimmune pancreatitis (AIP). A 73-year-old female was admitted to our hospital for further investigation of elevated levels of liver transaminase and pancreatic enzymes. Her serological tests showed a high antinuclear antibody titer, and elevated IgG and IgG4 levels. Liver biopsy revealed interface hepatitis and bridging necrosis with IgG4-positive lymphoplasmacytic infiltration in the portal area. Moreover, contrast-enhanced computed tomography (CECT) showed pancreatic tail enlargement, and magnetic resonance cholangiopancreatography showed skipped narrowing of the main pancreatic duct in the pancreatic tail. Endoscopic ultrasonography-fine needle aspiration specimens showed no malignant cells. Based on these results, we diagnosed her with IgG4-AIH simultaneously concomitant with probable type 1 AIP. She was started on prednisolone (PSL) at 35 mg/d, and her symptoms and liver transaminase levels improved. One month after starting treatment, CECT showed improvement of pancreatic tail enlargement. She is maintained on 5 mg PSL/d and has been in remission for two years.
Assuntos
Doenças Autoimunes , Pancreatite Autoimune , Hepatite Autoimune , Idoso , Doenças Autoimunes/complicações , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/tratamento farmacológico , Biópsia por Agulha Fina , Colangiopancreatografia por Ressonância Magnética , Feminino , Hepatite Autoimune/complicações , Hepatite Autoimune/tratamento farmacológico , Humanos , Imunoglobulina GRESUMO
BACKGROUND: Endoscopic submucosal dissection (ESD) was originally developed in Japan for en bloc resection of gastric neoplasms. OBJECTIVE: To clarify whether the novel ESD procedure is feasible and gives results that justify the pursuit of integrated minimally invasive procedures aimed at curing early squamous cell carcinoma of the esophagus (SCCE). DESIGN: Retrospective cohort study. SETTING: A single-institution trial by experienced endoscopists. PATIENTS: This study involved 300 consecutively enrolled patients with SCCE (Tumor, Nodes, Metastasis classification T1, N0) who underwent either EMR (n = 184) or ESD (n = 116) from March 1994 to July 2007. INTERVENTION: The patients underwent endoscopic resection and then were followed by periodic endoscopy for 8 to 174 months (mean 65 months). MAIN OUTCOME MEASUREMENTS: Resectability, cure rates, complications, disease-free survival of the two groups, and risk factors for local recurrence were explored. RESULTS: En bloc resection and the local recurrence rate were significantly better in the ESD group (P = .0009 and .065, respectively). The frequency of perforation was not significantly different between the two groups (P = .68). Four independent risk factors for local recurrence were identified by the Cox regression model: EMR, deep cancer invasion, upper esophagus location, and family history of esophageal cancer. Radical cure is mostly obtained by successful endoscopic retreatment of local recurrence after previous endoscopic resection. Disease-free survival was significantly better with ESD. LIMITATIONS: The study's retrospective nature prevents definitive conclusions. CONCLUSIONS: We provide evidence that ESD gives a higher cure rate and is safer than conventional endoscopic resection when applied to early SCCE. ESD warrants prospective comparative studies with conventional endoscopic resection.