RESUMEN
Pancreatic cancer is characterized by early metastatic spread, but the process of tumor cell dissemination is largely unknown. In this study we show that the soluble protein pancreatic adenocarcinoma upregulated factor (PAUF) has an important role in the metastasis and progression of the disease. Variations in the level of PAUF, either by overexpression or knockdown, resulted in altered migration, invasion and proliferation capacity of pancreatic cancer cells. Moreover, depletion of PAUF in metastatic cells dramatically abrogated the spread of the cells to distant organs in an orthotopic xenograft mouse model. PAUF elicited the activation of the extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and AKT intracellular signaling cascades and consequently their downstream transcription factors in an autocrine manner. Genome-wide expression analysis revealed that C-X-C chemokine receptor type 4 (CXCR4) expression was induced by PAUF overexpression but was repressed by PAUF knockdown. The PAUF-mediated increase in cancer cell motility was attenuated by the CXCR4 inhibitor, AMD3100, or by anti-CXCR4 antibody. Furthermore, immunohistochemical analysis of pancreatic tumor tissues clearly showed a significant positive correlation between PAUF and CXCR4 expression. Collectively, these findings indicate that PAUF enhances the metastatic potential of pancreatic cancer cells, at least in part, by upregulating CXCR4 expression.
Asunto(s)
Lectinas/genética , Neoplasias Pancreáticas/patología , Receptores CXCR4/genética , Regulación hacia Arriba , Animales , Bencilaminas , Western Blotting , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Ciclamas , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Compuestos Heterocíclicos/farmacología , Humanos , Inmunohistoquímica , Péptidos y Proteínas de Señalización Intercelular , Lectinas/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Invasividad Neoplásica , Metástasis de la Neoplasia , Neoplasias Experimentales/genética , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/patología , Análisis de Secuencia por Matrices de Oligonucleótidos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Interferencia de ARN , Receptores CXCR4/antagonistas & inhibidores , Receptores CXCR4/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Trasplante HeterólogoRESUMEN
BACKGROUND: It is unknown whether the development of cerebral microbleeds (MBs), small areas of signal loss on T2*-weighted gradient-echo imaging (GRE), follows a slow or a rapid process. We hypothesized that MBs may develop rapidly after certain critical events, such as strokes, and investigated the frequency, location, and factors associated with the formation of new MBs after acute ischemic stroke. METHODS: We retrospectively examined 237 consecutive acute ischemic stroke patients who underwent MRI within 24 hours and follow-up MRI during the week after symptom onset. We defined new MBs as MBs that newly appeared on follow-up GRE outside the infarcted area. We examined the association of new MBs with demographics, risk factors, laboratory data, baseline MBs, and small vessel disease (SVD; leukoaraiosis and lacunar infarctions). RESULTS: Seventy-five patients (31.6%) had baseline MBs, and 30 (12.7%) developed new MBs. Multiple logistic regression analysis indicated that the presence of baseline MBs (odds ratio [OR] 5.72, 95% confidence interval [CI] 2.12-15.42, p = 0.001) and severe SVD (OR 2.94, 95% CI 1.12-7.77, p = 0.03) independently predicted the development of new MBs. Of the 56 new MBs, 29 (51.8%) appeared in the lobar location, 17 (30.4%) appeared in the deep location, and 10 (17.9%) appeared in the infratentorial location. CONCLUSIONS: This study suggests that new microbleeds (MBs) can develop rapidly after acute ischemic stroke. Baseline MBs and severe small vessel disease are predictors for the development of new MBs. Further studies will be needed to investigate the clinical implications and mechanisms of these findings.
Asunto(s)
Isquemia Encefálica/fisiopatología , Encéfalo/irrigación sanguínea , Encéfalo/fisiopatología , Hemorragia Cerebral/fisiopatología , Accidente Cerebrovascular/fisiopatología , Enfermedad Aguda , Adulto , Anciano , Anciano de 80 o más Años , Encéfalo/patología , Isquemia Encefálica/diagnóstico , Isquemia Encefálica/patología , Hemorragia Cerebral/diagnóstico , Hemorragia Cerebral/patología , Femenino , Estudios de Seguimiento , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Factores de Riesgo , Accidente Cerebrovascular/diagnóstico , Accidente Cerebrovascular/patología , Factores de Tiempo , Adulto JovenAsunto(s)
Aneurisma/complicaciones , Aneurisma/diagnóstico por imagen , Enfermedades de las Arterias Carótidas/diagnóstico por imagen , Enfermedades de la Coroides/diagnóstico por imagen , Coroides/irrigación sanguínea , Coroides/diagnóstico por imagen , Enfermedades de los Nervios Craneales/diagnóstico por imagen , Angiografía , Enfermedades de las Arterias Carótidas/complicaciones , Seno Cavernoso/diagnóstico por imagen , Enfermedades de la Coroides/complicaciones , Enfermedades de los Nervios Craneales/etiología , Diagnóstico Diferencial , Diplopía/diagnóstico , Diplopía/etiología , Cefalea/diagnóstico , Cefalea/etiología , Humanos , Masculino , Persona de Mediana Edad , Síndrome , Tomografía Computarizada por Rayos XRESUMEN
The present study was conducted to evaluate the efficacy and safety of a combination regimen of capecitabine plus irinotecan in patients with advanced gastric cancer. Patients with previously untreated metastatic or recurrent, measurable gastric cancer received oral capecitabine 1000 mg m(-2) twice daily from day 1 to 14 and intravenous irinotecan 100 mg m(-2) on days 1 and 8, based on a 3-week cycle. Forty-one patients were enrolled in the current study, among whom 38 were assessable for efficacy and 40 assessable for toxicity. Three complete responses and 16 partial responses were confirmed, giving an overall response rate of 46.3%. At a median follow-up of 269 days, the median time to progression and overall survival were 5.1 and 8.6 months, respectively. Grade 3/4 neutropenia occurred in four patients and grade 3 febrile neutropenia was observed in two patients. Grade 3 diarrhoea and grade 2 hand-foot syndrome occurred in six patients and eight patients, respectively. The combination of capecitabine and irinotecan was found to be well tolerated and effective in patients with advanced gastric cancer. Accordingly, this regimen can be regarded as one of first-line treatment options for advanced gastric cancer.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Gástricas/tratamiento farmacológico , Adenocarcinoma/mortalidad , Adenocarcinoma/secundario , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Camptotecina/administración & dosificación , Camptotecina/efectos adversos , Camptotecina/análogos & derivados , Capecitabina , Desoxicitidina/administración & dosificación , Desoxicitidina/efectos adversos , Desoxicitidina/análogos & derivados , Relación Dosis-Respuesta a Droga , Femenino , Fluorouracilo/análogos & derivados , Humanos , Irinotecán , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/secundario , Masculino , Persona de Mediana Edad , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/mortalidad , Neoplasias Ováricas/secundario , Neoplasias Peritoneales/tratamiento farmacológico , Neoplasias Peritoneales/mortalidad , Neoplasias Peritoneales/secundario , Neoplasias Gástricas/mortalidad , Neoplasias Gástricas/patología , Tasa de SupervivenciaRESUMEN
Thrombocytopenia (TP) is a frequent complication after allogeneic stem cell transplantation (SCT) and regarded as a poor prognostic factor when assessed beyond day 100. However, little is known about the clinical significance of the platelet recovery pattern before chronic graft-versus-host disease (GVHD) develops. Eighty-five patients undergoing HLA-identical sibling SCT were stratified according to their platelet recovery pattern between day +30 and +90 and the transplant outcomes analyzed, along with the association of each component of the acute GVHD grading system. Fifteen patients (18%) were classified with persistent TP, 33 patients (39%) with unstable TP, and 37 patients (43%) as non-TP. Persistent TP, which was strongly associated with severe acute GVHD (P<0.001), exhibited the worst 2-year OS (P<0.0001) and highest NRM (P<0.0001) and opportunistic infection rates (P<0.0001). In multivariate analyses, the platelet recovery pattern was identified as an independent prognostic factor (P=0.02) together with the disease risk (P=0.02) in terms of OS, and the only independent prognostic factor in terms of NRM (P=0.005) and the incidence of infectious events (P<0.001). Persistent TP was strongly associated with the development of extensive chronic GVHD (P=0.03). The platelet recovery pattern between day +30 and +90 can be used to predict the prognosis of SCT recipients.
Asunto(s)
Plaquetas , Donadores Vivos , Trastornos Linfoproliferativos/mortalidad , Recuperación de la Función , Trasplante de Células Madre , Trombocitopenia/mortalidad , Adolescente , Adulto , Enfermedad Crónica , Femenino , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/mortalidad , Enfermedad Injerto contra Huésped/prevención & control , Prueba de Histocompatibilidad , Humanos , Trastornos Linfoproliferativos/complicaciones , Trastornos Linfoproliferativos/terapia , Masculino , Persona de Mediana Edad , Infecciones Oportunistas/etiología , Infecciones Oportunistas/mortalidad , Pronóstico , Hermanos , Trombocitopenia/etiología , Trasplante HomólogoRESUMEN
The current study attempted to evaluate the association between the IL-10 promoter gene single nucleotide polymorphism (SNP) and invasive pulmonary aspergillosis (IPA) after allogeneic stem cell transplantation (SCT) in 105 patients. Three single-nucleotide polymorphisms were investigated in the proximal region of the IL-10 promoter gene (-1082/-819/-592). Two haplotypes (1082*A/819*T/592*A [ATA] and 1082*A/819*C/592*C [ACC]) were found in the current study. The overall incidence of IPA was estimated as 14.1+/-4.5% with a median onset at 186 days post-transplant (62 approximately 405 days). An increased occurrence of IPA was noted dependent on the IL-10 haplotype (0% vs 11.5+/-6.4% vs 19.7+/-7.7% for ACC/ACC vs ATA/ACC vs ATA/ATA haplotype, P=0.0307 when comparing ACC with non-ACC haplotype). In a multivariate survival analysis using Cox's proportional hazard model, the IL-10 promoter gene SNPs were identified as an independent predictive factor for the development of IPA (P=0.012, hazard ratio (HR) 9.3), along with an histocompatibility leukocyte antigen (HLA)-identical donor (P=0.005, HR 16.3), the CD34+ cell dose transplanted (P=0.004, HR 26.5), and time-dependent chronic graft-versus-host disease (GVHD; P=0.049, HR 16.0). The IL-10 ACC haplotype was found to have an apparent protective role in the development of IPA after allogeneic transplantation, regardless of HLA-disparity or chronic GVHD.
Asunto(s)
Aspergilosis/microbiología , Aspergilosis/terapia , Interleucina-10/genética , Pulmón/microbiología , Polimorfismo Genético , Regiones Promotoras Genéticas , Trasplante de Células Madre/efectos adversos , Trasplante Homólogo/efectos adversos , Adolescente , Adulto , Antígenos CD34/biosíntesis , Femenino , Enfermedad Injerto contra Huésped/terapia , Antígenos HLA/química , Haplotipos , Humanos , Pulmón/patología , Masculino , Persona de Mediana Edad , Análisis Multivariante , Polimorfismo de Nucleótido Simple , Modelos de Riesgos Proporcionales , Factores de Tiempo , Resultado del TratamientoRESUMEN
We aimed to evaluate the efficacy and safety of concurrent chemoradiotherapy with capecitabine and cisplatin in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). In total, 37 patients with stage III or IV SCCHN were enrolled on the study. The chemotherapy consisted of two cycles of intravenous cisplatin of 80 mg m(-2) on day 1 and oral capecitabine 825 mg m(-2) twice daily from day 1 to day 14 at 3-week intervals. The radiotherapy (1.8-2.0 Gy 1 fraction day(-1) to a total dose of 70-70.2 Gy) was delivered to the primary tumour site and neck. The primary tumour sites were as follows: oral cavity (n=6), oropharynx (n=11), hypopharynx (n=8), larynx (n=3), nasopharynx (n=6), and paranasal sinus (n=3). After the chemoradiotherapy, 29 complete responses (78.4%) and 6 partial responses (16.2%) were confirmed. Grade 3 or 4 neutropenia occurred only in two patients, plus grade 3 febrile neutropenia was observed only in one patient. At a median follow-up duration of 19.8 months, the estimated overall survival and progression-free survival rate at 2-year was 76.8 and 57.9%, respectively. Concurrent chemoradiotherapy with capecitabine and cisplatin was found to be well tolerated and effective in patients with locally advanced SCCHN.