RESUMEN
BACKGROUND: Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) rank among the most frequently applied bariatric procedures worldwide due to their positive risk/benefit correlation. A systematic review revealed a similar excess weight loss (EWL) 2 years postoperatively between SG and RYGB. However, there is a lack of randomized controlled multi-centre trials comparing SG and RYGB, not only concerning EWL, but also in terms of remission of obesity-related co-morbidities, gastroesophageal reflux disease (GERD) and quality of life (QoL) in the mid- and long-term. METHODS: The BariSurg trial was designed as a multi-centre, randomized controlled patient and observer blind trial. The trial protocol was approved by the corresponding ethics committees of the centres. To demonstrate EWL non-inferiority of SG compared to RYGB, power calculation was performed according to a non-inferiority study design. Morbidity, mortality, remission of obesity-related co-morbidities, GERD course and QoL are major secondary endpoints. 248 patients between 18 and 70 years, with a body mass index (BMI) between 35-60 kg/m(2) and indication for bariatric surgery according to the most recent German S3-guidelines will be randomized. The primary and secondary endpoints will be assessed prior to surgery and afterwards at discharge and at the time points 3-6, 12, 24, 36, 48 and 60 months postoperatively. DISCUSSION: With its five year follow-up, the BariSurg-trial will provide further evidence based data concerning the impact of SG and RYGB on EWL, remission of obesity-related co-morbidities, the course of GERD and QoL. TRIAL REGISTRATION: The trial protocol has been registered in the German Clinical Trials Register DRKS00004766 .
Asunto(s)
Gastrectomía , Derivación Gástrica , Obesidad Mórbida/cirugía , Adolescente , Adulto , Anciano , Índice de Masa Corporal , Método Doble Ciego , Femenino , Estudios de Seguimiento , Reflujo Gastroesofágico/complicaciones , Humanos , Masculino , Persona de Mediana Edad , Obesidad/cirugía , Obesidad Mórbida/complicaciones , Calidad de Vida , Resultado del Tratamiento , Pérdida de Peso , Adulto JovenRESUMEN
Survival and quality of life after heart transplantation are limited by a significant incidence of cardiovascular complications. Side effects of immunosuppressives contribute unfavorably. Aim of this study was to determine (1) whether withdrawal of corticosteroids and dose reduction of cyclosporine A can be performed safely under immunosuppressive therapy with mycophenolate mofetil and (2) if this is beneficial for renal function and cardiovascular risk reduction. Long term heart transplant recipients on steroids and cyclosporine A were examined in a monocentric, prospective, single-arm cohort study. Steroids were withdrawn, mycophenolate mofetil introduced and cyclosporine A dose reduced (target level 50-90 ng/ml). Follow up was 24 months. 23 patients were analyzed: Renal parameters (creatinine, urea, uric acid) improved significantly (p<0.01), as did cardiovascular parameters (heart rate [p<0.05], systolic and diastolic blood pressure [p<0.01]), HbA1c (p<0.05) and triglycerides (p<0.05). In contrast, the self-percepted state of health (SF36™) decreased. Drop outs occurred mostly due to steroid withdrawal syndrome [n=7]. The incidence of adverse events reflected the usual course after heart transplantation. We conclude that CS free immunosuppression comprising reduced cyclosporine levels and addition of MMF in long term heart transplant recipients is safe and improves the cardiovascular risk profile, carbohydrate metabolism and renal function.
Asunto(s)
Corticoesteroides/administración & dosificación , Ciclosporina/administración & dosificación , Trasplante de Corazón , Terapia de Inmunosupresión/métodos , Inmunosupresores/uso terapéutico , Ácido Micofenólico/análogos & derivados , Corticoesteroides/efectos adversos , Corticoesteroides/sangre , Corticoesteroides/uso terapéutico , Ciclosporina/efectos adversos , Ciclosporina/sangre , Ciclosporina/uso terapéutico , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Quimioterapia Combinada , Femenino , Rechazo de Injerto/epidemiología , Rechazo de Injerto/prevención & control , Trasplante de Corazón/estadística & datos numéricos , Humanos , Inmunosupresores/administración & dosificación , Masculino , Persona de Mediana Edad , Ácido Micofenólico/administración & dosificación , Ácido Micofenólico/uso terapéutico , Estudios Prospectivos , Síndrome de Abstinencia a Sustancias/epidemiología , Síndrome de Abstinencia a Sustancias/etiologíaRESUMEN
BACKGROUND: Significant relationships have been reported between the uptake of mycophenolic acid (MPA) and the risk of acute rejection. In a prospective study after renal transplantation, we assessed the value of measuring inosine-monophosphate dehydrogenase (IMPDH) activity as a predictive indicator of an acute rejection episode in the initial postoperative period. PATIENTS AND METHODS: Fifty-two patients received 360 mg enteric-coated mycophenolate-sodium two times per day with concomitant tacrolimus/cyclosporine A, providing a total of 122 pharmacodynamic profiles. IMPDH activity was measured by a validated high-performance liquid chromatography method in four plasma samples collected at predose, 30 and 60 min, 2 and 4 hr, and preoperative, during weeks 1 and 2 and 3 months after transplantation. MPA concentrations were measured by mass spectrometry. Inhibition of IMPDH was correlated to the MPA values, MPA area under the curves, and predose levels of the different calcineurin inhibitors. RESULTS: Comparing the two groups (group I: rejection; n=17; mean age 51±15 years vs. group II: no rejection; n=35; mean age 51±14 years), we found a significantly (P<0.001) lower inhibition of IMPDH in group I (26.5%±11% vs. 56.7%±18%) already in the first week after transplantation. There was no correlation of MPA values (6.85±4 vs. 4.1±3 mg/L; first week) nor with the calcineurin inhibitor trough blood levels. Area under the curves for MPA did not differ significantly. Furthermore, IMPDH activity was a reliable predictor of rejection episodes and inflammation. CONCLUSION: The data suggest that measuring biologic response may be a more valuable indicator than traditional therapeutic drug monitoring of MPA. Patients at risk for rejection could be earlier identified, and the therapeutic potential of MPA will be optimized.
Asunto(s)
IMP Deshidrogenasa/sangre , Trasplante de Riñón/inmunología , Ácido Micofenólico/administración & dosificación , Ácido Micofenólico/uso terapéutico , Adulto , Anciano , Área Bajo la Curva , Cromatografía Líquida de Alta Presión , Ciclosporina/uso terapéutico , Quimioterapia Combinada , Rechazo de Injerto/prevención & control , Humanos , IMP Deshidrogenasa/efectos de los fármacos , Inmunosupresores/uso terapéutico , Cinética , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Comprimidos , Tacrolimus/uso terapéuticoRESUMEN
AIMS: The cyclic adenosine monophosphate-inducible basic helix-loop-helix (bHLH) domain containing class-B2 transcriptional factor BHLHB2 is differentially expressed in a number of human malignancies. In the present study, the expression, regulation, functions and prognostic impact of BHLHB2 in pancreatic cancer were investigated. METHODS: Expression analyses were carried out in tissues of the normal pancreas (n=10) and pancreatic ductal adenocarcinoma (n=77) as well as in eight pancreatic cancer cell lines using quantitative RT-PCR, semiquantitative immunohistochemistry, and immunoblot analyses. In vitro functional experiments were conducted using siRNA transfection, hypoxia, serum starvation, apoptosis induction with gemcitabine and actinomycin-D, and invasion assays. Survival analysis was performed using the Kaplan-Meier method. Prognostic factors were determined in a multivariable analysis using a Cox proportional hazards model. RESULTS: BHLHB2 mRNA and protein expressions were strongly induced by hypoxia and by serum starvation in pancreatic cancer cell lines. BHLHB2 silencing with RNAi had no significant effects on growth and invasion but increased apoptosis resistance against gemcitabine by reducing caspace-3 cleavage. In BHLHB2 silenced cells the ED50 of gemcitabine increased from 13.95 ± 1.353 to 38.70 ± 5.262 nM (p<0.05). Ex vivo, the weak/absent nuclear staining in normal pancreatic ducts and acinar cells was replaced by moderate to strong nuclear/cytoplasmic staining in PanIN lesions and pancreatic cancer cells. Patients with weak/absent nuclear BHLHB2 staining had significantly worse median survival compared to those with strong staining (13 months vs. 27 months, p=0.03). In a multivariable analysis, BHLHB2 staining was an independent prognostic factor (Hazard-Ratio=2.348, 95% CI=1.250-4.411, p=0.008). CONCLUSIONS: Hypoxia-inducible BHLHB2 expression is a novel independent prognostic marker in pancreatic cancer patients and indicates increased chemosensitivity towards gemcitabine.
Asunto(s)
Antimetabolitos Antineoplásicos/uso terapéutico , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Biomarcadores de Tumor/metabolismo , Carcinoma Ductal Pancreático/mortalidad , Desoxicitidina/análogos & derivados , Resistencia a Antineoplásicos , Proteínas de Homeodominio/metabolismo , Neoplasias Pancreáticas/mortalidad , Anciano , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Biomarcadores de Tumor/genética , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/metabolismo , Hipoxia de la Célula , Desoxicitidina/uso terapéutico , Femenino , Proteínas de Homeodominio/genética , Humanos , Masculino , Páncreas/metabolismo , Páncreas/patología , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/metabolismo , Pronóstico , Interferencia de ARN , GemcitabinaRESUMEN
AIMS: Cell-cell adhesion is a major factor in integrity of epithelia which is frequently disturbed in cancer leading to local invasion and distant metastasis. METHODS: To define expression and function of activated leukocyte cell adhesion molecule (ALCAM, CD166) in pancreatic cancer and in pancreatic neuroendocrine tumors (PNET), microarray analyses, RT-PCR, immunohistochemistry, RNAi, adhesion, migration, invasion, and chemoresistance assays were used. RESULTS: We demonstrate that expression of ALCAM is altered and its serum levels are increased in pancreatic ductal adenocarcinoma (PDAC). ALCAM was expressed on the membranes of islet cells in the normal pancreas whereas normal pancreatic ducts were ALCAM-negative. In PDAC, ALCAM expression was generally rare though in some tumors, membranous, or cytoplasmic ALCAM was found. PNET were mostly ALCAM-positive with a cytoplasmic staining pattern which was in contrast to the membrane expression observed in non-transformed islet cells. In vitro, ALCAM silencing using RNAi had no effects on growth or invasion of pancreatic cancer cells but reduced cell adhesion and induced chemoresistance. In neuroendocrine tumor cell lines, silencing of ALCAM decreased cell growth. CONCLUSIONS: We propose ALCAM as a novel serum biomarker in human pancreatic tumors which is associated with cell adhesion, growth and chemoresistance.
Asunto(s)
Molécula de Adhesión Celular del Leucocito Activado/sangre , Biomarcadores de Tumor/sangre , Carcinoma Ductal Pancreático/patología , Tumores Neuroendocrinos/patología , Neoplasias Pancreáticas/patología , Estudios de Casos y Controles , Adhesión Celular , Línea Celular Tumoral , Transformación Celular Neoplásica , Resistencia a Antineoplásicos , Humanos , Persona de Mediana Edad , Análisis de SupervivenciaRESUMEN
Exogenous application of recombinant TIMP-1 protein modified by addition of a glycosylphosphatidylinositol (GPI) anchor allows efficient insertion of the fusion protein into cell membranes. This 'cell surface engineering' leads to changes in the proteolytic environment. TIMP-1-GPI shows enhanced as well as novel in vitro biological activities including suppression of proliferation, reduced migration, and inhibition of invasion of the colon carcinoma cell line SW480. Treatment of SW480 tumors implanted in Rag (-/-) common gamma chain (-/-) C57BL/6 mice with peritumorally applied TIMP-1-GPI, control rhTIMP-1 protein, or vehicle shows that TIMP-1-GPI leads to a significant reduction in tumor growth.
Asunto(s)
Neoplasias del Colon/tratamiento farmacológico , Proteínas de Unión al ADN/fisiología , Glicosilfosfatidilinositoles/uso terapéutico , Inhibidor Tisular de Metaloproteinasa-1/uso terapéutico , Animales , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Proteínas de Unión al ADN/genética , Glicosilfosfatidilinositoles/química , Humanos , Metaloproteinasa 7 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Ratones , Ratones Endogámicos C57BL , Inhibidor Tisular de Metaloproteinasa-1/químicaRESUMEN
Bradykinin and its kinin B(2) receptor are autocrine and paracrine mediators in foetal membranes and decidua. As a first step we characterized the intracellular morphology of decidual cells. Cultured decidua tissue-derived cells immunolabel for vimentin fibrils, and are considered to be of mesenchymal origin. They show characteristics of macrophages and can be distinguished from endothelial cells and cells of the trophoblast lineage. These cellular features were determined by means of immunocytochemistry. Furthermore cultured decidua tissue-derived cells express kinin B(2) receptors and in this context we demonstrated its expression at mRNA level by in situ reverse transcriptase polymerase chain reaction. Following stimulation with bacterial lipopolysaccharide, we have observed a marginal upregulation of the expression of kinin B(1) receptors and carboxypeptidase M by quantitative RT-PCR. Equilibrium binding experiments with [(3)H]des-Arg(10)-kallidin, the kinin B(1) receptor agonist, did not result in detectable binding sites.