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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 .
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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.
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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
OBJECTIVE: Many patients experience problems with sexual functioning after renal transplantation (RTx). Research on the sexual functioning of the partners of those patients and the consequences for relationship satisfaction and quality of life is lacking. This study sought to explore changes in sexual and relationship functioning from before to after RTx in patients and their partners. MATERIAL AND METHODS: Twenty-nine patients (mean ± SD age 53.4 ± 14.2 years) and 13 partners (age 57.1 ± 11.6 years) provided data 12-15 months after RTx. They retrospectively evaluated sexual and relationship functioning as well as general life satisfaction before RTx and, in comparison, in the most recent months. RESULTS: Among the patients, most items on sexual experience indicated deterioration in sexual functioning. Among their partners, the wish for sexual activity with the patient and the actual frequency of sexual activity decreased from before to after RTx. The rate of partners indicating high personal importance for intercourse decreased from 83.3% to 69.2%, as did the rate of partners stating high sexual satisfaction (from 63.6% to 41.7%). Despite these trends, most patients and partners reported high relationship and life satisfaction after RTx. CONCLUSIONS: Partners of patients who had received a kidney transplant seem to be affected by negative changes in the patients' sexual functioning. Nonetheless, many couples maintain high relationship and life satisfaction.
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Relaciones Interpersonales , Trasplante de Riñón/efectos adversos , Calidad de Vida , Disfunciones Sexuales Fisiológicas/psicología , Disfunciones Sexuales Psicológicas/psicología , Parejas Sexuales/psicología , Adulto , Anciano , Femenino , Humanos , Fallo Renal Crónico/fisiopatología , Fallo Renal Crónico/psicología , Fallo Renal Crónico/cirugía , Masculino , Persona de Mediana Edad , Conducta Sexual/psicología , Disfunciones Sexuales Fisiológicas/etiología , Disfunciones Sexuales Psicológicas/etiología , Encuestas y CuestionariosRESUMEN
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.
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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.
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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.
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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
INTRODUCTION: For the better understanding of the pathophysiological events occurring in the sequence inflammation-metaplasia-carcinoma in esophageal adenocarcinoma, an animal model would be desirable. In the past, several rat models have been used yielding conflicting results. Some demonstrated a sequence similar to the human situation whereas others failed to initiate true esophageal adenocarcinoma or even Barrett's metaplasia. For the study of the molecular events involved in the carcinogenesis of Barrett's carcinoma, a mouse model would be much more promising since most of the genetically altered animals are mice. However, as of now no such model exists, in the past predominately due to the high mortality involved with the surgical procedure to create a mixed duodenogastric reflux. METHODS: Forty BALB-C mice weighing between 22 and 25 g underwent an esophagojejunostomy. The animals were sacrificed at 3, 4, and 5 months. Pathological evaluation was performed with HE staining. RESULTS: Overall mortality was 17%. However, mortality within the first ten animals was 30%. Reasons were technical problems with the anastomosis, opening of the pleural cavity, or bleeding events. All animals had a severe esophagitis regardless of the time. Intestinal metaplasia could be found in 60% of the animals after 4 months and esophageal adenocarcinoma in 55% after 5 months. One animal showed multiple lung metastases. CONCLUSION: After a certain learning curve esophagojejunostomy is feasible in mice with an acceptable mortality rate and leads to esophageal adenocarcinoma.
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Adenocarcinoma/cirugía , Neoplasias Esofágicas/cirugía , Esófago/cirugía , Yeyuno/cirugía , Anastomosis Quirúrgica , Animales , Modelos Animales de Enfermedad , Estudios de Factibilidad , Ratones , Ratones Endogámicos BALB CRESUMEN
PURPOSE: In locally advanced (uT(3), N(+)) adenocarcinomas of the esophagus, neoadjuvant chemotherapy improves patient outcome. However, only a subgroup of patients responds. Therefore, in the present study, we evaluated whether the response to neoadjuvant chemotherapy can be predicted by a pretreatment tumor biopsy analysis. EXPERIMENTAL DESIGN: Biopsies of 47 patients with locally advanced (uT(3), N(+)) adenocarcinoma of the esophagus were obtained during primary staging. All patients underwent neoadjuvant chemotherapy with cisplatin, 5-fluorouracil, and leucovorin and subsequent resection of the esophagus. Biopsies were used for microarray analysis. The predominance of tumor cells within the specimens was >70%. Affymetrix U133 plus 2.0 gene chips with 54675 probe sets were used. A statistical comparison of patients responding to chemotherapy versus nonresponding patients was done. All patients were examined with immunohistology against Ephrin B3 receptor and Ki-67. RESULTS: A total of 86 genes were at least 2-fold differentially regulated comparing responding with nonresponding adenocarcinomas of the esophagus. The predominant genes encoded for the regulation of the cell cycle, transduction, translation, cell-cell interaction, cytoskeleton, and the signal transduction. The strongest difference was seen for the Ephrin B3 receptor. This result could be confirmed by immunhistology. A statistical significant correlation between the Ephrin B3 receptor, chemotherapy response, pathologic staging, and grading could be shown. CONCLUSIONS: There were significant differences in the gene profile between patients with adenocarcinoma of the esophagus responding to neoadjuvant chemotherapy compared with nonresponding patients. This suggests that it could be possible to characterize patients responding to chemotherapy even before starting the treatment using customized microarray analysis.
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Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/genética , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/genética , Terapia Neoadyuvante , Análisis de Matrices Tisulares , Adenocarcinoma/patología , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor , Biopsia , Quimioterapia Adyuvante , Terapia Combinada , Neoplasias Esofágicas/patología , Femenino , Perfilación de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Resultado del TratamientoRESUMEN
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.
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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.