RESUMO
BACKGROUND: Blood loss is common during surgical procedures, especially in open cardiac surgery. Allogenic blood transfusion is associated with increased morbidity and mortality. Blood conservation programs in cardiac surgery recommend re-transfusion of shed blood directly or after processing, as this decreases transfusion rates of allogenic blood. But aspiration of blood from the wound area is often associated with increased hemolysis, due to flow induced forces, mainly through development of turbulence. METHODS: We evaluated magnetic resonance imaging (MRI) as a qualitative tool for detection of turbulence. MRI is sensitive to flow; this study uses velocity-compensated T1-weighted 3D MRI for turbulence detection in four geometrically different cardiotomy suction heads under comparable flow conditions (0-1250 mL/min). RESULTS: Our standard control suction head Model A showed pronounced signs of turbulence at all flow rates measured, while turbulence was only detectable in our modified Models 1-3 at higher flow rates (Models 1 and 3) or not at all (Model 2). CONCLUSIONS: The comparison of flow performance of surgical suction heads with different geometries via acceleration-sensitized 3D MRI revealed significant differences in turbulence development between our standard control Model A and the modified alternatives (Models 1-3). As flow conditions during measurement have been comparable, the specific geometry of the respective suction heads must have been the main factor responsible. The underlying mechanisms and causative factors can only be speculated about, but as other investigations have shown, hemolytic activity is positively associated with degree of turbulence. The turbulence data measured in this study correlate with data from other investigations about hemolysis induced by surgical suction heads. The experimental MRI technique used showed added value for further elucidating the underlying physical phenomena causing blood damage due to non-physiological flow.
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Procedimentos Cirúrgicos Cardíacos , Hemólise , Humanos , Sucção , Imageamento por Ressonância Magnética , Transfusão de Sangue Autóloga/métodosRESUMO
Blood hemolysis caused by mechanical impact is a serious problem in medicine. In addition to the heart-lung machine (artificial surfaces, flow irritating connection points) which contributes to hemolysis, blood suction and surgical suction devices are influencing factors. Goal of our research is to develop best flow optimizing suction geometry that represents the best compromise between all influencing effects. Based on data that negative pressure and turbulence have a negative impact on blood components, 27 surgical suction tips have been examined for acoustic stress and negative pressure behavior. Furthermore, a dimensionless factor Q was introduced to assess the overall performance of the suction tips investigated.
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Transfusão de Sangue Autóloga , Ponte Cardiopulmonar , Máquina Coração-Pulmão , Hemólise , Humanos , SucçãoRESUMO
BACKGROUND: Re-explorations soon after cardiac surgery are mostly related to bleeding or unclear hemodynamic situations possibly related to heart compression resulting from pericardial hematoma. This condition has a significant impact on mortality, morbidity, and costs. The aim of this study was to analyze indications and outcomes of re-exploration for bleeding or pericardial tamponade early after cardiac surgery in adults. METHODS: The clinical data of 4790 consecutive adult patients who underwent cardiac surgery in our institution from January 2011 to May 2016 were retrospectively analyzed. RESULTS: We identified 331 re-explorations performed in 231 patients. Sixty-seven of these patients had >1 re- exploration. In most cases (88%), repeat sternotomy was performed. Most procedures (57%) were performed within the first 48 hours. In two-thirds of re-explorations, active bleeding or pericardial hematoma was verified. In the remaining cases, neither bleeding nor significant pericardial hematoma leading to tamponade was found. Among the cases with active bleeding causes, the most bleeding sites were found to be at the coronary anastomosis and the epicardial exposure harvesting site, as well as from the side branches of bypass grafts and intercostal arteries. CONCLUSIONS: The incidence of re-exploration after cardiac surgery in adults was low (4.8%). In about two-thirds of the cases, active bleeding or significant pericardial hematoma was found. The most common bleeding causes were the easiest to treat.
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Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Derrame Pericárdico/cirurgia , Hemorragia Pós-Operatória/cirurgia , Esternotomia/métodos , Adulto , Feminino , Seguimentos , Alemanha/epidemiologia , Humanos , Incidência , Masculino , Derrame Pericárdico/epidemiologia , Hemorragia Pós-Operatória/epidemiologia , Reoperação , Estudos Retrospectivos , Taxa de Sobrevida/tendências , Fatores de TempoRESUMO
BACKGROUND: Re-transfusion of autologous blood is an important aspect of intraoperative blood management. Hemolysis and platelet dysfunction due to turbulence in the blood suction system strongly impede later usage of suction blood for re-transfusion. The aim of this study was to analyze the effects of a novel surgical-blood suction system with an automatic control setup for minimization of turbulence in the blood flow. METHODS: We compared the turbulence-controlled suction system (TCSS) with a conventional suction system and untreated control blood in vitro. Blood cell counts, hemolysis levels according to free hemoglobin (fHb) and platelet function were analyzed to determine the integrity of the suction blood. RESULTS: In the conventional suction system, we found a strong increase of the fHb levels. In contrast, erythrocyte integrity was almost completely preserved when using the TCSS. We obtained similar results regarding platelet function. The expression of platelet glycoproteins, such as GP IIb/IIIa and P-selectin, native or after stimulation with ADP, were markedly impaired by the conventional system, but not by the TCSS. In addition, platelet aggregometry revealed significant platelet dysfunction in conventional suction blood, but less aggregation impairments were present in blood samples from the TCSS. CONCLUSION: Our findings on an in vitro assessment show major improvements in red blood cell integrity and platelet function of suction blood when using the TCSS compared to a conventional suction system. These results reflect a significant benefit for autologous re-transfusion. We suggest testing the TCSS in surgery for clinical evaluation.
Assuntos
Perda Sanguínea Cirúrgica/prevenção & controle , Plaquetas/patologia , Transfusão de Sangue Autóloga , Hemólise , Sucção/instrumentação , Ponte Cardiopulmonar , Hemoglobinas/análise , Hemostasia , Humanos , Testes de Função Plaquetária , Estudos Prospectivos , Procedimentos Cirúrgicos VascularesRESUMO
BACKGROUND: Renal injury is a serious complication after cardiac surgery and therefore, early detection and much more prediction of postoperative kidney injury is desirable. Neutrophil gelatinase-associated lipocalin (NGAL) is a predictive biomarker of acute kidney injury and may increase after cardiopulmonary bypass (CPB). However, time correlation of NGAL expression and severity of renal injury is still unclear. The aim of our study was to investigate CPB-related urine NGAL (uNGAL) secretion in correlation to postoperative renal function. METHODS: Data of NGAL expression along with clinical data of 81 patients (52 male and 29 female) were included in this study. Mean age of the patients was 66.8 ± 12.8 years. Urine NGAL was measured at seven time points (T0: baseline; T1: start CPB, T2: 40 min on CPB; T3: 80 min on CPB; T4: 120 min on CPB; Tp1: 15 min after CPB; Tp2: 4 h after admission to the intensive care unit) and renal function in the postoperative period was classified daily according to Acute Kidney Injury Network (Ronco et al, Int J Artif Organs 30(5): 373-6) criteria (AKIN). RESULTS: Expression of uNGAL increased at T4 (120 min on CPB) and post-CPB (Tp1 and Tp2; p < 0.01 vs. baseline) but there was no correlation between uNGAL level and duration of CPB nor between uNGAL expression and occurrence of postoperative kidney injury. The renal function over 10 days after surgery remained normal in 50 patients (AKIN level 0), 18 patients (22%) developed mild and insignificant renal injury (AKIN level 1), eight patients (10%) developed moderate renal failure (AKIN level 2), and five patients (6%) severe kidney failure (AKIN level 3). Twenty-four out of 31 patients developed renal failure within the first 48 h after surgery. However, there was no correlation between uNGAL expression and severity of acute renal failure. CONCLUSION: Although uNGAL expression increased after CPB, the peak values neither predict acute postoperative kidney injury, nor severity of the injury.
Assuntos
Injúria Renal Aguda/epidemiologia , Procedimentos Cirúrgicos Cardíacos , Ponte Cardiopulmonar , Lipocalina-2/urina , Complicações Pós-Operatórias/epidemiologia , Injúria Renal Aguda/fisiopatologia , Injúria Renal Aguda/urina , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/fisiopatologia , Complicações Pós-Operatórias/urina , Prognóstico , Índice de Gravidade de DoençaRESUMO
Renal blood flow (RBF) may vary during cardiopulmonary bypass and low flow may cause insufficient blood supply of the kidney triggering renal failure postoperatively. Still, a valid intraoperative method of continuous RBF measurement is not available. A new catheter combining thermodilution and intravascular Doppler was developed, first calibrated in an in vitro model, and the catheter specific constant was determined. Then, application of the device was evaluated in a pilot study in an adult cardiovascular population. The data of the clinical pilot study revealed high correlation between the flow velocities detected by intravascular Doppler and the RBF measured by thermodilution (Pearson's correlation range: 0.78 to 0.97). In conclusion, the RBF can be measured excellently in real time using the new catheter, even under cardiopulmonary bypass.
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Procedimentos Cirúrgicos Cardíacos/instrumentação , Circulação Renal , Idoso , Ponte Cardiopulmonar/instrumentação , Desenho de Equipamento , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos PilotoRESUMO
AIM: The study aimed to assess job demands at the patient's bedside and to evaluate the contribution of this central workplace to the stress and satisfaction of nurses. DESIGN: In this cross-sectional survey study, a questionnaire was compiled and all registered nurses from intensive, general and intermediate care wards at a large German hospital were invited to participate. METHODS: The questionnaire used a list of care activities to assess nurses' workload at the patient's bed. The German Copenhagen Psychosocial Questionnaire and an adapted version of the German Perceived Stress Scale were used to measure nurses' stress and burn-out, and single items to assess health status, organisational commitment, job satisfaction, and satisfaction with the quality of care. The questionnaire was returned by 389 nurses. RESULTS: Expected correlations of workload at the patient's bed with stress, burn-out and satisfaction of the nurses were shown. A moderating effect of organisational commitment was non-existent but was shown for the self-assessed health on the correlation between workload and satisfaction with the quality of care. Organisational commitment correlated negatively with stress and burn-out and positively with satisfaction. The study provides evidence that rates of burn-out and stress do not differ based on the work area of nurses. Because job demands at the patient's bed correlated with all outcomes, measures to improve this specific workspace are sensible.
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Esgotamento Profissional , Satisfação do Paciente , Humanos , Estudos Transversais , Esgotamento Profissional/psicologia , Local de Trabalho/psicologia , Satisfação no Emprego , Satisfação PessoalRESUMO
OBJECTIVE: To investigate the effects of the Silent Laboratory Optimization System (SLOS), a technical-noise reduction and communication-management system, on noise load and stress among medical-laboratory workers. METHODS: We conducted a quasiexperimental field study (20 days with SLOS as the experimental condition, and 20 days without SLOS as the control condition) in a within-subjects design. Survey data from 13 workers were collected before and after the shift. Also, a survey was conducted after the control and experimental conditions, respectively. Noise was measured in dBA and as a subjective assessment. Stress was operationalized via a stress composite score (STAI and Perkhofer Stress Scale), the Perceived Stress Scale (PSS), an exhaustion score (Leipziger StimmungsBogen in German [LSB]), and salivary cortisol values in µg/L. RESULTS: SLOS users perceived significantly less noise (V = 76.5; P =.003). Multilevel models revealed a stress reduction with the SLOS on the composite score, compared with a stress increase in the control condition (F[1, 506.99] = 6.00; P = .01). A lower PSS score (F[1,13] = 4.67; P = .05) and a lower exhaustion level (F[1, 508.72] = 9.057; P = .003) in the experimental condition were found, whereas no differences in cortisol (F[1,812.58.6] = 0.093; P = .76) were revealed. CONCLUSION: The workers showed reduced noise perception and stress across all criteria except cortisol when using SLOS.
Assuntos
Comunicação , Hidrocortisona , Humanos , Inquéritos e QuestionáriosRESUMO
OBJECTIVE: Acute kidney injury (AKI) is a major complication after cardiovascular surgery. The unclear etiology of this highly complex event challenges definition, diagnosis and prediction of AKI, and hence hampers adequate patient management. Identification of associated risk factors have the potential to overcome this limitation. METHODS: This retrospective study comprised 3574 patients who underwent cardiac surgery in a hospital in Germany. The patient cohort was interrogated for risk factors for AKI. RESULTS: The analysis identified risk factors for AKI development, such as type of surgery (particularly bypass surgery) (P = 0.02), previous coronary surgeries (P < 0.01), the application of intra-aortic balloon pump in surgery (P < 0.01), and blood loss during surgery (P < 0.01). In addition, old age, duration of surgery as well as ischemia, perfusion and reperfusion times contributed to AKI development (P < 0.01). Further, perioperative hypothermia also appeared as putative risk factor in the analysis (P < 0.01). CONCLUSIONS: This study identified several risk factors for the development of AKI after cardiac surgery. Further validation of these risk factors could allow the implementation of adequate patient management, and the appropriate implementation of risk-adverse interventions in cardiovascular surgery.
RESUMO
BACKGROUND: Acute kidney injury (AKI) is a frequent and serious complication of cardiac surgery, associated with a high incidence of morbidity and mortality. Although the RIFLE criteria serve as a prominent tool to identify patients at high risk of AKI, an optimized diagnosis model in clinical practice is desired. METHODS: Based on the SOP-criteria, 365 patients (10%) developed AKI following surgery and were subjected to RRT. In contrast, the incidence of AKI, defined according to the RIFLE criteria, was only 7% (n = 251 patients). Prominent risk factors identified by SOP were patients' sex, valve and combined valve and bypass surgery, deep hypothermia, use of intra-aortic balloon pump (IABP) and previous coronary interventions. Ischemia, reperfusion, blood loss and surgery time also served as significant risk factors for patient evaluated by SOP. RESULTS: Risk assessment by RIFLE differed in as much as most patients with normothermia and those receiving only cardiovascular bypass developed AKI. However, patients' sex and valve surgery did not serve as a risk factor. CONCLUSION: Evaluation of patients by the RIFLE versus SOP criteria yielded different results with more AKI patients detected by SOP. Based on the present data, it is concluded that patients may not prone to AKI when surgery and ischemia time will be kept short, when blood loss is mitigated to a minimum and when surgery is performed under non-hypothermic conditions.
Assuntos
Injúria Renal Aguda/etiologia , Ponte Cardiopulmonar/efeitos adversos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Adulto JovemRESUMO
OBJECTIVES: The use of digital chest drainage units (CDUs) has become increasingly common in thoracic surgery due to several advantages. However, in cardiac surgery, its use is still limited in favour of conventional analogue CDUs. In order to investigate the potential benefit of digital CDUs in cardiac surgery, we compared the safety and efficacy of both systems in patients undergoing cardiac surgery at our centre. METHODS: We retrospectively investigated 265 consecutive patients who underwent cardiac surgery at our institution between June 2017 and October 2017. These patients were divided into 2 groups: patients with analogue (A, n = 65) and digital CDUs (D, n = 200). Postoperative outcome was analysed and compared between both groups. In addition, the 'user experience' was evaluated by means of a questionnaire. RESULTS: The median age of the cohort was 70 years (P = 0.167), 25.3% of patients were female (P = 0.414). There were no differences in terms of re-explorative surgery or use of blood products. Nor was there a difference in the overall amount of fluid collected. However, during the first 6 h, more fluid was collected by the digital CDUs. The overall rate of technical failure was 0.4%. We observed a significantly higher rate of clotting in the tubing system of the digital CDUs (P = 0.042). Concerning the user experience, the digital CDUs were associated with a more favourable ease of use on the regular wards (P < 0.001). With regard to the overall user experience, the digital CDUs outperformed the analogue systems (P = 0.002). CONCLUSIONS: Digital CDUs can be safely and effectively applied in patients after cardiac surgery. Due to the improved patient mobility and simplified chest tube management, the use of digital CDUs may be advantageous for patients after cardiac surgery. However, the issue of clotting of the tubing systems should be addressed by further technical improvements.
Assuntos
Procedimentos Cirúrgicos Cardíacos/métodos , Tubos Torácicos , Drenagem/métodos , Cuidados Pós-Operatórios/métodos , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Inquéritos e QuestionáriosRESUMO
OBJECTIVE: To evaluate CpG island methylation patterns of cancer-associated genes for their applicability as molecular biomarkers for the detection of superficial bladder cancer and for the discrimination of invasive from noninvasive tumours. PATIENTS AND METHODS: We analysed the methylation status of CpG islands in the promoter region of the cancer-associated genes GSTP1, DAPK, MDR1, TPEF, PAX6, and TSLC1 in primary papillary bladder cancer specimens from 39 patients (pT1 10, pTis one, pTa 20, pT2 five). Tumour-adjacent normal mucosa served as the control. The DNAs were bisulphite-treated and submitted to methylation-specific real-time polymerase chain reactions. RESULTS: Only TPEF and PAX6 had substantial CpG island methylation percentages. The TPEF- and PAX6-promoters also had significantly higher methylation rates in tumour tissue compared with the normal tumour-adjacent tissue. Interestingly, the methylation rates of the TPEF- and the PAX6-promoter were higher in adjacent normal tissues from bladders with pTa then in those with pT1 tumours. CONCLUSION: Our results shed a critical light on the hypothesis that CpG island hypermethylation of the GSTP1-, DAPK-, MDR1- and TSLC1-promoter could represent molecular biomarkers for bladder cancer diagnosis and detection. However, methylated PAX6- or TPEF-promoters could represent biomarkers for this disease. Additional studies are needed to evaluate whether methylation rates of these genes in normal bladder tissues are applicable as accessory markers for the tumour state or its invasive behaviour.
Assuntos
Ilhas de CpG/genética , Metilação de DNA , Proteínas do Olho/metabolismo , Proteínas de Homeodomínio/metabolismo , Proteínas de Membrana/metabolismo , Proteínas de Neoplasias/metabolismo , Fatores de Transcrição Box Pareados/metabolismo , Regiões Promotoras Genéticas/genética , Proteínas Repressoras/metabolismo , Neoplasias da Bexiga Urinária/diagnóstico , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Proteínas do Olho/genética , Proteínas de Homeodomínio/genética , Humanos , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Fator de Transcrição PAX6 , Fatores de Transcrição Box Pareados/genética , Proteínas Repressoras/genética , Neoplasias da Bexiga Urinária/genéticaRESUMO
OBJECTIVE: To investigate whether a high frequency of allelic imbalance (AI) is associated with clinicopathological variables of patients with prostate cancer. PATIENTS AND METHODS: We analysed loss of heterozygosity (LOH) and microsatellite (MS) instability (MSI) on circulating plasma DNA in a polymerase chain reaction (PCR)-based MS study of 230 patients with prostate cancer and 43 with benign prostatic hyperplasia (BPH) using a panel of 13 polymorphic MS markers. RESULTS: The overall incidence of AI was significantly higher in primary tumours (34%) than in blood plasma samples from patients with prostate cancer (11%). Although LOH (2.0%) and MSI (1.5%) were also found in BPH plasma samples, their frequencies were low. AI identified in plasma samples from patients with prostate cancer could be retrieved in 63% of the paired tumour samples. The highest concordance of AI and retention of heterozygosity between tumour and plasma samples was 83% at the marker D8S360. There were high frequencies of LOH at the markers THRB, D7S522 and D8S137 in both types of specimens. The markers D11S898 and D11S1313 on the chromosome arm 11q showed frequent MSI. The comparison with established risk factors showed significant associations of an increase in prostate volume with AI at the combined markers D6S474/D7S522 in tumour tissues and at D7S522 in plasma samples (P < 0.04). In the primary tumours there was a further correlation of LOH at D11S1313 with increasing tPSA value (P = 0.005). The combination of total prostate-specific antigen (PSA) and % free PSA was associated with LOH at THRB in plasma samples. CONCLUSIONS: Plasma-based MS analysis may have clinical value for the molecular staging of prostate cancer.
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Desequilíbrio Alélico/genética , DNA de Neoplasias/sangue , Repetições de Microssatélites/genética , Hiperplasia Prostática/genética , Neoplasias da Próstata/genética , Marcadores Genéticos , Humanos , Perda de Heterozigosidade , Masculino , Reação em Cadeia da Polimerase , Estudos Prospectivos , Antígeno Prostático Específico/sangue , Hiperplasia Prostática/sangue , Hiperplasia Prostática/patologia , Neoplasias da Próstata/sangue , Neoplasias da Próstata/patologia , Sensibilidade e EspecificidadeRESUMO
OBJECTIVE: To assess the value of nuclear matrix protein-22 (NMP22), compared with urinary cytology, in predicting the recurrence of bladder cancer that is not transitional cell carcinoma (non-TCC). PATIENTS AND METHODS: We tested the sensitivity, specificity and the predictive accuracy of NMP22 in the context of non-TCC bladder cancer recurrence, and compared it to the performance of urinary cytology. The study group comprised 2687 patients with history of non-muscle-invasive bladder cancer from 10 centres across four continents. RESULTS: The mean patient age was 64.8 years and 75.4% were men; of all patients, 513 (19.1%) had positive urinary cytology, 906 (33.7%) had a positive NMP22 test (>or=10 units/mL) and 80 (3.0%) had non-TCC recurrence. Most of these, i.e. 60 (75%), were stage >or=T2. The sensitivity and specificity of urinary cytology were, respectively, 20.0% and 94.8%, vs 77.5% and 81.8% for NMP22 of >or=10 units/mL. The predictive accuracy of urinary cytology was 57.5%, vs 87.1% for NMP22 >or= 10 units/mL. A combined model that included dichotomized NMP22 and urinary cytology was 85.3% accurate. CONCLUSION: The ability of a NMP22 level of >or=10 units/mL to predict non-TCC recurrence was better than that of urinary cytology, suggesting that NMP22 might have a role in the surveillance of patients at risk of non-TCC recurrence.
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Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/patologia , Recidiva Local de Neoplasia/diagnóstico , Proteínas Nucleares/metabolismo , Neoplasias da Bexiga Urinária/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/urina , Criança , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/urina , Valor Preditivo dos Testes , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Sensibilidade e Especificidade , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/urinaRESUMO
There is increasing evidence for the role of epigenetic gene silencing in superficial bladder cancer. The aim of the current study was to investigate the prognostic value of epigenetic alterations in patients with non-muscle invasive bladder carcinoma. We checked the methylation status of 20 cancer associated genes (p14ARF, p16 CDKN2A, STAT-1, SOCS-1, DR-3, DR-6, PIG-7, BCL-2, H-TERT, BAX, EDNRB, DAPK, RASSF-1A, FADD, TMS-1, E-Cadherin, ICAM-1, TIMP-3, MLH-1, COX-2) for DNA methylation. We analysed microdissected tumour samples from 105 consecutive patients with primary non-muscle invasive bladder carcinoma. Quantitative methylation analysis of CpG sites in the promoter region of the genes was performed with methylation sensitive quantitative real time PCR ('Methylight'). Univariate analysis for association with tumour recurrence was carried out with the Kaplan-Meier analysis and the log-rank test. Follow-up data were available in 95/105 patients (91.4%). A tumour recurrence was observed in 26 patients (27.3%). We could identify six genes (SOCS-1, STAT-1, BCL-2, DAPK, TIMP-3, E-Cadherin), where methylation was associated with tumour recurrence. In Kaplan-Meier analysis, TIMP-3 showed a significant association with recurrence free survival. Methylation of TIMP-3 predicted prolonged disease free interval. In this study, we report a comprehensive analysis on prognostic relevance of gene methylation in non-muscle invasive bladder cancer. We identified one gene (TIMP-3) where methylation was associated with a more favourable outcome. Our data strongly support the usefulness of gene methylation as a prognostic marker in patients with non-muscle invasive bladder cancer.
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Genes Neoplásicos , Neoplasias da Bexiga Urinária/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Estudos de Coortes , Metilação de DNA , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Reação em Cadeia da Polimerase/métodos , PrognósticoRESUMO
PURPOSE: There is increasing evidence for a fundamental role for epigenetic silencing of apoptotic pathways in cancer. Changes in DNA methylation can be detected with a high degree of sensitivity, so we used the MethyLight assay to determine how methylation patterns of apoptosis-associated genes change during bladder carcinogenesis and whether DNA methylation could be detected in urine sediments. EXPERIMENTAL DESIGN: We analyzed the methylation status of the 5' regions of 12 apoptosis-associated genes (ARF, FADD, TNFRSF21, BAX, LITAF, DAPK, TMS-1, BCL2, RASSF1A, TERT, TNFRSF25, and EDNRB) in 18 bladder cancer cell lines, 127 bladder cancer samples, and 37 samples of adjacent normal bladder mucosa using the quantitative MethyLight assay. We also analyzed the methylation status in urine sediments of 20 cancer-free volunteers and 37 bladder cancer patients. RESULTS: The 5' regions of DAPK, BCL2, TERT, RASSFIA, and TNFRSF25 showed significant increases in methylation levels when compared with nonmalignant adjacent tissue (P < or = 0.01). Methylation levels of BCL2 were significantly associated with tumor staging and grading (P < or = 0.01), whereas methylation levels of RASSF1A and ARF were only associated with tumor stage (P < or = 0.04), and TERT methylation and EDNRB methylation were predictors of tumor grade (P < or = 0.02). To investigate clinical usefulness for noninvasive bladder cancer detection, we further analyzed the methylation status of the markers in urine samples of patients with bladder cancer. Methylation of DAPK, BCL2, and TERT in urine sediment DNA from bladder cancer patients was detected in the majority of samples (78%), whereas they were unmethylated in the urine sediment DNA from age-matched cancer-free individuals. CONCLUSIONS: Our results indicate that methylation of the 5' region of apoptosis-associated genes is a common finding in patients with bladder carcinoma. The ability to detect methylation not only in bladder tissue, but also in urine sediments, suggests that methylation markers are promising tools for noninvasive detection of bladder cancers. Our results also indicate that some methylation markers, such as those in regions of RASSF1A and TNFRSF25, might be of limited use for detection because they are also methylated in normal bladder tissues.
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Apoptose , Metilação de DNA , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/urina , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Linhagem Celular Tumoral , Ilhas de CpG , Primers do DNA/química , Humanos , Lipopolissacarídeos/química , Pessoa de Meia-Idade , Mucosa/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Receptores do Fator de Necrose Tumoral/biossíntese , Membro 25 de Receptores de Fatores de Necrose Tumoral , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Tempo , Proteínas Supressoras de Tumor/genética , Bexiga Urinária/metabolismoRESUMO
BACKGROUND: Preliminary research has suggested the potential prognostic value of circulating tumor cells (CTC) in patients with advanced nonmetastatic urothelial carcinoma of the bladder (UCB). OBJECTIVE: Prospectively analyze the clinical relevance and human epidermal growth factor receptor 2 (HER2) expression of CTC in patients with clinically nonmetastatic UCB. DESIGN, SETTING, AND PARTICIPANTS: Blood samples from 100 consecutive UCB patients treated with radical cystectomy (RC) were investigated for the presence (CellSearch system) of CTC and their HER2 expression status (immunohistochemistry). HER2 expression of the corresponding primary tumors and lymph node metastasis were analyzed using fluorescence in situ hybridization. INTERVENTION: Blood samples were taken preoperatively. Patients underwent RC with lymphadenectomy. MEASUREMENTS: Outcomes were assessed according to CTC status. HER2 expression of CTC was compared with that of the corresponding primary tumor and lymph node metastasis. RESULTS AND LIMITATIONS: CTC were detected in 23 of 100 patients (23%) with nonmetastatic UCB (median: 1; range: 1-100). Presence, number, and HER2 status of CTC were not associated with clinicopathologic features. CTC-positive patients had significantly higher risks of disease recurrence and cancer-specific and overall mortality (p values: ≤ 0.001). After adjusting for effects of standard clinicopathologic features, CTC positivity remained an independent predictor for all end points (hazard ratios: 4.6, 5.2, and 3.5, respectively; p values ≤ 0.003). HER2 was strongly positive in CTC from 3 of 22 patients (14%). There was discordance between HER2 expression on CTC and HER2 gene amplification status of the primary tumors in 23% of cases but concordance between CTC, primary tumors, and lymph node metastases in all CTC-positive cases (100%). The study was limited by its sample size. CONCLUSIONS: Preoperative CTC are already detectable in almost a quarter of patients with clinically nonmetastatic UCB treated with RC and were a powerful predictor of early disease recurrence and cancer-specific and overall mortality. Thus CTC may serve as an indication for multimodal therapy. Molecular characterization of CTC may serve as a liquid biopsy to guide individual targeted therapy in future clinical trials.
Assuntos
Biomarcadores Tumorais/sangue , Cistectomia , Células Neoplásicas Circulantes/química , Receptor ErbB-2/sangue , Neoplasias da Bexiga Urinária/cirurgia , Idoso , Biomarcadores Tumorais/genética , Quimioterapia Adjuvante , Distribuição de Qui-Quadrado , Intervalo Livre de Doença , Feminino , Alemanha , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Estimativa de Kaplan-Meier , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Células Neoplásicas Circulantes/patologia , Seleção de Pacientes , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , Estudos Prospectivos , Radioterapia Adjuvante , Receptor ErbB-2/genética , Medição de Risco , Fatores de Risco , Resultado do Tratamento , Neoplasias da Bexiga Urinária/sangue , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/mortalidade , Neoplasias da Bexiga Urinária/patologiaAssuntos
Carcinoma Papilar/terapia , Carcinoma de Células de Transição/terapia , Papiloma/terapia , Neoplasias da Bexiga Urinária/terapia , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/uso terapêutico , Carcinoma Papilar/tratamento farmacológico , Carcinoma Papilar/cirurgia , Carcinoma de Células de Transição/tratamento farmacológico , Carcinoma de Células de Transição/cirurgia , Cistoscopia , Epirubicina/administração & dosagem , Epirubicina/uso terapêutico , Seguimentos , Humanos , Recidiva Local de Neoplasia , Papiloma/tratamento farmacológico , Papiloma/cirurgia , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , Fatores de Tempo , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/cirurgiaAssuntos
Inibidores de Ciclo-Oxigenase/uso terapêutico , Isoenzimas/metabolismo , Prostaglandina-Endoperóxido Sintases/metabolismo , Hiperplasia Prostática/enzimologia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/enzimologia , Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase 2 , Amplificação de Genes , Regulação Neoplásica da Expressão Gênica , Genes erbB-2/genética , Humanos , Imuno-Histoquímica , Isoenzimas/genética , Masculino , Proteínas de Membrana , Estadiamento de Neoplasias , Prognóstico , Prostaglandina-Endoperóxido Sintases/genética , Próstata/enzimologia , Próstata/metabolismo , Próstata/patologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Receptores Proteína Tirosina Quinases/genética , Fatores de RiscoRESUMO
OBJECTIVE: To investigate the prostate cancer (PCa) prevalence and risk factors of men with prostate-specific antigen (PSA) level< or =4.0 ng/ml and an unsuspicious digital rectal examination (DRE) in a large biopsy referral cohort. MATERIALS AND METHODS: Between 1997 and 2005, 855 men underwent initial transrectal ultrasound (TRUS)-guided prostate biopsy at the University Hospital Hamburg-Eppendorf. Patients with any previous surgical or medical treatment were excluded from analyses. Logistic regression analyses were performed to determine risk factors of PCa at biopsy and high-grade PCa defined as biopsy Gleason sum> or =7. RESULTS: Overall PCa detection rate was 23.1%. The majority had a biopsy Gleason sum of 6 (79.5%) and 20.5% had a biopsy Gleason sum> or =7. Total PSA (tPSA) and percentage of free PSA (%fPSA) were statistically significantly different in men with and without PCa (all p<0.001). In tPSA strata < or = 0.5, 0.6-1.0, 1.1-2.0, 2.1-3.0, and 3.1-4.0 ng/ml, PCa prevalence was 4.0%, 10.6%, 14.8%, 24.5%, and 32.1%, respectively. In logistic regression analyses addressing PCa and Gleason sum > or = 7 at biopsy, %fPSA and prostate volume represented independent and most informative risk factors. CONCLUSION: Our data demonstrate that a substantial percentage (23.1%) of men with a PSA< or =4.0 ng/ml and an unsuspicious DRE in a biopsy referral population harbor PCa, with 20.5% being high grade. Low %fPSA and low prostate volume represent important parameters in PCa and in high grade disease detection at biopsy, respectively.