RESUMEN
RATIONALE, AIMS AND OBJECTIVES: A physician-led clinic for the preoperative optimization and management of high-risk surgical patients was implemented in a South Australian public hospital in 2008. This study aimed to estimate the costs and effects of the clinic using a mixed retrospective and prospective observational study design. METHOD: Alternative propensity score estimation methods were applied to retrospective routinely collected administrative and clinical data, using weighted and matched cohorts. Supplementary survey-based prospective data were collected to inform the analysis of the retrospective data and reduce potential unmeasured confounding. RESULTS: Using weighted cohorts, clinic patients had a significantly longer mean length of stay and higher mean cost. With the matched cohorts, reducing the calliper width resulted in a shorter mean length of stay in the clinic group, but the costs remained significantly higher. The prospective data indicated potential unmeasured confounding in all analyses other than in the most tightly matched cohorts. CONCLUSIONS: The application of alternative propensity-based approaches to a large sample of retrospective data, supplemented with a smaller sample of prospective data, informed a pragmatic approach to reducing potential observed and unmeasured confounding in an evaluation of a physician-led preoperative clinic. The need to generate tightly matched cohorts to reduce the potential for unmeasured confounding indicates that significant uncertainty remains around the effects of the clinic. This study illustrates the value of mixed retrospective and prospective observational study designs but also underlines the need to prospectively plan for the evaluation of costs and effects alongside the implementation of significant service innovations.
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Instituciones de Atención Ambulatoria , Periodo Preoperatorio , Puntaje de Propensión , Anciano , Instituciones de Atención Ambulatoria/normas , Australia , Bases de Datos Factuales , Femenino , Hospitales Públicos , Humanos , Masculino , Estudios de Casos Organizacionales , Estudios Prospectivos , Calidad de Vida , Estudios RetrospectivosRESUMEN
BACKGROUND: There are a subset of potentially modifiable co-morbidities that may be targeted in the preoperative phase with a view to optimizing control and improving post-operative outcomes. This study aims to estimate the effect of potentially modifiable co-morbidities on post-operative outcomes and to identify potential targets for preoperative management. METHODS: Retrospective data on hospital separations in South Australia were analyzed using multiple regression to estimate the association between nine potentially modifiable co-morbidities and length of stay, post-operative complications and in-hospital mortality. RESULTS: After adjusting for primary diagnosis, age, gender and other potential confounders, significant increases in length of stay and complications were recorded for eight and six of the nine modifiable co-morbidities, respectively. As examples, previous heart failure was associated with a 54% increase in length of stay and an odds ratio of 1.75 for complications. Asthma and chronic obstructive pulmonary disease was associated with a 38% increase in length of stay and an odds ratio of 1.64 for complications. CONCLUSIONS: A set of potentially modifiable co-morbidities is associated with a range of poorer post-operative outcomes, relative to patients without those co-morbidities. There is a clinical rationale that outcomes will be worse in the subset of patients for whom such co-morbidities are poorly controlled, and that timely intervention to improve control in the period prior to surgery will improve post-operative outcomes. Further research is required on post-operative outcomes for patients with and without controlled co-morbidities and on the effects of timely intervention to improve control prior to surgery.
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Comorbilidad , Complicaciones Posoperatorias/etiología , Periodo Preoperatorio , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Mortalidad Hospitalaria , Humanos , Tiempo de Internación , Modelos Logísticos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Evaluación de Resultado en la Atención de Salud , Complicaciones Posoperatorias/mortalidad , Complicaciones Posoperatorias/prevención & control , Cuidados Preoperatorios , Estudios Retrospectivos , Riesgo , Medición de Riesgo , Factores de RiesgoRESUMEN
Circulating microRNAs (miRNAs) are emerging as useful non-invasive markers of disease. The objective of this study was to use a mouse model of prostate cancer as a tool to discover serum miRNAs that could be assessed in a clinical setting. Global miRNA profiling identified 46 miRNAs at significantly altered levels (p ≤ 0.05) in the serum of TRansgenic Adenocarcinoma of Mouse Prostate (TRAMP) mice with advanced prostate cancer compared to healthy controls. A subset of these miRNAs with known human homologues were validated in an independent cohort of mice and then measured in serum from men with metastatic castration-resistant prostate cancer (mCRPC; n = 25) or healthy men (n = 25). Four miRNAs altered in mice, mmu-miR-141, mmu-miR-298, mmu-miR-346 and mmu-miR-375, were also found to be at differential levels in the serum of men with mCRPC. Three of these (hsa-miR-141, hsa-miR-298 and hsa-miR-375) were upregulated in prostate tumors compared with normal prostate tissue, suggesting that they are released into the blood as disease progresses. Moreover, the intra-tumoral expression of hsa-miR-141 and hsa-miR-375 were predictors of biochemical relapse after surgery. This study is the first to demonstrate that specific serum miRNAs are common between human prostate cancer and a mouse model of the disease, highlighting the potential of such models for the discovery of novel biomarkers.
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Biomarcadores de Tumor/sangre , MicroARNs/sangre , Neoplasias de la Próstata/genética , Animales , Biomarcadores de Tumor/genética , Perfilación de la Expresión Génica , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , MicroARNs/genética , Análisis de Secuencia por Matrices de Oligonucleótidos , Pronóstico , Neoplasias de la Próstata/sangre , Neoplasias de la Próstata/patologíaRESUMEN
Lower urinary tract symptoms (LUTS) are common among Australian men over the age of 45 years; most men with LUTS will have benign prostatic hyperplasia (BPH), overactive bladder (OAB), or both. The cause of LUTS should be diagnosed by assessing symptom severity and excluding of medical or pharmaceutical causes. All men with LUTS should undergo digital rectal examination; other diagnostic tools include urine and blood testing, voiding charts and imaging. Depending on disease severity, impact on quality of life, patient preference, presence of complications and fitness for surgery, BPH is managed with watchful waiting, pharmacotherapy (α-blockers or 5-α-reductase inhibitors), minimally invasive surgical therapies or surgery. OAB is initially treated with behavioural therapy; if this is ineffective, pharmacotherapy (usually antimuscarinics) can be used. Patients with LUTS with a provisional diagnosis other than BPH or OAB, or with complications or poor response to pharmacotherapy, should be referred to a urologist.
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Hiperplasia Prostática/complicaciones , Hiperplasia Prostática/tratamiento farmacológico , Calidad de Vida , Trastornos Urinarios/tratamiento farmacológico , Trastornos Urinarios/etiología , Inhibidores de 5-alfa-Reductasa/uso terapéutico , Antagonistas Adrenérgicos alfa/uso terapéutico , Anciano , Anciano de 80 o más Años , Terapia Conductista , Progresión de la Enfermedad , Quimioterapia Combinada , Humanos , Masculino , Persona de Mediana Edad , Antagonistas Muscarínicos/uso terapéutico , Prevalencia , Hiperplasia Prostática/diagnóstico , Hiperplasia Prostática/epidemiología , Hiperplasia Prostática/cirugía , Ensayos Clínicos Controlados Aleatorios como Asunto , Factores de Riesgo , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Micción , Trastornos Urinarios/diagnóstico , Trastornos Urinarios/epidemiología , Espera VigilanteRESUMEN
The response of prostate cells to androgens reflects a combination of androgen receptor (AR) transactivation and transrepression, but how these two processes differ mechanistically and influence prostate cancer risk and disease outcome remain elusive. Given recent interest in targeting AR transrepressive processes, a better understanding of AR/corepressor interaction and responses is warranted. Here, we used transactivation and interaction assays with wild-type and mutant ARs, and deletion AR fragments, to dissect the relationship between AR and the corepressor, silencing mediator for retinoic acid and thyroid hormone receptors (SMRT). We additionally tested how these processes are influenced by AR agonist and antagonist ligands, as well as by variation in the polyglutamine tract in the AR amino terminal domain (NTD), which is encoded by a polymorphic CAG repeat in the gene. SMRT was recruited to the AR ligand binding domain by agonist ligand, and as determined by the effect of strategic mutations in activation function 2 (AF-2), requires a precise conformation of that domain. A distinct region of SMRT also mediated interaction with the AR-NTD via the transactivation unit 5 (TAU5; residues 315-538) region. The degree to which SMRT was able to repress AR increased from 17% to 56% as the AR polyglutamine repeat length was increased from 9 to 42 residues, but critically this effect could be abolished by increasing the SMRT:AR molar ratio. These data suggest that the extent to which the CAG encoded polyglutamine repeat influences AR activity represents a balance between corepressor and coactivator occupancy of the same ligand-dependent and independent AR interaction surfaces. Changes in the homeostatic relationship of AR to these molecules, including SMRT, may explain the variable penetrance of the CAG repeat and the loss of AR signaling flexibility in prostate cancer progression.
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Proteínas Co-Represoras/metabolismo , Co-Represor 2 de Receptor Nuclear/metabolismo , Péptidos/metabolismo , Neoplasias de la Próstata/metabolismo , Receptores Androgénicos/metabolismo , Secuencias Repetitivas de Ácidos Nucleicos , Antagonistas de Receptores Androgénicos/metabolismo , Andrógenos/análisis , Animales , Línea Celular , Chlorocebus aethiops , Proteínas Co-Represoras/genética , Masculino , Mutación , Co-Represor 2 de Receptor Nuclear/genética , Péptidos/genética , Próstata/metabolismo , Neoplasias de la Próstata/genética , Dominios y Motivos de Interacción de Proteínas , Receptores Androgénicos/genética , Activación TranscripcionalRESUMEN
OBJECTIVE: The role of endogenous testosterone in the pathogenesis of type 2 diabetes mellitus remains vague. We investigated whether associations between endogenous testosterone and diabetes prevalence in men could be partially explained by modifiable risk factors. STUDY DESIGN: A random population-based cross-sectional study of 1195 men aged 35-80 years living in the north-west regions of Adelaide, Australia. Data collections occurred between 2002 and 2005, and response rate was 45.1%. MATERIALS AND METHODS: Diabetes (non-specific) was classified by either: (1) self-report for doctor diagnosis of diabetes; (2) prescription medication for diabetes; (3) fasting plasma glucose ≥ 7 mmol/L; or (4) glycosylated haemoglobin ≥ 6.2%. Logistic regressions were used to estimate odds ratios (OR [with 95% confidence intervals]) for diabetes, with stepwise adjustments for demographic, lifestyle, and clinical factors. RESULTS: Diabetes prevalence was positively associated with age groups 45-54 years (2.8 [1.4, 5.8]), 55-64 years (3.9 [1.9, 8.3]) and ≥ 65 years (4.0 [1.8, 8.9]), lowest income group (1.8 [1.0, 3.4]), ex-smoker (1.8 [1.2, 2.9]), lowest (3.2 [1.9, 5.5]) and middle (1.9 [1.1, 3.4]) alcohol tertiles, cardiovascular disease (1.9 [1.2, 2.8]), metabolic syndrome (4.0 [2.6, 6.1]), and lowest plasma total testosterone tertile (1.8 [1.1, 3.0]), but negatively associated with middle (0.5 [0.3, 0.8]) and highest (0.4 [0.3, 0.7]) sugar intake tertiles, arthritis (0.6 [0.3, 1.0]), and elevated LDL cholesterol (0.5 [0.3, 0.8]); ORs showed an inverted 'U' shape for middle and highest voiding lower urinary tract symptoms tertiles. Body composition, muscle strength, and cardio-metabolic factors partially explained the association between low plasma total testosterone and diabetes. CONCLUSIONS: Plasma total testosterone was inversely and independently associated with diabetes prevalence, that might have been partially explained by several modifiable risk factors.
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Diabetes Mellitus Tipo 2/etiología , Testosterona/sangre , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Consumo de Bebidas Alcohólicas , Artritis/complicaciones , Australia/epidemiología , Glucemia/metabolismo , Composición Corporal , Enfermedades Cardiovasculares/complicaciones , Estudios Transversales , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/epidemiología , Sacarosa en la Dieta/administración & dosificación , Humanos , Hipercolesterolemia/sangre , Hipercolesterolemia/complicaciones , Modelos Logísticos , Masculino , Síndrome Metabólico/complicaciones , Persona de Mediana Edad , Oportunidad Relativa , Prevalencia , Factores de Riesgo , Autoinforme , Fumar , Enfermedades Urológicas/complicacionesRESUMEN
PURPOSE: To define specific medical conditions associated with clinically significant depressive symptoms in men. METHODS: A cross-sectional study was conducted in a community-based sample of Australian men (N = 1,195, aged 35-80 years; for 2002-2005). Depression was defined by: (1) symptomatic depression (current symptoms) or (2) current prescription for antidepressant(s) or (3) previously diagnosed depression. Logistic regression was used to determine prevalence odds ratios (OR) for depression independently associated with an extensive range of demographic, lifestyle, and clinical factors. Adjusted population attributable risk (PAR%) estimates were also computed. RESULTS: Depression was significantly (ORs at P < 0.05) associated with previously diagnosed anxiety (12.0) and insomnia (4.4), not married (1.7), current smoker (1.7), low muscle strength tertile (1.7, P = 0.059), high triglycerides (1.6), high storage lower urinary tract symptoms (LUTS) tertile (1.8), past year general practitioner visits 5-9 (1.9), middle energy density tertile (0.4), and high systolic blood pressure (0.5). Significant PAR% estimates (at P < 0.05) were for previous anxiety (27.0%) and insomnia (16.1%), middle energy density tertile (-17.2%), high SBP (-23.5%), high triglycerides (15.2%), and high storage LUTS tertile (12.6%). Results strengthened when depression-related factors (previous anxiety and insomnia, psycholeptics, and cognition) were omitted, and became significant for CVD (OR 1.6; PAR 13.9%). CONCLUSIONS: Medical conditions associated with depression in men include high triglycerides, low muscle strength, CVD, and LUTS. Depressed men are likely to use health services frequently, be current smokers, not be married, eat unhealthily, and report previous diagnosis of anxiety and insomnia; which has important implications for clinicians managing male patients.
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Trastorno Depresivo/epidemiología , Servicios de Salud/estadística & datos numéricos , Adulto , Anciano , Anciano de 80 o más Años , Comorbilidad , Estudios Transversales , Dieta , Conductas Relacionadas con la Salud , Humanos , Modelos Logísticos , Masculino , Estado Civil , Persona de Mediana Edad , Prevalencia , Australia del Sur/epidemiologíaRESUMEN
PURPOSE: To determine the prevalence of, and associated risk factors for, voiding and storage lower urinary tract symptoms (LUTS) in a population-based sample of Australian men. METHODS: Data were collected from 1,103 men randomly selected, community-dwelling men, as part of the Florey Adelaide Male Ageing Study, after exclusion of men with prostate or bladder cancer or prior surgery to either organ. The presence of LUTS was assessed using the International Prostate Symptom Score. Urine flow was measured via flow meter. Demographic, clinical, and bio-psychosocial data were collected by questionnaire. RESULTS: The prevalence of total, storage, and voiding LUTS was 18.1, 28.0 and 12.6%, respectively. The most common storage symptoms were frequency (12.3%), nocturia (9.9%) and urgency (8.1%), and voiding symptoms were weak stream (8.5%), intermittency (5.4%), incomplete emptying (5.1%) and straining (2.4%). There were linear associations between storage LUTS and increased abdominal fat mass, plasma glucose and low HDL cholesterol (components of the metabolic syndrome), obstructive sleep apnoea (OSA) risk, and retirement. Voiding symptoms were associated with a previous diagnosis of benign prostatic enlargement (BPH), mean peak urine flow, total energy intake, elevated risk of OSA, erectile dysfunction, physician-diagnosed thyroid dysfunction and higher household income. CONCLUSIONS: The close association of storage LUTS with the metabolic syndrome, and of both storage and voiding LUTS with OSA, suggest that these conditions should be considered in men presenting with LUTS.
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Disfunción Eréctil/complicaciones , Síndrome Metabólico/complicaciones , Hiperplasia Prostática/complicaciones , Prostatismo/epidemiología , Sistema Urinario/fisiopatología , Trastornos Urinarios/epidemiología , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Australia/epidemiología , Estudios de Cohortes , Estudios Transversales , Disfunción Eréctil/fisiopatología , Humanos , Modelos Lineales , Masculino , Síndrome Metabólico/fisiopatología , Persona de Mediana Edad , Prevalencia , Hiperplasia Prostática/fisiopatología , Prostatismo/fisiopatología , Características de la Residencia , Factores de Riesgo , Fenómenos Fisiológicos del Sistema Urinario , Trastornos Urinarios/fisiopatologíaRESUMEN
BACKGROUND: Epigenetic alterations are common in prostate cancer, yet how these modifications contribute to carcinogenesis is poorly understood. We investigated whether specific histone modifications are prognostic for prostate cancer relapse, and whether the expression of epigenetic genes is altered in prostate tumorigenesis. METHODS: Global levels of histone H3 lysine-18 acetylation (H3K18Ac) and histone H3 lysine-4 dimethylation (H3K4diMe) were assessed immunohistochemically in a prostate cancer cohort of 279 cases. Epigenetic gene expression was investigated in silico by analysis of microarray data from 23 primary prostate cancers (8 with biochemical recurrence and 15 without) and 7 metastatic lesions. RESULTS: H3K18Ac and H3K4diMe are independent predictors of relapse-free survival, with high global levels associated with a 1.71-fold (P < 0.0001) and 1.80-fold (P = 0.006) increased risk of tumor recurrence, respectively. High levels of both histone modifications were associated with a 3-fold increased risk of relapse (P < 0.0001). Epigenetic gene expression profiling identified a candidate gene signature (DNMT3A, MBD4, MLL2, MLL3, NSD1, and SRCAP), which significantly discriminated nonmalignant from prostate tumor tissue (P = 0.0063) in an independent cohort. CONCLUSIONS: This study has established the importance of histone modifications in predicting prostate cancer relapse and has identified an epigenetic gene signature associated with prostate tumorigenesis. IMPACT: Our findings suggest that targeting the epigenetic enzymes specifically involved in a particular solid tumor may be a more effective approach. Moreover, testing for aberrant expression of epigenetic genes such as those identified in this study may be beneficial in predicting individual patient response to epigenetic therapies.
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Histonas/genética , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Estudios de Cohortes , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Epigénesis Genética , Regulación Neoplásica de la Expresión Génica , Histonas/metabolismo , Humanos , Masculino , Análisis por Micromatrices , Pronóstico , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/cirugíaRESUMEN
BACKGROUND: Knowledge of preanalytic conditions that biospecimens are subjected to is critically important because novel surgical procedures, tissue sampling, handling, and storage might affect biomarker expression or invalidate tissue samples as analytes for some technologies. METHODS: We investigated differences in RNA quality, gene expression by quantitative real-time PCR, and immunoreactive protein expression of selected prostate cancer biomarkers between tissues from retropubic radical prostatectomy (RRP) and robot-assisted laparoscopic prostatectomy (RALP). Sections of tissue microarray of 23 RALP and 22 RRP samples were stained with antibodies to androgen receptor (AR) and prostate-specific antigen (PSA) as intersite controls, and 14 other candidate biomarkers of research interest to three laboratories within the Australian Prostate Cancer BioResource tissue banking network. Quantitative real-time PCR was done for AR, PSA (KLK3), KLK2, KLK4, and HIF1A on RNA extracted from five RALP and five RRP frozen tissue cores. RESULTS: No histologic differences were observed between RALP and RRP tissue. Biomarker staining grouped these samples into those with increased (PSA, CK8/18, CKHMW, KLK4), decreased (KLK2, KLK14), or no change in expression (AR, ghrelin, Ki67, PCNA, VEGF-C, PAR2, YB1, p63, versican, and chondroitin 0-sulfate) in RALP compared with RRP tissue. No difference in RNA quality or gene expression was detected between RALP and RRP tissue. CONCLUSIONS: Changes in biomarker expression between RALP and RRP tissue exist at the immunoreactive protein level, but the etiology is unclear. IMPACT: Future studies should account for changes in biomarker expression when using RALP tissues, and mixed cohorts of RALP and RRP tissue should be avoided.
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Biomarcadores de Tumor/biosíntesis , Laparoscopía/métodos , Prostatectomía/métodos , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/cirugía , ARN Neoplásico/metabolismo , Anciano , Biomarcadores de Tumor/genética , Expresión Génica , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Antígeno Prostático Específico/biosíntesis , Antígeno Prostático Específico/genética , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , ARN Neoplásico/genética , Receptores Androgénicos/biosíntesis , Receptores Androgénicos/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Robótica/métodos , Manejo de EspecímenesRESUMEN
The androgen receptor (AR) is an important signaling molecule in multiple tissues, yet its mode of action and cell-specific activities remain enigmatic. AR function has been best studied in the prostate, in which it is essential for growth and homeostasis of the normal organ as well as each stage of cancer development. Investigation of mechanisms responsible for continued AR action that evolve during prostate cancer progression or after hormonal management of the disease have been instructive in defining AR signaling pathways. In the current paper, we use sequence similarity and the collocation of somatic mutations in prostate cancer to define residues 501-535 of the AR amino-terminal domain as an important mediator of receptor function. Specifically, the 501-535 region is required for optimal interaction of the amino-terminal domain with both the p160 coactivator, nuclear receptor coactivator-2, and the AR-ligand binding domain in the amino/carboxyl (N/C) interaction. The N/C interaction is decreased by deletion of the 501-535 region but is distinct from deletion of the (23)FQNLF(27) peptide in that it does not affect the capacity of the AR to activate transcription from a chromatin integrated reporter or recruitment of the receptor to androgen-responsive loci in vivo. Collectively, we have been able to outline two classes of N/C-deficient AR variant that are divergent in their capacity to act in a chromatin context, thereby further defining the interplay between N/C interaction and coregulator recruitment via multiple receptor domains. These mechanisms are likely to be key determinants of the cell and promoter specific activities of the AR.
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Cromatina/genética , Variación Genética/genética , Neoplasias de la Próstata/genética , Dominios y Motivos de Interacción de Proteínas/genética , Receptores Androgénicos/genética , Secuencia de Aminoácidos , Animales , Células COS , Línea Celular Tumoral , Chlorocebus aethiops , Cromatina/fisiología , Progresión de la Enfermedad , Masculino , Datos de Secuencia Molecular , Mutación Missense/genética , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/fisiopatología , Dominios y Motivos de Interacción de Proteínas/fisiología , Receptores Androgénicos/fisiología , Transducción de Señal/fisiologíaRESUMEN
BACKGROUND: Previous studies from our laboratory demonstrated a strong association between an elevated level of chondroitin sulfate (CS) in peritumoral stroma and PSA-relapse in patients with early stage disease. In this study we determined whether CS levels could predict overall survival in men diagnosed with advanced prostate cancer subsequently treated by orchiectomy alone. METHODS: CS was localized in archived prostatic tissues by immunohistochemistry, and the level of CS expression as measured by video image analysis was compared in cohorts of 157 and 60 men with early stage or advanced disease, respectively. RESULTS: The CS levels in the peritumoral stroma of patients without relapse after treatment for early stage disease was significantly reduced compared to levels in prostate tissue from patients who either relapsed (P = 0.003) or were diagnosed with advanced prostate cancer (P < 0.00001). There was no difference between the median CS level in the peritumoral prostatic stroma of early stage patients that relapsed after treatment and patients diagnosed with advanced prostate cancer. Increased CS levels (P < 0.0001) and high Gleason score (P < 0.0001) were associated with an increased rate of PSA-relapse in the cohort of patients with early stage disease. However, neither CS level nor Gleason score alone or in combination could predict survival outcome in patients with advanced prostate cancer following androgen deprivation therapy. CONCLUSIONS: Although peritumoral CS levels and Gleason score are strong predictors of relapse-free survival in early stage prostate cancer patients, neither peritumoral CS levels nor Gleason score can predict survival outcome in patients with advanced disease.
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Sulfatos de Condroitina/metabolismo , Neoplasias de la Próstata/metabolismo , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Humanos , Procesamiento de Imagen Asistido por Computador , Inmunohistoquímica , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Orquiectomía , Valor Predictivo de las Pruebas , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/cirugía , Estudios RetrospectivosRESUMEN
OBJECTIVE: To describe trends in prostate-specific antigen (PSA) testing, prostate cancer incidence and mortality in New South Wales. DESIGN AND SETTING: Descriptive analysis using routinely collected data of observed trends in PSA testing from 1989 to 2006, and prostate cancer cases and deaths from 1972 to 2005 in NSW. MAIN OUTCOME MEASURES: Age-standardised and age-specific rates and joinpoint regression to identify changes in trends; projected trends observed before the introduction of PSA testing to quantify its impact on incidence and mortality rates. RESULTS: The number of PSA tests per year more than doubled between 1994 and 2006. Age-standardised incidence of prostate cancer peaked in 1994, fell by 10.0% per year to 1998 and then increased by 4.9% per year from 2001 to 2005. An estimated 19 602 (43%) more men than expected from preceding trends were diagnosed with prostate cancer between 1989 and 2005 after PSA testing was introduced. The incidence of recorded advanced prostate cancer at diagnosis fell from 13.0 per 100,000 men in 1987-1991 to 7.0 per 100,000 men in 2002-2005. The age-standardised mortality from prostate cancer increased by 3.6% per year between 1984 and 1990 and then fell by 2.0% per year to 2005. CONCLUSIONS: There was a sustained increase in prostate cancer incidence in NSW after PSA testing was introduced. While falls in the incidence of advanced disease at diagnosis and mortality from prostate cancer after 1993 are consistent with a benefit from PSA testing, other explanations cannot be excluded.
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Tamizaje Masivo/estadística & datos numéricos , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata/diagnóstico , Neoplasias de la Próstata/epidemiología , Distribución por Edad , Anciano , Anciano de 80 o más Años , Humanos , Incidencia , Masculino , Tamizaje Masivo/tendencias , Nueva Gales del Sur/epidemiología , Neoplasias de la Próstata/mortalidad , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
The glycosaminoglycan chondroitin sulfate is significantly increased in the peritumoral stroma of prostate tumors compared with normal stroma and is an independent predictor of prostate-specific antigen (PSA) relapse following radical prostatectomy. In this study, we determined whether specific alterations in the sulfation pattern of glycosaminoglycan chains in clinically organ-confined prostate cancer are associated with PSA relapse. Immunoreactivity to distinct glycosaminoglycan disaccharide epitopes was assessed by manually scoring the staining intensity in prostate tissues from patients with benign prostatic hyperplasia (n = 19), early-stage cancer (cohort 1, n = 55 and cohort 2, n = 275), and advanced-stage cancer (n = 20). Alterations to glycosaminoglycans in benign and malignant prostate tissues were determined by cellulose acetate chromatography and high-pressure liquid chromatography. Glycosaminoglycan disaccharide epitopes were localized to the peritumoral stroma of clinically localized prostate cancer. The level of immunostaining for unsulfated disaccharides (C0S) in the peritumoral stroma, but not for 4-sulfated (C4S) or 6-sulfated disaccharides (C6S), was significantly associated with the rate of PSA relapse following radical prostatectomy. High levels of C0S immunostaining were determined to be an independent predictor of PSA relapse (1.6-fold, P = 0.020). Advanced-stage prostate cancer tissues exhibited reduced electrophoretic mobility for chondroitin sulfate and increased unsulfated disaccharides when compared with benign prostatic hyperplasia tissues, whereas the sulfated disaccharide levels were unaffected. The level of C0S immunostaining in the peritumoral stroma is an independent determinant of PSA failure in clinically localized prostate cancer. Specific alterations to chondroitin sulfate side chains occurring during tumor development may be a crucial step for disease progression in prostate cancer.
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Condroitín/metabolismo , Disacáridos/metabolismo , Neoplasias de la Próstata/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/metabolismo , Epítopos , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Antígeno Prostático Específico/metabolismo , Neoplasias de la Próstata/patologíaRESUMEN
BACKGROUND: In this study, we investigated the expression of HER-2/neu and AR in clinically organ-confined prostate cancer to determine whether alterations in these signaling pathways contribute to the development of metastatic disease. METHODS: HER-2/neu and AR immunoreactivity were evaluated in archived prostatic tissues obtained from 53 men with clinically organ-confined disease who underwent radical prostatectomy. Associations between AR and HER-2/neu immunostaining and disease outcome were determined. RESULTS: Seventy percent (37/53) of tumors exhibited high levels of HER-2/neu immunostaining and 68% (36/53) of tumors had elevated AR levels. Patients with high levels of both HER-2/neu and AR had the highest rate of PSA failure (56%, 15/27) compared with no PSA failures amongst seven patients with low levels of both HER-2/neu and AR (log rank statistic 7.69, P = 0.021). Concurrent high levels of HER-2/neu and AR expression were significantly associated with high pathological stage (P = 0.027) and development of metastatic disease (P = 0.022). CONCLUSIONS: These findings support the notion that both the HER-2/neu and AR signaling pathways may contribute to development of metastatic disease. The subset of prostate tumors with increased HER-2/neu and AR levels may benefit from treatment strategies that target both signaling pathways.
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Neoplasias de la Próstata/patología , Receptor ErbB-2/análisis , Receptores Androgénicos/análisis , Anciano , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Recurrencia Local de Neoplasia/diagnóstico , Antígeno Prostático Específico/sangre , Prostatectomía , Neoplasias de la Próstata/diagnóstico , Neoplasias de la Próstata/cirugía , Receptor ErbB-2/inmunología , Receptores Androgénicos/inmunologíaRESUMEN
PURPOSE: The aim of the study was to demonstrate the safety and effectiveness of single-stage percutaneous nephrolithotomy performed in the supine position. PATIENTS AND METHODS: A single surgeon performed 322 consecutive percutaneous nephrolithotomies in patients in the supine position between 1999 and 2006, which were studied prospectively. RESULTS: There were no complications related to the supine position, and in only one patient was there failed access. This patient's kidney was subsequently punctured with the patient in the supine position. There were no colonic injuries, no pneumothoraces, and a transfusion rate of 3.7%. Surgery on all patients with stones, including staghorn calculi and bilateral stones managed synchronously, was in the supine position. The median time to percutaneous access in a timed cohort of 27 patients was 5 minutes. The stone clearance rate was 91%. The median length of hospital stay was reduced from 6 days in the initial unstented patients to 3 days in the study overall when most patients received stents. CONCLUSIONS: Percutaneous nephrolithotomy in the supine position is safe, effective, and suitable for the majority of patients. It offers the potential advantages of better urethral access, less patient handling, and the need to only drape once, thus reducing the overall operative time compared to the traditional prone position.
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Cálculos Renales/cirugía , Nefrostomía Percutánea/métodos , Posición Supina , Adulto , Anciano , Anciano de 80 o más Años , Cistoscopía/métodos , Femenino , Estudios de Seguimiento , Humanos , Cálculos Renales/diagnóstico , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
Although the androgen receptor (AR) is accepted as the major determinant of prostate cancer cell survival throughout disease progression, it is currently unclear how the receptor sustains genomic signaling under conditions of systemic androgen ablation. Here, we show that the evolutionarily conserved Hsp70/Hsp90 cochaperone, small glutamine-rich tetratricopeptide repeat containing protein alpha (alphaSGT), interacts with the hinge region of the human AR in yeast and mammalian cells. Overexpression and RNA interference revealed that alphaSGT acts to (a) promote cytoplasmic compartmentalization of the AR, thereby silencing the receptors basal/ligand-independent transcriptional activity, (b) regulate the sensitivity of receptor signaling by androgens, and (c) limit the capacity of noncanonical ligands to induce AR agonist activity. Immunofluorescence, coactivator, and chromatin immunoprecipitation analyses strongly suggest that these effects of alphaSGT on AR function are mediated by interaction in the cytoplasm and are distinct from the receptors response to classic coregulators. Quantitative immunohistochemical analysis of alphaSGT and AR levels in a cohort of 32 primary and 64 metastatic human prostate cancers revealed dysregulation in the level of both proteins during disease progression. The significantly higher AR/alphaSGT ratio in metastatic samples is consistent with the sensitization of prostate tumor cells to androgen signaling with disease progression, particularly in a low-hormone environment. These findings implicate alphaSGT as a molecular rheostat of in vivo signaling competence by the AR, and provide new insight into the determinants of androgen sensitivity during prostate cancer progression.
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Proteínas Portadoras/metabolismo , Neoplasias de la Próstata/metabolismo , Receptores Androgénicos/metabolismo , Secuencia de Aminoácidos , Citoplasma/metabolismo , Progresión de la Enfermedad , Proteínas HSP70 de Choque Térmico/metabolismo , Proteínas HSP90 de Choque Térmico/metabolismo , Humanos , Masculino , Modelos Moleculares , Chaperonas Moleculares , Datos de Secuencia Molecular , Metástasis de la Neoplasia , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Receptores Androgénicos/genética , Transducción de Señal , Transcripción GenéticaRESUMEN
Previous studies have demonstrated that high levels of hyaluronan (HA) and the chondroitin sulfate proteoglycan, versican in the peritumoral stroma are associated with metastatic spread of clinical prostate cancer. In vitro integration of HA and versican into a pericellular sheath is a prerequisite for proliferation and migration of vascular smooth muscle cells. In this study, a particle exclusion assay was used to determine whether human prostate cancer cell lines are capable of assembling a pericellular sheath following treatment with versican-containing medium and whether formation of a pericellular sheath modulated cell motility. PC3 and DU145, but not LNCaP cells formed prominent polarized pericellular sheaths following treatment with prostate fibroblast-conditioned medium. The capacity to assemble a pericellular sheath correlated with the ability to express membranous HA receptor, CD44. HA and versican histochemical staining were observed surrounding PC3 and DU145 cells following treatment with prostatic fibroblast-conditioned medium. The dependence on HA for integrity of the pericellular sheath was demonstrated by its removal following treatment with hyaluronidase. Purified versican or conditioned medium from Chinese hamster ovary K1 cells overexpressing versican V1, but not conditioned medium from parental cells, promoted pericellular sheath formation and motility of PC3 cells. Using time lapse microscopy, motile PC3 cells treated with versican but not non-motile cells exhibited a polar pericellular sheath. Polar pericellular sheath was particularly evident at the trailing edge but was excluded from the leading edge of PC3 cells. These studies indicate that prostate cancer cells recruit stromal components to remodel their pericellular environment and promote their motility.