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1.
Br J Cancer ; 121(7): 578-583, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31409910

RESUMO

BACKGROUND: After radical prostatectomy (RP) for prostate cancer (PC), p53 alterations predict biochemical relapse (BCR), however, recent evidence suggests that metastatic relapse (MR) not BCR is a surrogate for PC specific mortality (PCSM). This updated analysis of a previously published study investigated the association between p53 aberrations, MR and PCSM in men with localised PC. METHODS: Two hundred and seventy-one men with localised PC treated with RP were included. RP specimens stained for p53 by immunohistochemistry were scored as (a) percentage of p53-positive tumour nuclei; and (b) clustering, where ≥12 p53-positive cells within a ×200 power field was deemed 'cluster positive'. Associations between p53 status and clinical outcomes (BCR, MR and PCSM) were evaluated. RESULTS: Increasing percentage of p53-positive nuclei was significantly associated with shorter time to BCR, MR and PCSM (All p < 0.001). Half of the patients were p53 cluster positive. p53 cluster positivity was significantly associated with poorer outcomes at all clinical endpoints (BCR: HR 2.0, 95% CI 1.51-2.65, p < 0.001; MR: HR 4.1, 95% CI 2.02-8.14, p < 0.001; PCSM: HR 12.2, 95% CI 1.6-93; p = 0.016). These associations were independent of other established prognostic variables. CONCLUSIONS: p53 aberrations in radical prostatectomy tissue predict clinically relevant endpoints of MR and PCSM.


Assuntos
Núcleo Celular/metabolismo , Recidiva Local de Neoplasia/metabolismo , Neoplasias da Próstata/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Adulto , Idoso , Genes p53 , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Gradação de Tumores , Recidiva Local de Neoplasia/mortalidade , Estadiamento de Neoplasias , Prognóstico , Antígeno Prostático Específico/sangue , Prostatectomia , Neoplasias da Próstata/genética , Neoplasias da Próstata/mortalidade , Neoplasias da Próstata/cirurgia , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/metabolismo , Estudos Retrospectivos , Fatores de Tempo
3.
Prostate ; 67(10): 1081-90, 2007 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-17476687

RESUMO

BACKGROUND: Secreted frizzled-related proteins (sFRP4) inhibits Wnt signaling and thus cellular proliferation in androgen-independent prostate cancer cells in vitro. However, increased expression of membranous sFRP4 is associated with a good prognosis in human localized androgen-dependent prostate cancer, suggesting a role for sFRP4 in early stage disease. Here, we investigated the phenotype of sFRP4 overexpression in an androgen-dependent prostate cancer model. METHODS: An sFRP4-overexpressing androgen-dependent (LNCaP) prostate cancer model was established to assess changes in cellular proliferation, the expression, and subcellular localization of adhesion molecules and cellular invasiveness, and compared with the findings in sFRP4-overexpressing androgen-independent cells (PC3). RESULTS: sFRP4 overexpression in both cell line models resulted in a morphologic change to a more epithelioid cell type with increased localization of beta-catenin and cadherins (E-cadherin in LNCaP, N-cadherin in PC3) to the cell membrane. Functionally, sFRP4 overexpression was associated with a decreased rate of proliferation (P = 0.0005), decreased anchorage-independent growth (P < 0.001), and decreased invasiveness in PC3 cells (P < 0.0001). Furthermore, increased membranous sFRP4 expression was associated with increased membranous beta-catenin expression (P = 0.02) in a cohort of 224 localized human androgen-dependent prostate cancers. CONCLUSIONS: These data suggest that sFRP4 is an inhibitor of prostate cancer growth and invasion in vitro independent of androgen receptor (AR) signaling with correlative evidence in human androgen-dependent disease suggesting similar changes in the clinical setting. Consequently, potential therapeutic strategies to modulate Wnt signaling by sFRP4 will be relevant to both localized androgen-dependent prostate cancer and advanced metastatic disease.


Assuntos
Proliferação de Células , Invasividade Neoplásica/fisiopatologia , Metástase Neoplásica/fisiopatologia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Proteínas Proto-Oncogênicas/metabolismo , Caderinas/genética , Caderinas/metabolismo , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Invasividade Neoplásica/prevenção & controle , Fenótipo , Neoplasias da Próstata/fisiopatologia , Proteínas Proto-Oncogênicas/genética , Receptores Androgênicos/metabolismo , Transdução de Sinais/fisiologia , Proteínas Wnt/genética , Proteínas Wnt/metabolismo , beta Catenina/genética , beta Catenina/metabolismo
4.
J Natl Cancer Inst ; 98(19): 1420-4, 2006 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-17018789

RESUMO

The risk of metastatic progression for prostate cancer patients who undergo radical prostatectomy is best estimated presently based on prostate-specific antigen (PSA) doubling time (PSADT). However, additional markers of risk are needed to identify patients who may benefit from aggressive salvage treatment. A decrease in zinc-alpha2-glycoprotein (AZGP1) mRNA levels in malignant prostate epithelium was previously shown to predict biochemical recurrence, as defined by rising levels of serum PSA after radical prostatectomy. We assessed the reliability with which AZPG1 expression could predict clinical recurrence and metastatic progression. Using immunohistochemical methods, we analyzed AZPG1 expression in malignant prostate epithelium in prostatectomy specimens from 228 prostate cancer patients. Low (i.e., absent or weak) AZGP1 expression was associated with clinical recurrence (defined as confirmed localized recurrence, metastasis, or death from prostate cancer; hazard ratio [HR] = 4.8, 95% confidence interval [CI] = 2.2 to 10.7, P<.001) and with bony metastases or death from prostate cancer (HR = 8.0, 95% CI = 2.6 to 24.3, P<.001). Among the 17 patients in the cohort in whom clinical recurrence was associated with short PSADT, absent or weak AZGP1 expression was observed in 13 patients. If these preliminary findings are validated in independent cohorts, the measurement of AZGP1 levels in radical prostatectomy specimens may permit an accurate and timely assessment of risk of metastatic progression after radical prostatectomy.


Assuntos
Biomarcadores Tumorais/metabolismo , Prostatectomia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Proteínas de Plasma Seminal/metabolismo , Idoso , Biomarcadores Tumorais/genética , Progressão da Doença , Intervalo Livre de Doença , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/metabolismo , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Prognóstico , Modelos de Riscos Proporcionais , Antígeno Prostático Específico/sangue , Prostatectomia/métodos , Neoplasias da Próstata/cirurgia , RNA/metabolismo , Projetos de Pesquisa , Medição de Risco , Proteínas de Plasma Seminal/genética , Glicoproteína Zn-alfa-2
5.
Cancer Epidemiol Biomarkers Prev ; 15(4): 711-6, 2006 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-16614113

RESUMO

Studies to elucidate dysregulated gene expression patterns in premalignant prostate lesions have identified several candidate genes with the potential to be targeted to prevent the development and progression of prostate cancer and act as biomarkers of early disease. Herein, we explored the importance of two proteins, neuropeptide Y (NPY) and macrophage inhibitory cytokine-1 (MIC-1), as biomarkers of preinvasive prostate disease and investigated the relationship of expression to biochemical recurrence following treatment for localized prostate cancer. NPY and MIC-1 protein expression was determined by immunohistochemistry on tissue microarrays containing 1,626 cores of benign, low-grade prostatic intraepithelial neoplasia (PIN), high-grade PIN (HGPIN), and prostate cancer tissue from 243 radical prostatectomy patients. Both NPY and MIC-1 showed higher proportional immunostaining in HGPIN and prostate cancer compared with benign epithelium (P < 0.0001). NPY and MIC-1 immunostaining was higher in low-grade PIN compared with other benign tissues (both P < 0.0001) and was equivalent to immunostaining in HGPIN. NPY immunostaining of prostate cancer was independently associated with relapse, after adjusting for traditional prognostic factors, as a categorical variable in 20% intervals (P = 0.0449-0.0103) and as a continuous variable (P = 0.0017). Low MIC-1 immunostaining (20% categories) was associated with pathologic stage >2C after adjusting for predictors of pathologic stage (P = 0.3894-0.0176). This is the first study to show that altered NPY and MIC-1 expression are significantly associated with prostate cancer progression and suggests that these molecules be developed further as biomarkers in the management of prostate disease.


Assuntos
Citocinas/genética , Neuropeptídeo Y/genética , Neoplasia Prostática Intraepitelial/genética , Neoplasias da Próstata/metabolismo , Progressão da Doença , Expressão Gênica , Fator 15 de Diferenciação de Crescimento , Humanos , Imuno-Histoquímica , Masculino , Prognóstico , Modelos de Riscos Proporcionais , Neoplasias da Próstata/patologia
6.
Cancer Res ; 65(6): 2330-6, 2005 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-15781647

RESUMO

The extracellular matrix (ECM) is a reservoir of cellular binding proteins and growth factors that are critical for normal cell behavior, and aberrations in the ECM invariably accompany malignancies such as prostate cancer. Carcinomas commonly overexpress macrophage inhibitory cytokine 1 (MIC-1), a proapoptotic and antitumorigenic transforming growth factor-beta superfamily cytokine. Here we show that MIC-1 is often secreted in an unprocessed propeptide containing form. It is variably processed intracellularly, with unprocessed forms being secreted from several tumor lines, including prostate carcinoma lines, PC-3 and LNCaP. Once secreted, only unprocessed proMIC-1 binds ECM, demonstrating for the first time the occurrence of extracellular stores of MIC-1. The propeptide mediates this association via its COOH-terminal 89 amino acids. Xenograft models bearing tumors secreting various engineered forms of MIC-1 show that the propeptide regulates the balance between ECM stores and circulating serum levels of mature MIC-1 in vivo. The absence of propeptide results in approximately 20-fold increase in serum MIC-1 levels. The significance of stromal MIC-1 stores was evaluated in prostate cancer tissue cores, which show major variation in stromal levels of MIC-1. Stromal MIC-1 levels are linked to prostate cancer outcome following radical prostatectomy, with decreasing stromal levels providing an important independent predictor of disease relapse. In low-grade localized prostate cancer (Gleason sum score < or = 6), the level of MIC-1 stromal stores was the best predictor of future relapse when compared with all other clinicopathologic variables. The secretion and ECM association of unprocessed proMIC-1 is likely to play a central role in modulating local bioavailability of MIC-1 which can affect patient outcome in prostate cancer and other epithelial tumors.


Assuntos
Citocinas/biossíntese , Neoplasias da Próstata/metabolismo , Precursores de Proteínas/biossíntese , Animais , Linhagem Celular Tumoral , Citocinas/metabolismo , Cães , Células Epiteliais/metabolismo , Matriz Extracelular/metabolismo , Fator 15 de Diferenciação de Crescimento , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Transplante de Neoplasias , Prognóstico , Neoplasias da Próstata/patologia , Precursores de Proteínas/metabolismo , Células Estromais/metabolismo , Transplante Heterólogo
7.
Int J Cancer ; 113(3): 415-22, 2005 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-15455387

RESUMO

Beta-catenin in its role as a nuclear signaling molecule has been implicated in prostate carcinogenesis primarily through modulation of androgen receptor activity. We defined the pattern of beta-catenin protein expression in the nuclei of normal, hyperplastic and malignant human prostate tissue and determined whether differences in expression were associated with disease progression and prognosis. Five normal prostates, 26 benign prostatic hypertrophy specimens, 232 radical prostatectomy specimens from patients with clinically localized prostate cancer (PC) and 20 cases of advanced PC were assessed for beta-catenin expression using immunohistochemistry. Nuclear beta-catenin expression in localized PC was significantly lower than that in benign prostate tissue (p < 0.001) and significantly higher than that in advanced PC tissue (p < 0.001). In addition, lower levels of nuclear beta-catenin expression (< 10% of cancer cells) predicted for a shorter biochemical relapse-free survival in patients with localized PC (p = 0.008) and were inversely correlated with preoperative prostate-specific antigen (PSA) levels (p = 0.01). Analysis of the low-risk subgroup of patients with preoperative PSA levels < 10 ng/ml demonstrated that lower levels of nuclear beta-catenin expression (< 10% of cancer cells) again predicted for a poorer prognosis (p = 0.006). In conclusion, lower levels of nuclear beta-catenin expression are found in malignant compared to benign prostate tissue. In addition, lower nuclear beta-catenin expression is associated with a poorer prognosis in localized PC, in particular, in the low-risk subgroup of patients with preoperative PSA levels < 10 ng/ml. Thus, the level of nuclear beta-catenin expression may be of clinical utility as a preoperative prognostic marker in low-risk localized PC.


Assuntos
Núcleo Celular/metabolismo , Proteínas do Citoesqueleto/metabolismo , Recidiva Local de Neoplasia/metabolismo , Hiperplasia Prostática/metabolismo , Neoplasias da Próstata/metabolismo , Transativadores/metabolismo , Adolescente , Adulto , Idoso , Caderinas/metabolismo , Estudos de Casos e Controles , Humanos , Técnicas Imunoenzimáticas , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/cirurgia , Valor Preditivo dos Testes , Prognóstico , Próstata/metabolismo , Próstata/patologia , Antígeno Prostático Específico/metabolismo , Prostatectomia , Hiperplasia Prostática/patologia , Hiperplasia Prostática/cirurgia , Neoplasias da Próstata/patologia , Neoplasias da Próstata/cirurgia , Fatores de Risco , Taxa de Sobrevida , beta Catenina
8.
Mol Cancer Ther ; 3(8): 921-32, 2004 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-15299075

RESUMO

Current treatments for advanced stage, hormone-resistant prostate cancer are largely ineffective, leading to high patient mortality and morbidity. To fulfill this unmet medical need, we used global gene expression profiling to identify new potential antibody-drug conjugate (ADC) targets that showed maximal prostate cancer-specific expression. TMEFF2, a gene encoding a plasma membrane protein with two follistatin-like domains and one epidermal growth factor-like domain, had limited normal tissue distribution and was highly overexpressed in prostate cancer. Immunohistochemistry analysis using a specific monoclonal antibody (mAb) to human TMEFF2 showed significant protein expression in 74% of primary prostate cancers and 42% of metastatic lesions from lymph nodes and bone that represented both hormone-naïve and hormone-resistant disease. To evaluate anti-TMEFF2 mAbs as potential ADCs, one mAb was conjugated to the cytotoxic agent auristatin E via a cathepsin B-sensitive valine-citrulline linker. This ADC, Pr1-vcMMAE, was used to treat male severe combined immunodeficient mice bearing xenografted LNCaP and CWR22 prostate cancers expressing TMEFF2. Doses of 3 to 10 mg/kg of this specific ADC resulted in significant and sustained tumor growth inhibition, whereas an isotype control ADC had no significant effect. Similar efficacy and specificity was shown with huPr1-vcMMAE, a humanized anti-TMEFF2 ADC. No overt in vivo toxicity was observed with either murine or human ADC, despite significant cross-reactivity of anti-TMEFF2 mAb with the murine TMEFF2 protein, implying minimal toxicity to other body tissues. These data support the further evaluation and clinical testing of huPr1-vcMMAE as a novel therapeutic for the treatment of metastatic and hormone-resistant prostate cancer.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Proteínas de Membrana/química , Proteínas de Membrana/imunologia , Proteínas de Neoplasias/química , Proteínas de Neoplasias/imunologia , Oligopeptídeos/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Sequência de Aminoácidos , Animais , Anticorpos Monoclonais/química , Antineoplásicos/química , Encéfalo/metabolismo , Membrana Celular/metabolismo , Proliferação de Células , Clonagem Molecular , DNA Complementar/metabolismo , Citometria de Fluxo , Folistatina/química , Humanos , Hibridomas/química , Imuno-Histoquímica , Cinética , Metástase Linfática , Masculino , Camundongos , Microscopia de Fluorescência , Dados de Sequência Molecular , Metástase Neoplásica , Análise de Sequência com Séries de Oligonucleotídeos , Oligopeptídeos/química , Próstata/metabolismo , Neoplasias da Próstata/metabolismo , Estrutura Terciária de Proteína , RNA Mensageiro/metabolismo , Proteínas Recombinantes de Fusão/metabolismo , Homologia de Sequência de Aminoácidos , Ressonância de Plasmônio de Superfície , Fatores de Tempo , Transfecção
9.
Prostate ; 59(3): 234-42, 2004 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-15042598

RESUMO

BACKGROUND: The role of the bone morphogenetic protein (BMP) pathway in prostate cancer (PC) is unclear. This study aimed to characterize aspects of the BMP pathway in PC by assessing BMP2, Smad8, and Smad4 expression in normal, hyperplastic, and malignant prostate tissue, and to correlate findings with progression to PC. METHODS: Radical prostatectomy (RP) specimens from 74 patients with clinically localized PC (median follow-up 51 months, range 15-152), 44 benign prostatic hypertrophy (BPH) lesions, and 4 normal prostates (NPs) were assessed for BMP2, Smad8, and Smad4 expression using immunohistochemistry. RESULTS: Both BMP2 (P < 0.001) and nuclear Smad4 (P < 0.0001) expression were significantly decreased in PC compared to benign prostate tissue. Nuclear Smad8 was present in normal/benign prostate tissue but absent in PC and adjacent hyperplasia. Furthermore, loss of BMP2 (P < 0.001) and decreased nuclear Smad4 (P = 0.05) expression correlated with increasing Gleason score. CONCLUSIONS: These data suggest that decreased BMP2, nuclear smad8 and nuclear Smad4 expression are associated with the progression to PC, and in particular loss of BMP2 and Smad4 are related to progression to a more aggressive phenotype.


Assuntos
Proteínas Morfogenéticas Ósseas/biossíntese , Transformação Celular Neoplásica , Proteínas de Ligação a DNA/biossíntese , Regulação Neoplásica da Expressão Gênica , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Transativadores/biossíntese , Adulto , Idoso , Proteína Morfogenética Óssea 2 , Estudos de Coortes , Progressão da Doença , Genes Supressores de Tumor , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Prognóstico , Prostatectomia , Hiperplasia Prostática/genética , Hiperplasia Prostática/patologia , Neoplasias da Próstata/cirurgia , Transdução de Sinais , Proteína Smad4 , Proteína Smad8 , Fator de Crescimento Transformador beta
10.
Clin Cancer Res ; 10(2): 615-25, 2004 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-14760084

RESUMO

PURPOSE: Activation of the Wnt-signaling pathway is implicated in aberrant cellular proliferation in a variety of cancers. Secreted frizzled-related protein 4 (sFRP4) is a secreted protein with putative inhibitory activity of the Wnt-signaling cascade through binding and sequestering Wnt ligands. Because sFRP4 mRNA is overexpressed in prostate cancers (PCs), the aim of this study was to define the pattern of sFRP4 protein expression in normal and malignant human prostate tissue and to determine whether changes in expression were associated with disease progression and prognosis, as well as to define the phenotype of sFRP4-overexpression in an in vitro model of PC. EXPERIMENTAL DESIGN: Polyclonal antibodies were raised against a COOH-terminal peptide of sFRP4, characterized and used to assess sFRP4 protein expression in benign prostate tissue and 229 patients with clinically localized PC (median follow-up 77 months, range 1-156). In vitro studies of the function of sFRP4 overexpression were performed using PC3 cells transfected with sFRP4. RESULTS: Benign and malignant prostate tissue demonstrated cytoplasmic sFRP4 immunoreactivity, but there was a decrease in the expression of membranous sFRP4 in PCs compared with the hyperplastic lesions (P < 0.0001). Kaplan-Meier analysis revealed that patients whose PC expressed membranous sFRP4 in >20% of cells had improved relapse-free survival compared with those with

Assuntos
Membrana Celular/metabolismo , Prognóstico , Neoplasias da Próstata/metabolismo , Proteínas Proto-Oncogênicas/biossíntese , Proteínas Proto-Oncogênicas/metabolismo , Adolescente , Adulto , Idoso , Divisão Celular , Linhagem Celular Tumoral , Estudos de Coortes , Citoplasma/metabolismo , DNA Complementar/metabolismo , Intervalo Livre de Doença , Vetores Genéticos , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Humanos , Immunoblotting , Imuno-Histoquímica , Hibridização In Situ , Técnicas In Vitro , Masculino , Microscopia de Fluorescência , Pessoa de Meia-Idade , Análise Multivariada , Análise de Sequência com Séries de Oligonucleotídeos , Peptídeos/química , Fenótipo , Fosforilação , Modelos de Riscos Proporcionais , Próstata/metabolismo , Próstata/patologia , Estrutura Terciária de Proteína , RNA Mensageiro/metabolismo , Recidiva , Transdução de Sinais , Fatores de Tempo , Transfecção , Proteínas Wnt
11.
J Urol ; 171(2 Pt 1): 692-6, 2004 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-14713788

RESUMO

PURPOSE: We examined whether the year in which radical prostatectomy (RP) was performed is a predictor of treatment outcome after controlling for standard prognostic factors. MATERIALS AND METHODS: We examined the association between RP year and outcome in 6,556 patients from 7 centers using preoperative and pathological features. Patients underwent surgery between 1985 and 2000. The variables analyzed were RP year, clinical stage, pretreatment prostate specific antigen, biopsy Gleason sum, RP Gleason sum, margin status, level of extracapsular extension, seminal vesicle status, lymph node status, neoadjuvant hormones and adjuvant therapy. Median followup was 23 months (maximum 166). Separate Cox multivariate regression analyses were performed to analyze preoperative and postoperative factors. RESULTS: RP year was a predictor of outcome on preoperative analysis (p = 0.006) but not on postoperative analysis (p = 0.130). Patient outcome steadily improved with surgery through the mid 1990s and then it appeared to level off. CONCLUSIONS: When controlling for preoperative features, the year in which RP was performed is a predictor of outcome on multivariate analysis. This effect could not be explained by stage migration.


Assuntos
Prostatectomia/normas , Neoplasias da Próstata/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Resultado do Tratamento
12.
Cancer ; 98(12): 2560-5, 2003 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-14669274

RESUMO

BACKGROUND: In the current study, the authors sought to further stratify the prognosis of patients with Gleason score (GS) 7 prostate carcinoma. They assessed the influence on outcome of a predominant poorly differentiated Gleason pattern (primary Gleason pattern [GP] 4) and/or a coincident small focus of poorly differentiated tumor of higher grade (tertiary GP 5). METHODS: The authors studied 412 patients (mean postoperative follow-up, 33 months) with GS 7 tumors treated with radical prostatectomy at a single Australian campus between November 1989 and December 2002. The chi-square test, Kaplan-Meier method, and Cox proportional hazards analyses were used to evaluate the correlation between primary GP 4 and tertiary GP 5 with the occurrence of adverse pathologic features and disease recurrence. RESULTS: In this cohort, 307 patients (75%) had primary GP 3 tumors, 105 (25%) had primary GP 4 tumors, and 17 (2.3%) had a tertiary element of high-grade tumor (GP 5). Patients with primary GP 4 tumors displayed higher rates of seminal vesicle involvement and extraprostatic extension and, along with patients with tertiary GP 5, had significantly shorter times to disease recurrence. Univariate analysis demonstrated that primary GP 4 (P = 0.0003) and tertiary GP 5 (P < 0.0001) were strong predictors of disease recurrence. Primary GP 4 (P = 0.0122) remained an independent predictor of disease recurrence on stepwise multivariate analysis. CONCLUSIONS: Primary GP 4 tumors represented an aggressive subset of GS 7 prostate carcinomas. Primary GP was an easily accessible and clinically relevant predictor of disease recurrence in patients with GS 7 prostate carcinoma.


Assuntos
Neoplasias da Próstata/patologia , Progressão da Doença , Intervalo Livre de Doença , Humanos , Linfonodos/patologia , Metástase Linfática , Masculino , Invasividade Neoplásica , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Prognóstico , Neoplasias da Próstata/cirurgia , Taxa de Sobrevida
13.
J Urol ; 170(5): 1798-803, 2003 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-14532779

RESUMO

PURPOSE: We developed a preoperative nomogram for prediction of lymph node metastases in patients with clinically localized prostate cancer. MATERIALS AND METHODS: The study was a retrospective, nonrandomized analysis of 7,014 patients treated with radical prostatectomy at 6 institutions between 1985 and 2000. Exclusion criteria consisted of preoperative androgen ablation therapy, salvage radical prostatectomy and pretreatment prostate specific antigen (PSA) greater than 50 ng/ml. Preoperative predictors of lymph node metastases consisted of pretreatment PSA, clinical stage (1992 TNM) and biopsy Gleason sum. These predictors were used in logistic regression analysis based nomograms to predict the probability of lymph node metastases. RESULTS: Overall 5,510 patients with complete clinical and pathological information were included in the study. Lymph nodes metastases were present in 206 patients (3.7%). Pretreatment PSA, biopsy Gleason sum, clinical stage and institution represented predictors of lymph node status (p <0.001). Bootstrap corrected predictive accuracy of the 3-variable nomogram (clinical stage, Gleason sum and PSA) was 0.76. Inclusion of a fourth variable, which accounts for institutional differences in lymph node metastases, yielded an area under the receiver operating characteristics curve of 0.78. The negative predictive value of our nomograms was 0.99 when they predicted 3% or less chance of positive lymph nodes. CONCLUSIONS: Using clinical information, we produced 2 calibrated and validated nomograms, which accurately predict pathologically negative lymph nodes in men with localized prostate cancer who are candidates for radical prostatectomy.


Assuntos
Linfonodos/patologia , Metástase Linfática/patologia , Terapia Neoadjuvante , Prostatectomia , Neoplasias da Próstata/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/sangue , Humanos , Modelos Logísticos , Excisão de Linfonodo , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Probabilidade , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/patologia , Terapia de Salvação
14.
Oncogene ; 22(38): 6005-12, 2003 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-12955079

RESUMO

We have utilized oligonucleotide microarrays to identify novel genes of potential clinical and biological importance in prostate cancer. RNA from 74 prostate cancers and 164 normal body samples representing 40 different tissues were analysed using a customized Affymetrix GeneChip oligonucleotide microarray representative of over 90% of the expressed human genome. The gene for the zinc transporter ZnT4 was one of several genes that displayed significantly higher expression in prostate cancer compared to normal tissues from other organs. A polyclonal antipeptide antibody was used to demonstrate ZnT4 expression in the epithelium of all 165 elements of benign and 326 elements of localized prostate cancers examined and in nine of 10 advanced prostate cancer specimens by immunohistochemistry. Interestingly, decreased intensity of ZnT4 immunoreactivity occurred in the progression from benign to invasive localized prostate cancer and to metastatic disease. Immunofluorescence analysis and surface biotinylation studies of cells expressing ZnT4 localised the protein to intracellular vesicles and to the plasma membrane. These findings are consistent with a role for ZnT4 in vesicular transport of zinc to the cell membrane and potentially in efflux of zinc in the prostate.


Assuntos
Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Regulação Neoplásica da Expressão Gênica , Hiperplasia Prostática/metabolismo , Hiperplasia Prostática/patologia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Adolescente , Adulto , Sequência de Aminoácidos , Proteínas de Transporte de Cátions , Membrana Celular/metabolismo , Progressão da Doença , Humanos , Masculino , Dados de Sequência Molecular , Análise de Sequência com Séries de Oligonucleotídeos , Próstata/fisiologia , Hiperplasia Prostática/genética , Neoplasias da Próstata/genética , Valores de Referência , Vesículas Transportadoras/metabolismo
15.
Cancer Res ; 63(14): 4196-203, 2003 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-12874026

RESUMO

Current models of prostate cancer classification are poor at distinguishing between tumors that have similar histopathological features but vary in clinical course and outcome. Here, we applied classical survival analysis to genome-wide gene expression profiles of prostate cancers and preoperative prostate-specific antigen (PSA) levels from each patient, to identify prognostic markers of disease relapse that provide additional predictive value relative to PSA concentration. Three of approximately 200 probesets showing strongest correlation with relapse were identified as the gene for the putative calcium channel protein, trp-p8, with loss of trp-p8 mRNA expression associated with a significantly shorter time to PSA relapse-free survival. We observed subsequently that trp-p8 is lost in the transition to androgen independence in a prostate cancer xenograft model and in prostate cancer tissue from patients treated preoperatively with antiandrogen therapy, suggesting that trp-p8 is androgen regulated, and its loss may be associated with more advanced disease. The identification of trp-p8 and other proteins implicated in the phosphatidylinositol signal transduction pathway that are associated with prostate cancer outcome, both here and in other published work, suggests an integral role for this pathway in prostate carcinogenesis. Thus, our findings demonstrate that multivariable survival analysis can be applied to gene expression profiles of prostate cancers with censored follow-up data and used to identify molecular markers of prostate cancer relapse with strong predictive power and relevance to the etiology of this disease.


Assuntos
Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Animais , Análise por Conglomerados , Perfilação da Expressão Gênica , Humanos , Masculino , Camundongos , Análise de Sequência com Séries de Oligonucleotídeos , Prognóstico , Neoplasias da Próstata/metabolismo , Análise de Sobrevida , Transplante Heterólogo
16.
Cancer ; 97(8): 1884-93, 2003 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-12673714

RESUMO

BACKGROUND: Predicting outcome for men with clinically localized prostate carcinoma treated with curative intent remains imprecise and further evaluation of accepted and potential predictive factors is needed. METHODS: The authors studied 696 men with localized prostate carcinoma diagnosed on transrectal biopsy and treated with radical prostatectomy at one institution between 1986 and 1999 to determine the relation between putative pretreatment prognostic factors and disease-free survival. Clinical stage, Gleason score, perineural invasion, number of biopsies containing tumor, and serum prostate specific antigen (PSA) were evaluated as predictors of extracapsular extension, seminal vesicle involvement, lymph node metastases, and surgical margin involvement as well as outcome after surgery. Kaplan-Meier method and Cox regression analyses were used to evaluate the contribution of different factors to adverse pathologic features and relapse. RESULTS: At mean follow-up of 56.9 months (range, 1.0-177.9 months; median, 54.9 months), 26.1% (182 of 696 patients) of patients had developed a disease recurrence. Pretreatment serum PSA concentration, biopsy Gleason score, and clinical stage as well as number of biopsies involved with tumor as a percentage of the total number obtained were found to be independent predictors of outcome. In patients with PSA > 10 ng/mL, biopsy perineural invasion and percentage of biopsies containing tumor were found to independently predicted disease recurrent. Increased number of biopsies involved with tumor independently predicted extracapsular extension, margin involvement, seminal vesicle, and lymph node involvement. CONCLUSIONS: This study demonstrated that the proportion of prostate biopsy cores containing tumor is an independent predictor of outcome after subsequent radical prostatectomy and suggested that perineural invasion has a predictive role in patients with a preoperative PSA > 10 ng/ml.


Assuntos
Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Biópsia por Agulha , Recidiva Local de Neoplasia/diagnóstico , Neoplasias do Sistema Nervoso Periférico/diagnóstico , Próstata/inervação , Prostatectomia , Neoplasias da Próstata/patologia , Neoplasias da Próstata/cirurgia , Adenocarcinoma/sangue , Idoso , Intervalo Livre de Doença , Humanos , Masculino , Invasividade Neoplásica , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Cuidados Pré-Operatórios , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/sangue , Glândulas Seminais/patologia
17.
J Clin Oncol ; 20(15): 3206-12, 2002 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-12149292

RESUMO

PURPOSE: We evaluated the predictive accuracy of a recently published preoperative nomogram for prostate cancer that predicts 5-year freedom from recurrence. We applied this nomogram to patients from seven different institutions spanning three continents. METHODS: Clinical data of 6,754 patients were supplied for validation, and 6,232 complete records were used. Nomogram-predicted probabilities of 60-month freedom from recurrence were compared with actual follow-up in two ways. First, areas under the receiver operating characteristic curves (AUCs) were determined for the entire data set according to several variables, including the institution where treatment was delivered. Second, nomogram classification-based risk quadrants were compared with actual Kaplan-Meier plots. RESULTS: The AUC for all institutions combined was 0.75, with individual institution AUCs ranging from 0.67 to 0.83. Nomogram predictions for each risk quadrant were similar to actual freedom from recurrence rates: predicted probabilities of 87% (low-risk group), 64% (intermediate-low-risk group), 39% (intermediate-high-risk group), and 14% (high-risk group) corresponded to actual rates of 86%, 64%, 42%, and 17%, respectively. The use of neoadjuvant therapy, variation in the prostate-specific antigen recurrence definitions between institutions, and minor differences in the way the Gleason grade was reported did not substantially affect the predictive accuracy of the nomogram. CONCLUSION: The nomogram is accurate when applied at international treatment institutions with similar patient selection and management strategies. Despite the potential for heterogeneity in patient selection and management, most predictions demonstrated high concordance with actual observations. Our results demonstrate that accurate predictions may be expected across different patient populations.


Assuntos
Neoplasias da Próstata/patologia , Neoplasias da Próstata/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Valor Preditivo dos Testes , Prognóstico , Modelos de Riscos Proporcionais , Prostatectomia , Curva ROC , Fatores de Risco , Análise de Sobrevida
18.
J Clin Oncol ; 20(4): 951-6, 2002 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-11844816

RESUMO

PURPOSE: A postoperative nomogram for prostate cancer was developed at Baylor College of Medicine. This nomogram uses readily available clinical and pathologic variables to predict 7-year freedom from recurrence after radical prostatectomy. We evaluated the predictive accuracy of the nomogram when applied to patients of four international institutions. PATIENTS AND METHODS: Clinical and pathologic data of 2,908 patients were supplied for validation, and 2,465 complete records were used. Nomogram-predicted probabilities of 7-year freedom from recurrence were compared with actual follow-up in two ways. First, the area under the receiver operating characteristic curve (AUC) was calculated for all patients and stratified by the time period of surgery. Second, calibration of the nomogram was achieved by comparing the predicted freedom from recurrence with that of an ideal nomogram. For patients in whom the pathologic report does not distinguish between focal and established extracapsular extension (an input variable of the nomogram), two separate calculations were performed assuming one or the other. RESULTS: The overall AUC was 0.80 when applied to the validation data set, with individual institution AUCs ranging from 0.77 to 0.82. The predictive accuracy of the nomogram was apparently higher in patients who were operated on between 1997 and 2000 (AUC, 0.83) compared with those treated between 1987 and 1996 (AUC, 0.78). Nomogram predictions of 7-year freedom from recurrence were within 10% of an ideal nomogram. CONCLUSION: The postoperative Baylor nomogram was accurate when applied at international treatment institutions. Our results suggest that accurate predictions may be expected when using this nomogram across different patient populations.


Assuntos
Modelos Estatísticos , Recidiva Local de Neoplasia , Prostatectomia , Neoplasias da Próstata/patologia , Neoplasias da Próstata/cirurgia , Adulto , Idoso , Calibragem , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Fatores de Risco
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