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1.
J Urol ; 197(4): 1026-1033, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-27810448

RESUMO

PURPOSE: During active surveillance for localized prostate cancer, the timing of the first surveillance biopsy varies. We analyzed the Canary PASS (Prostate Cancer Active Surveillance Study) to determine biopsy timing influence on rates of prostate cancer adverse reclassification at the first active surveillance biopsy. MATERIALS AND METHODS: Of 1,085 participants in PASS, 421 had fewer than 34% of cores involved with cancer and Gleason sum 6 or less, and thereafter underwent on-study active surveillance biopsy. Reclassification was defined as an increase in Gleason sum and/or 34% or more of cores with prostate cancer. First active surveillance biopsy reclassification rates were categorized as less than 8, 8 to 13 and greater than 13 months after diagnosis. Multivariable logistic regression determined association between reclassification and first biopsy timing. RESULTS: Of 421 men, 89 (21.1%) experienced reclassification at the first active surveillance biopsy. Median time from prostate cancer diagnosis to first active surveillance biopsy was 11 months (IQR 7.8-13.8). Reclassification rates at less than 8, 8 to 13 and greater than 13 months were 24%, 19% and 22% (p = 0.65). On multivariable analysis, compared to men biopsied at less than 8 months the OR of reclassification at 8 to 13 and greater than 13 months were 0.88 (95% CI 0.5,1.6) and 0.95 (95% CI 0.5,1.9), respectively. Prostate specific antigen density 0.15 or greater (referent less than 0.15, OR 1.9, 95% CI 1.1, 4.1) and body mass index 35 kg/m2 or greater (referent less than 25 kg/m2, OR 2.4, 95% CI 1.1,5.7) were associated with increased odds of reclassification. CONCLUSIONS: Timing of the first active surveillance biopsy was not associated with increased adverse reclassification but prostate specific antigen density and body mass index were. In low risk patients on active surveillance, it may be reasonable to perform the first active surveillance biopsy at a later time, reducing the overall cost and morbidity of active surveillance.


Assuntos
Próstata/patologia , Neoplasias da Próstata/classificação , Neoplasias da Próstata/patologia , Conduta Expectante/métodos , Idoso , Biópsia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Tempo
2.
J Urol ; 195(2): 313-20, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26327354

RESUMO

PURPOSE: Active surveillance represents a strategy to address the overtreatment of prostate cancer, yet uncertainty regarding individual patient outcomes remains a concern. We evaluated outcomes in a prospective multicenter study of active surveillance. MATERIALS AND METHODS: We studied 905 men in the prospective Canary PASS enrolled between 2008 and 2013. We collected clinical data at study entry and at prespecified intervals, and determined associations with adverse reclassification, defined as increased Gleason grade or greater cancer volume on followup biopsy. We also evaluated the relationships of clinical parameters with pathology findings in participants who underwent surgery after a period of active surveillance. RESULTS: At a median followup of 28 months 24% of participants experienced adverse reclassification, of whom 53% underwent treatment while 31% continued on active surveillance. Overall 19% of participants received treatment, 68% with adverse reclassification, while 32% opted for treatment without disease reclassification. In multivariate Cox proportional hazards modeling the percent of biopsy cores with cancer, body mass index and prostate specific antigen density were associated with adverse reclassification (p=0.01, 0.04, 0.04, respectively). Of 103 participants subsequently treated with radical prostatectomy 34% had adverse pathology, defined as primary pattern 4-5 or nonorgan confined disease, including 2 with positive lymph nodes, with no significant relationship between risk category at diagnosis and findings at surgery (p=0.76). CONCLUSIONS: Most men remain on active surveillance at 5 years without adverse reclassification or adverse pathology at surgery. However, clinical factors had only a modest association with disease reclassification, supporting the need for approaches that improve the prediction of this outcome.


Assuntos
Neoplasias da Próstata/patologia , Conduta Expectante , Idoso , Biomarcadores Tumorais/análise , Biópsia , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Vigilância da População , Estudos Prospectivos , Prostatectomia , Neoplasias da Próstata/cirurgia , Fatores de Risco , Resultado do Tratamento , Carga Tumoral
3.
J Urol ; 192(4): 1081-7, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24747657

RESUMO

PURPOSE: The DOCUMENT multicenter trial in the United States validated the performance of an epigenetic test as an independent predictor of prostate cancer risk to guide decision making for repeat biopsy. Confirming an increased negative predictive value could help avoid unnecessary repeat biopsies. MATERIALS AND METHODS: We evaluated the archived, cancer negative prostate biopsy core tissue samples of 350 subjects from a total of 5 urological centers in the United States. All subjects underwent repeat biopsy within 24 months with a negative (controls) or positive (cases) histopathological result. Centralized blinded pathology evaluation of the 2 biopsy series was performed in all available subjects from each site. Biopsies were epigenetically profiled for GSTP1, APC and RASSF1 relative to the ACTB reference gene using quantitative methylation specific polymerase chain reaction. Predetermined analytical marker cutoffs were used to determine assay performance. Multivariate logistic regression was used to evaluate all risk factors. RESULTS: The epigenetic assay resulted in a negative predictive value of 88% (95% CI 85-91). In multivariate models correcting for age, prostate specific antigen, digital rectal examination, first biopsy histopathological characteristics and race the test proved to be the most significant independent predictor of patient outcome (OR 2.69, 95% CI 1.60-4.51). CONCLUSIONS: The DOCUMENT study validated that the epigenetic assay was a significant, independent predictor of prostate cancer detection in a repeat biopsy collected an average of 13 months after an initial negative result. Due to its 88% negative predictive value adding this epigenetic assay to other known risk factors may help decrease unnecessary repeat prostate biopsies.


Assuntos
Biópsia/métodos , DNA de Neoplasias/genética , Epigênese Genética , Glutationa S-Transferase pi/genética , Próstata/patologia , Neoplasias da Próstata/genética , Proteínas Supressoras de Tumor/genética , Metilação de DNA , Epigenômica/métodos , Seguimentos , Genes APC , Glutationa S-Transferase pi/biossíntese , Humanos , Masculino , Reação em Cadeia da Polimerase , Valor Preditivo dos Testes , Prognóstico , Próstata/metabolismo , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Proteínas Supressoras de Tumor/biossíntese , Procedimentos Desnecessários/estatística & dados numéricos
4.
Mol Cell Proteomics ; 11(12): 1870-84, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22986220

RESUMO

Current protocols for the screening of prostate cancer cannot accurately discriminate clinically indolent tumors from more aggressive ones. One reliable indicator of outcome has been the determination of organ-confined versus nonorgan-confined disease but even this determination is often only made following prostatectomy. This underscores the need to explore alternate avenues to enhance outcome prediction of prostate cancer patients. Fluids that are proximal to the prostate, such as expressed prostatic secretions (EPS), are attractive sources of potential prostate cancer biomarkers as these fluids likely bathe the tumor. Direct-EPS samples from 16 individuals with extracapsular (n = 8) or organ-confined (n = 8) prostate cancer were used as a discovery cohort, and were analyzed in duplicate by a nine-step MudPIT on a LTQ-Orbitrap XL mass spectrometer. A total of 624 unique proteins were identified by at least two unique peptides with a 0.2% false discovery rate. A semiquantitative spectral counting algorithm identified 133 significantly differentially expressed proteins in the discovery cohort. Integrative data mining prioritized 14 candidates, including two known prostate cancer biomarkers: prostate-specific antigen and prostatic acid phosphatase, which were significantly elevated in the direct-EPS from the organ-confined cancer group. These and five other candidates (SFN, MME, PARK7, TIMP1, and TGM4) were verified by Western blotting in an independent set of direct-EPS from patients with biochemically recurrent disease (n = 5) versus patients with no evidence of recurrence upon follow-up (n = 10). Lastly, we performed proof-of-concept SRM-MS-based relative quantification of the five candidates using unpurified heavy isotope-labeled synthetic peptides spiked into pools of EPS-urines from men with extracapsular and organ-confined prostate tumors. This study represents the first efforts to define the direct-EPS proteome from two major subclasses of prostate cancer using shotgun proteomics and verification in EPS-urine by SRM-MS.


Assuntos
Próstata/metabolismo , Neoplasias da Próstata/metabolismo , Proteínas Secretadas pela Próstata/análise , Proteínas Secretadas pela Próstata/urina , Proteínas 14-3-3/análise , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/metabolismo , Exonucleases/análise , Exorribonucleases , Regulação Neoplásica da Expressão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/análise , Marcação por Isótopo , Masculino , Proteínas Oncogênicas/análise , Antígeno Prostático Específico/metabolismo , Análise Serial de Proteínas , Proteína Desglicase DJ-1 , Proteoma/análise , Inibidor Tecidual de Metaloproteinase-1/análise , Transglutaminases/análise
5.
Nat Commun ; 15(1): 5069, 2024 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-38871730

RESUMO

Urine is a complex biofluid that reflects both overall physiologic state and the state of the genitourinary tissues through which it passes. It contains both secreted proteins and proteins encapsulated in tissue-derived extracellular vesicles (EVs). To understand the population variability and clinical utility of urine, we quantified the secreted and EV proteomes from 190 men, including a subset with prostate cancer. We demonstrate that a simple protocol enriches prostatic proteins in urine. Secreted and EV proteins arise from different subcellular compartments. Urinary EVs are faithful surrogates of tissue proteomes, but secreted proteins in urine or cell line EVs are not. The urinary proteome is longitudinally stable over several years. It can accurately and non-invasively distinguish malignant from benign prostatic lesions and can risk-stratify prostate tumors. This resource quantifies the complexity of the urinary proteome and reveals the synergistic value of secreted and EV proteomes for translational and biomarker studies.


Assuntos
Vesículas Extracelulares , Neoplasias da Próstata , Proteoma , Humanos , Neoplasias da Próstata/urina , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Masculino , Vesículas Extracelulares/metabolismo , Proteoma/metabolismo , Idoso , Biomarcadores Tumorais/urina , Biomarcadores Tumorais/metabolismo , Proteômica/métodos , Pessoa de Meia-Idade , Próstata/metabolismo , Próstata/patologia , Linhagem Celular Tumoral
6.
Proteomics ; 13(10-11): 1667-1671, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23533145

RESUMO

Expressed prostatic secretions (EPS) are proximal fluids of the prostate that are increasingly being utilized as a clinical source for diagnostic and prognostic assays for prostate cancer (PCa). These fluids contain an abundant amount of microvesicles reflecting the secretory function of the prostate gland, and their protein composition remains poorly defined in relation to PCa. Using expressed prostatic secretions in urine (EPS-urine), exosome preparations were characterized by a shotgun proteomics procedure. In pooled EPS-urine exosome samples, ~900 proteins were detected. Many of these have not been previously observed in the soluble proteome of EPS generated by our labs or other related exosome proteomes. We performed systematic comparisons of our data against previously published, prostate-related proteomes, and global annotation analyses to highlight functional processes within the proteome of EPS-urine derived exosomes. The acquired proteomic data have been deposited to the Tranche repository and will lay the foundation for more extensive investigations of PCa derived exosomes in the context of biomarker discovery and cancer biology.


Assuntos
Exossomos/metabolismo , Neoplasias da Próstata/metabolismo , Proteoma/metabolismo , Estudos de Casos e Controles , Humanos , Masculino , Neoplasias da Próstata/urina , Proteinúria/urina , Proteoma/isolamento & purificação
7.
Cureus ; 15(3): e36042, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-37056551

RESUMO

Nelson syndrome (NS) is a dangerous condition that can sometimes manifest after bilateral adrenalectomy (BA), typically in treating Cushing's disease. It is defined by the collection of systemic signs and symptoms that can arise in a state where there are chronically and massively elevated levels of adrenocorticotropic hormone (ACTH). Traditionally it may manifest from six months to 24 years following the loss of both adrenal glands, with the meantime of development being 15 years following BA. The diagnostic criteria are controversial, with historically many different methods being used, ranging from visual field defects and an enlarged pituitary corticotrophinoma to elevated plasma ACTH levels and skin hyperpigmentation. What remains consistent between criteria is that it is secondary to total BA, traditionally in treating refractory Cushing's disease. We describe here a rare case of a patient diagnosed with bilateral renal cell carcinoma (RCC) treated with right partial and left total nephrectomy, and incidental BA, presenting with the symptoms and signs of NS. Although NS classically presents following total BA for the treatment of Cushing disease, further research is required to look for etiologies of Nelson's-like pathology outside the context of Cushing's disease treatment, thereby necessitating a change to the traditional diagnostic criteria for the syndrome to identify cases that would otherwise go untreated. In addition, this case report's outlining, drafting, and conclusions were written in part by or with the support of Chat Generative Pre-Trained Transformer (ChatGPT), a large language transformer open-source artificial intelligence.

8.
bioRxiv ; 2023 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-37546794

RESUMO

Urine is a complex biofluid that reflects both overall physiologic state and the state of the genitourinary tissues through which it passes. It contains both secreted proteins and proteins encapsulated in tissue-derived extracellular vesicles (EVs). To understand the population variability and clinical utility of urine, we quantified the secreted and EV proteomes from 190 men, including a subset with prostate cancer. We demonstrate that a simple protocol enriches prostatic proteins in urine. Secreted and EV proteins arise from different subcellular compartments. Urinary EVs are faithful surrogates of tissue proteomes, but secreted proteins in urine or cell line EVs are not. The urinary proteome is longitudinally stable over several years. It can accurately and non-invasively distinguish malignant from benign prostatic lesions, and can risk-stratify prostate tumors. This resource quantifies the complexity of the urinary proteome, and reveals the synergistic value of secreted and EV proteomes for translational and biomarker studies.

9.
J Proteome Res ; 11(4): 2386-96, 2012 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-22339264

RESUMO

Urinary expressed prostatic secretion or "EPS-urine" is proximal tissue fluid that is collected after a digital rectal exam (DRE). EPS-urine is a rich source of prostate-derived proteins that can be used for biomarker discovery for prostate cancer (PCa) and other prostatic diseases. We previously conducted a comprehensive proteome analysis of direct expressed prostatic secretions (EPS). In the current study, we defined the proteome of EPS-urine employing Multidimensional Protein Identification Technology (MudPIT) and providing a comprehensive catalogue of this body fluid for future biomarker studies. We identified 1022 unique proteins in a heterogeneous cohort of 11 EPS-urines derived from biopsy negative noncancer diagnoses with some benign prostatic diseases (BPH) and low-grade PCa, representative of secreted prostate and immune system-derived proteins in a urine background. We further applied MudPIT-based proteomics to generate and compare the differential proteome from a subset of pooled urines (pre-DRE) and EPS-urines (post-DRE) from noncancer and PCa patients. The direct proteomic comparison of these highly controlled patient sample pools enabled us to define a list of prostate-enriched proteins detectable in EPS-urine and distinguishable from a complex urine protein background. A combinatorial analysis of both proteomics data sets and systematic integration with publicly available proteomics data of related body fluids, human tissue transcriptomic data, and immunohistochemistry images from the Human Protein Atlas database allowed us to demarcate a robust panel of 49 prostate-derived proteins in EPS-urine. Finally, we validated the expression of seven of these proteins using Western blotting, supporting the likelihood that they originate from the prostate. The definition of these prostatic proteins in EPS-urine samples provides a reference for future investigations for prostatic-disease biomarker studies.


Assuntos
Próstata/química , Proteínas Secretadas pela Próstata/urina , Proteoma/análise , Proteômica/métodos , Estudos de Casos e Controles , Cromatografia Líquida de Alta Pressão , Bases de Dados de Proteínas , Perfilação da Expressão Gênica , Humanos , Masculino , Espectrometria de Massas , Próstata/metabolismo , Doenças Prostáticas/metabolismo , Doenças Prostáticas/urina , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/urina , Proteínas Secretadas pela Próstata/química , Proteínas Secretadas pela Próstata/metabolismo , Proteoma/metabolismo , Reprodutibilidade dos Testes
10.
ACS Omega ; 7(34): 29714-29727, 2022 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-36061737

RESUMO

The composition of N-linked glycans that are conjugated to the prostate-specific membrane antigen (PSMA) and their functional significance in prostate cancer progression have not been fully characterized. PSMA was isolated from two metastatic prostate cancer cell lines, LNCaP and MDAPCa2b, which have different tissue tropism and localization. Isolated PSMA was trypsin-digested, and intact glycopeptides were subjected to LC-HCD-EThcD-MS/MS analysis on a Tribrid Orbitrap Fusion Lumos mass spectrometer. Differential qualitative and quantitative analysis of site-specific N-glycopeptides was performed using Byonic and Byologic software. Comparative quantitative analysis demonstrates that multiple glycopeptides at asparagine residues 51, 76, 121, 195, 336, 459, 476, and 638 were in significantly different abundance in the two cell lines (p < 0.05). Biochemical analysis using endoglycosidase treatment and lectin capture confirm the MS and site occupancy data. The data demonstrate the effectiveness of the strategy for comprehensive analysis of PSMA glycopeptides. This approach will form the basis of ongoing experiments to identify site-specific glycan changes in PSMA isolated from disease-stratified clinical samples to uncover targets that may be associated with disease progression and metastatic phenotypes.

11.
BMC Clin Pathol ; 11: 14, 2011 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-22188997

RESUMO

BACKGROUND: Histopathology is the standard method for cancer diagnosis and grading to assess aggressiveness in clinical biopsies. Molecular biomarkers have also been described that are associated with cancer aggressiveness, however, the portion of tissue analyzed is often processed in a manner that is destructive to the tissue. We present here a new method for performing analysis of small molecule biomarkers and histology in exactly the same biopsy tissue. METHODS: Prostate needle biopsies were taken from surgical prostatectomy specimens and first fixed, each in a separate vial, in 2.5 ml of 80% methanol:water. The biopsies were fixed for 24 hrs at room temperature and then removed and post-processed using a non-formalin-based fixative (UMFIX), embedded, and analyzed by hematoxylin and eosin (H&E) and by immunohistochemical (IHC) staining. The retained alcohol pre-fixative was analyzed for small molecule biomarkers by mass spectrometry. RESULTS: H&E analysis was successful following the pre-fixation in 80% methanol. The presence or absence of tumor could be readily determined for all 96 biopsies analyzed. A subset of biopsy sections was analyzed by IHC, and cancerous and non-cancerous regions could be readily visualized by PIN4 staining. To demonstrate the suitability for analysis of small molecule biomarkers, 28 of the alcohol extracts were analyzed using a mass spectrometry-based metabolomics platform. All extracts tested yielded successful metabolite profiles. 260 named biochemical compounds were detected in the alcohol extracts. A comparison of the relative levels of compounds in cancer containing vs. non-cancer containing biopsies showed differences for 83 of the compounds. A comparison of the results with prior published reports showed good agreement between the current method and prior reported biomarker discovery methods that involve tissue destructive methods. CONCLUSIONS: The Molecular Preservation by Extraction and Fixation (mPREF) method allows for the analysis of small molecule biomarkers from exactly the same tissue that is processed for histopathology.

12.
J Proteome Res ; 9(5): 2109-16, 2010 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-20334419

RESUMO

It is expected that clinically obtainable fluids that are proximal to organs contain a repertoire of secreted proteins and shed cells reflective of the physiological state of that tissue and thus represent potential sources for biomarker discovery, investigation of tissue-specific biology, and assay development. The prostate gland secretes many proteins into a prostatic fluid that combines with seminal vesicle fluids to promote sperm activation and function. Proximal fluids of the prostate that can be collected clinically are seminal plasma and expressed prostatic secretion (EPS) fluids. In the current study, MudPIT-based proteomics was applied to EPS obtained from nine men with prostate cancer and resulted in the confident identification of 916 unique proteins. Systematic bioinformatics analyses using publicly available microarray data of 21 human tissues (Human Gene Atlas), the Human Protein Atlas database, and other published proteomics data of shed/secreted proteins were performed to systematically analyze this comprehensive proteome. Therefore, we believe this data will be a valuable resource for the research community to study prostate biology and potentially assist in the identification of novel prostate cancer biomarkers. To further streamline this process, the entire data set was deposited to the Tranche repository for use by other researchers.


Assuntos
Biomarcadores Tumorais/metabolismo , Mineração de Dados/métodos , Próstata/metabolismo , Neoplasias da Próstata/metabolismo , Proteoma/metabolismo , Proteômica/métodos , Análise por Conglomerados , Bases de Dados de Proteínas , Humanos , Imuno-Histoquímica , Masculino , Proteínas Secretadas pela Próstata/análise , Proteínas Secretadas pela Próstata/metabolismo , Análise Serial de Proteínas , Proteoma/análise
13.
J Urol ; 183(5): 1822-8, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20303100

RESUMO

PURPOSE: Health related quality of life concerns factor prominently in prostate cancer management. We describe health related quality of life impact and recovery profiles of 4 commonly used operative treatments for localized prostate cancer. MATERIALS AND METHODS: Beginning in February 2000 all patients treated with open radical prostatectomy, robot assisted laparoscopic prostatectomy, brachytherapy or cryotherapy were asked to complete the UCLA-PCI questionnaire before treatment, and at 3, 6, 12, 18, 24, 30 and 36 months after treatment. Outcomes were compared across treatment types with statistical analysis using univariate and multivariate models. RESULTS: A total of 785 patients treated between February 2000 and December 2008 were included in the analysis with a mean followup of 24 months. All health related quality of life domains were adversely affected by all treatments and recovery profiles varied significantly by treatment type. Overall urinary function and bother outcomes scored significantly higher after brachytherapy and cryotherapy compared to open radical prostatectomy and robotic assisted laparoscopic radical prostatectomy. Brachytherapy and cryotherapy had a 3-fold higher rate of return to baseline urinary function compared to open radical prostatectomy and robotic assisted laparoscopic radical prostatectomy. Sexual function and bother scores were highest after brachytherapy, with a 5-fold higher rate of return to baseline function compared to cryotherapy, open radical prostatectomy and robotic assisted laparoscopic radical prostatectomy. All 4 treatments were associated with relatively transient and less pronounced impact on bowel function and bother. CONCLUSIONS: In a study of sequential health related quality of life assessments brachytherapy and cryotherapy were associated with higher urinary function and bother scores compared to open radical prostatectomy and da Vinci prostatectomy. Brachytherapy was associated with higher sexual function and bother scores compared to open radical prostatectomy, robotic assisted laparoscopic radical prostatectomy and cryotherapy.


Assuntos
Braquiterapia , Criocirurgia , Prostatectomia , Neoplasias da Próstata/radioterapia , Neoplasias da Próstata/cirurgia , Qualidade de Vida , Robótica , Idoso , Análise de Variância , Distribuição de Qui-Quadrado , Progressão da Doença , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias , Modelos de Riscos Proporcionais , Estudos Prospectivos , Inquéritos e Questionários , Resultado do Tratamento
14.
Cancer Biomark ; 18(4): 381-387, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28106542

RESUMO

BACKGROUND: Abnormal methylation of urinary TWIST1 and NID2 conferred high sensitivity and specificity for the detection of urothelial carcinoma. OBJECTIVE: We examine the performance of the urine-based TWIST1/NID2 methylation assay with the addition of urine cytology for the detection of urothelial carcinoma. MATERIALS AND METHODS: A prospective multi-institutional study was conducted to assess the performance of a methylation assay for patients with hematuria or under surveillance for non-muscle invasive bladder cancer (NMIBC). All patients underwent cystoscopy, a methylation assay, and cytology. Receiver operator characteristic (ROC) curves were constructed for cytology alone, the methylation assay alone, and a combined model. Areas under the curve (AUC) were compared using likelihood ratio tests. RESULTS: A total of 172 patients were enrolled (37% for hematuria and 63% NMIBC). The AUC for cytology alone with equivocal cytologies positive was 0.704, and improved to 0.773 with the addition of the DNA methylation assay (p < 0.001). When the equivocal cytologies were considered negative, the AUC improved from 0.558 to 0.697 with the addition of the DNA methylation assay (p = 0.003). CONCLUSIONS: Addition of a TWIST1/NID2-based DNA methylation assay adds diagnostic value to urine cytology and the model is sensitive to the classification of equivocal cytology.


Assuntos
Carcinoma de Células de Transição/urina , Moléculas de Adesão Celular/urina , Proteínas Nucleares/urina , Proteína 1 Relacionada a Twist/urina , Neoplasias da Bexiga Urinária/urina , Idoso , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/urina , Proteínas de Ligação ao Cálcio , Carcinoma de Células de Transição/genética , Carcinoma de Células de Transição/patologia , Moléculas de Adesão Celular/genética , Cistoscopia , Metilação de DNA/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Nucleares/genética , Proteína 1 Relacionada a Twist/genética , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia
15.
Nat Commun ; 7: 11906, 2016 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-27350604

RESUMO

Biomarkers are rapidly gaining importance in personalized medicine. Although numerous molecular signatures have been developed over the past decade, there is a lack of overlap and many biomarkers fail to validate in independent patient cohorts and hence are not useful for clinical application. For these reasons, identification of novel and robust biomarkers remains a formidable challenge. We combine targeted proteomics with computational biology to discover robust proteomic signatures for prostate cancer. Quantitative proteomics conducted in expressed prostatic secretions from men with extraprostatic and organ-confined prostate cancers identified 133 differentially expressed proteins. Using synthetic peptides, we evaluate them by targeted proteomics in a 74-patient cohort of expressed prostatic secretions in urine. We quantify a panel of 34 candidates in an independent 207-patient cohort. We apply machine-learning approaches to develop clinical predictive models for prostate cancer diagnosis and prognosis. Our results demonstrate that computationally guided proteomics can discover highly accurate non-invasive biomarkers.


Assuntos
Biomarcadores/urina , Neoplasias da Próstata/urina , Humanos , Biópsia Líquida , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , Próstata/patologia , Neoplasias da Próstata/patologia , Proteoma , Proteômica
16.
Am J Surg Pathol ; 40(11): 1439-1456, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27635949

RESUMO

Histologic grading remains the gold standard for prognosis in prostate cancer, and assessment of Gleason score plays a critical role in active surveillance management. We sought to optimize the prognostic stratification of grading and developed a method of recording and studying individual architectural patterns by light microscopic evaluation that is independent of standard Gleason grade. Some of the evaluated patterns are not assessed by current Gleason grading (eg, reactive stromal response). Individual histologic patterns were correlated with recurrence-free survival in a retrospective postradical prostatectomy cohort of 1275 patients represented by the highest-grade foci of carcinoma in tissue microarrays. In univariable analysis, fibromucinous rupture with varied epithelial complexity had a significantly lower relative risk of recurrence-free survival in cases graded as 3+4=7. Cases having focal "poorly formed glands," which could be designated as pattern 3+4=7, had lower risk than cribriform patterns with either small cribriform glands or expansile cribriform growth. In separate multivariable Cox proportional hazard analyses of both Gleason score 3+3=6 and 3+4=7 carcinomas, reactive stromal patterns were associated with worse recurrence-free survival. Decision tree models demonstrate potential regrouping of architectural patterns into categories with similar risk. In summary, we argue that Gleason score assignment by current consensus guidelines are not entirely optimized for clinical use, including active surveillance. Our data suggest that focal poorly formed gland and cribriform patterns, currently classified as Gleason pattern 4, should be in separate prognostic groups, as the latter is associated with worse outcome. Patterns with extravasated mucin are likely overgraded in a subset of cases with more complex epithelial bridges, whereas stromogenic cancers have a worse outcome than conveyed by Gleason grade alone. These findings serve as a foundation to facilitate optimization of histologic grading and strongly support incorporating reactive stroma into routine assessment.


Assuntos
Adenocarcinoma/patologia , Gradação de Tumores/métodos , Neoplasias da Próstata/patologia , Adenocarcinoma/mortalidade , Algoritmos , Estudos de Coortes , Intervalo Livre de Doença , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Neoplasias da Próstata/mortalidade , Estudos Retrospectivos , Análise Serial de Tecidos
17.
J Clin Oncol ; 22(3): 439-45, 2004 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-14691120

RESUMO

PURPOSE: To determine if obesity is associated with higher prostate specific antigen recurrence rates after radical prostatectomy (RP), and to explore racial differences in body mass index (BMI) as a potential explanation for the disparity in outcome between black and white men. PATIENTS AND METHODS: A retrospective, multi-institutional pooled analysis of 3,162 men undergoing RP was conducted at nine US military medical centers between 1987 and 2002. Patients were initially categorized as obese (BMI > or = 30 kg/m(2)), overweight (BMI 25 to 30 kg/m(2)), or normal (BMI < or = 25 kg/m(2)). For analysis, normal and overweight groups were combined (BMI < 30 kg/m(2)) and compared with the obese group (BMI > or = 30 kg/m(2)) with regard to biochemical recurrence (prostate-specific antigen > or = 0.2 ng/mL) after RP. RESULTS: Of 3,162 patients, 600 (19.0%) were obese and 2,562 (81%) were not obese. BMI was an independent predictor of higher Gleason grade cancer (P <.001) and was associated with a higher risk of biochemical recurrence (P =.027). Blacks had higher BMI (P <.001) and higher recurrence rates (P =.003) than whites. Both BMI (P =.028) and black race (P =.002) predicted higher prostate specific antigen recurrence rates. In multivariate analysis of race, BMI, and pathologic factors, black race (P =.021) remained a significant independent predictor of recurrence. CONCLUSION: Obesity is associated with higher grade cancer and higher recurrence rates after RP. Black men have higher recurrence rates and greater BMI than white men. These findings support the hypothesis that obesity is associated with progression of latent to clinically significant prostate cancer (PC) and suggest that BMI may account, in part, for the racial variability in PC risk.


Assuntos
População Negra , Recidiva Local de Neoplasia/etnologia , Obesidade/etnologia , Prostatectomia , Neoplasias da Próstata/etnologia , População Branca , Índice de Massa Corporal , Humanos , Masculino , Militares , Recidiva Local de Neoplasia/sangue , Recidiva Local de Neoplasia/etiologia , Estadiamento de Neoplasias , Obesidade/complicações , Prognóstico , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/etiologia , Neoplasias da Próstata/cirurgia , Estudos Retrospectivos , Fatores de Risco , Estados Unidos
18.
Alaska Med ; 47(2): 6-9, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-16459477

RESUMO

Extracorporeal shockwave lithotripsy (ESWL) is a commonly used non-invasive treatment for urolithiasis. Helical CT scans provide much better and detailed imaging of the patient with urolithiasis including the ability to measure density of urinary stones. In this study we tested the hypothesis that density of urinary calculi as measured by CT can predict successful ESWL treatment. 198 patients were treated at Alaska Urological Associates with ESWL between January 2002 and April 2004. Of these 101 met study inclusion with accessible CT scans and stones ranging from 5-15 mm. Follow-up imaging demonstrated stone freedom in 74.2%. The overall mean Houndsfield density value for stone-free compared to residual stone groups were significantly different ( 93.61 vs 122.80 p < 0.0001). We determined by receiver operator curve (ROC) that HDV of 93 or less carries a 90% or better chance of stone freedom following ESWL for upper tract calculi between 5-15mm.


Assuntos
Litotripsia/métodos , Cálculos Urinários/diagnóstico , Cálculos Urinários/terapia , Adulto , Alaska , Estudos de Coortes , Sedação Consciente , Feminino , Fluoroscopia , Seguimentos , Humanos , Litotripsia/efeitos adversos , Masculino , Pessoa de Meia-Idade , Medição da Dor , Seleção de Pacientes , Curva ROC , Estudos Retrospectivos , Medição de Risco , Índice de Gravidade de Doença , Resultado do Tratamento
19.
J Laparoendosc Adv Surg Tech A ; 25(6): 503-7, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25978559

RESUMO

INTRODUCTION: Minimally invasive surgical techniques are currently used for numerous urologic disorders and generally offer decreased morbidity and equivalent outcomes compared with open surgery. There is a relative paucity of data on robot-assisted ureteral re-implantation (RAUR) in adult patients for benign stricture disease. PATIENTS AND METHODS: We retrospectively reviewed our recent experience with mid-/distal ureteral reconstruction at a single tertiary-care center. From 2010 to 2012, 13 consecutive patients presenting with benign obstruction of mid-/distal ureters were managed with RAUR. RESULTS: In all cases the operative procedure was undertaken with six-port transperitoneal access, and all procedures were completed robotically. All ureters (left, n=5; right, n=7; bilateral, n=1) were re-implanted in a standard Bricker fashion into the dome of the bladder with (n=8) or without (n=6) a psoas hitch. Catheters were removed 4-11 days postoperatively, and all cystograms were negative for leak. Stents were removed 14-48 days after surgery. All were negative for hydronephrosis. Average follow-up was 10 (range, 2-20) months. There were two grade 1, two grade 2, two grade 3, and no grade 4 or 5 complications in 3 patients. CONCLUSIONS: RAUR is a safe and effective procedure. Extensive laparoscopic lysis of adhesions represents the primary challenge to an otherwise straightforward minimally invasive surgery. At our institution, RAUR has replaced open ureteral re-implantation as the preferred treatment for benign mid-/distal ureteral stricture disease.


Assuntos
Robótica/métodos , Obstrução Ureteral/cirurgia , Adulto , Idoso , Constrição Patológica/cirurgia , Feminino , Humanos , Laparoscopia/métodos , Masculino , Pessoa de Meia-Idade , Procedimentos de Cirurgia Plástica/métodos , Reimplante/métodos , Estudos Retrospectivos , Resultado do Tratamento , Procedimentos Cirúrgicos Urológicos
20.
Urol Oncol ; 33(9): 387.e1-6, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26027762

RESUMO

OBJECTIVES: We previously reported a clinical trial in which we were unable to replicate the excellent diagnostic metrics produced in the developmental study of the TWIST1 and NID2 gene methylation assay. In this expanded trial with subjects enrolled from another institution, we reexamine the diagnostic capabilities of the test to externally validate our previous study. MATERIALS AND METHODS: TWIST1 and NID2 gene methylation was assessed in DNA isolated from the urine of subjects at risk of bladder cancer undergoing cystoscopy for hematuria or bladder cancer surveillance. The diagnostic gold standard was cystoscopy. Two thresholds of TWIST1 and NID2 gene methylation were used for determining test result positivity, those published by Renard et al. and Abern et al. The sensitivity, specificity, positive and negative predictive values, diagnostic likelihood ratios, and receiver operating characteristic curves were calculated for each gene, as well as their combination. In all, 3 methods were used to combine TWIST1 and NID2 into a single composite test: (1) believe-the-positive decision rule-if either gene is methylated the test result is positive, which maximizes test sensitivity; (2) believe-the-negative decision rule-if either gene is not methylated the test result is negative, which maximizes test specificity; and (3) a likelihood-based logistic regression model approach that balances sensitivity and specificity. Clinical utility was determined using a decision curve analysis. RESULTS: A total of 209 subjects were evaluated: 40% for hematuria and 60% for bladder cancer surveillance. Approximately 75% were male, most of the prior cancers being low-grade Ta. Using cystoscopy as the gold standard, areas under the curve were 0.67 for TWIST1, 0.64 for NID2, and 0.66 for combined TWIST1 and NID2. Decision rule results revealed optimization of sensitivity at 67% using Renard thresholds and specificity using the Abern thresholds at 69%. We found improved sensitivity (78%) in current smokers. Decision curve analyses revealed that the methylation assay provided only a modest benefit even at high probabilities of missed cancer. CONCLUSION: A urine DNA test measuring TWIST1 and NID2 methylation was externally examined with a larger cohort and its results continue to be poor. These 2 biomarkers are unlikely to replace cystoscopy, but they may be worthy of study in active smokers.


Assuntos
Biomarcadores Tumorais/análise , Carcinoma de Células de Transição/diagnóstico , Moléculas de Adesão Celular/urina , Metilação de DNA , Proteínas Nucleares/urina , Proteína 1 Relacionada a Twist/urina , Neoplasias da Bexiga Urinária/diagnóstico , Idoso , Área Sob a Curva , Proteínas de Ligação ao Cálcio , Carcinoma de Células de Transição/genética , Carcinoma de Células de Transição/urina , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Estudos de Coortes , Feminino , Humanos , Funções Verossimilhança , Masculino , Pessoa de Meia-Idade , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Curva ROC , Reação em Cadeia da Polimerase em Tempo Real , Sensibilidade e Especificidade , Proteína 1 Relacionada a Twist/genética , Proteína 1 Relacionada a Twist/metabolismo , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/urina
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