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1.
Int J Mol Sci ; 25(18)2024 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-39337566

RESUMO

RNAs, especially non-coding RNAs (ncRNAs), are crucial players in regulating cellular mechanisms due to their ability to interact with and regulate other molecules. Altered expression patterns of ncRNAs have been observed in prostate cancer (PCa), contributing to the disease's initiation, progression, and treatment response. This study aimed to evaluate the ability of a specific set of RNAs, including long ncRNAs (lncRNAs), microRNAs (miRNAs), and mRNAs, to discriminate between PCa and the non-neoplastic condition benign prostatic hyperplasia (BPH). After selecting by literature mining the most relevant RNAs differentially expressed in biofluids from PCa patients, we evaluated their discriminatory power in samples of unfiltered urine from 50 PCa and 50 BPH patients using both real-time PCR and droplet digital PCR (ddPCR). Additionally, we also optimized a protocol for urine sample manipulation and RNA extraction. This two-way validation study allowed us to establish that miRNAs (i.e., miR-27b-3p, miR-574-3p, miR-30a-5p, and miR-125b-5p) are more efficient biomarkers for PCa compared to long RNAs (mRNAs and lncRNAs) (e.g., PCA3, PCAT18, and KLK3), as their dysregulation was consistently reported in the whole urine of patients with PCa compared to those with BPH in a statistically significant manner regardless of the quantification methodology performed. Moreover, a significant increase in diagnostic performance was observed when molecular signatures composed of different miRNAs were considered. Hence, the abovementioned circulating ncRNAs represent excellent potential non-invasive biomarkers in urine capable of effectively distinguishing individuals with PCa from those with BPH, potentially reducing cancer overdiagnosis.


Assuntos
Biomarcadores Tumorais , MicroRNAs , Hiperplasia Prostática , Neoplasias da Próstata , Humanos , Masculino , Hiperplasia Prostática/urina , Hiperplasia Prostática/genética , Hiperplasia Prostática/diagnóstico , Neoplasias da Próstata/urina , Neoplasias da Próstata/genética , Neoplasias da Próstata/diagnóstico , Idoso , MicroRNAs/urina , MicroRNAs/genética , Biomarcadores Tumorais/urina , Biomarcadores Tumorais/genética , Pessoa de Meia-Idade , Diagnóstico Diferencial , RNA Longo não Codificante/urina , RNA Longo não Codificante/genética , RNA Mensageiro/urina , RNA Mensageiro/genética , Regulação Neoplásica da Expressão Gênica , Idoso de 80 Anos ou mais
2.
BMC Urol ; 24(1): 163, 2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-39090720

RESUMO

BACKGROUND: This study investigated the use of urinary exosomal mRNA as a potential biomarker for the early detection of prostate cancer (PCa). METHODS: Next-generation sequencing was utilized to analyze exosomal RNA from 10 individuals with confirmed PCa and 10 individuals without cancer. Subsequent validation through qRT-PCR in a larger sample of 43 PCa patients and 92 healthy controls revealed distinct mRNA signatures associated with PCa. RESULTS: Notably, mRNAs for RAB5B, WWP1, HIST2H2BF, ZFY, MARK2, PASK, RBM10, and NRSN2 showed promise as diagnostic markers, with AUC values between 0.799 and 0.906 and significance p values. Combining RAB5B and WWP1 in an exoRNA diagnostic model outperformed traditional PSA tests, achieving an AUC of 0.923, 81.4% sensitivity, and 89.1% specificity. CONCLUSIONS: These findings highlight the potential of urinary exosomal mRNA profiling, particularly focusing on RAB5B and WWP1, as a valuable strategy for improving the early detection of PCa.


Assuntos
Biomarcadores Tumorais , Detecção Precoce de Câncer , Exossomos , Neoplasias da Próstata , RNA Mensageiro , Humanos , Masculino , Neoplasias da Próstata/urina , Neoplasias da Próstata/genética , Neoplasias da Próstata/diagnóstico , Exossomos/genética , RNA Mensageiro/urina , Biomarcadores Tumorais/urina , Biomarcadores Tumorais/genética , Detecção Precoce de Câncer/métodos , Idoso , Pessoa de Meia-Idade
3.
Clin Biochem ; 131-132: 110808, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39069115

RESUMO

INTRODUCTION: Current diagnostic approaches for bladder cancer (BLCA) are often invasive or lack the required sensitivity and specificity. This underscores the need for an early non-invasive diagnostic test for BLCA. This work aimed to explore the potential of molecular markers in urine-exfoliated cells for the diagnosis of non-muscle-invasive bladder cancer (NMIBC). MATERIALS AND METHODS: Urine specimens (n = 140) were collected from NMIBC patients (n = 68) and control subjects (31 healthy volunteers and 41 non-cancer patients with common urological diseases [CUD]. Total RNA was extracted from the cells isolated from urine specimens. mRNA expression of selected genes: CDC20, KRT15, FOXM1, CXCR2, UPK1B, MDK, KRT20, and KRT17 was determined using RT-qPCR. The receiver operating characteristic (ROC) curve was then plotted to obtain the area under the curve (AUC), specificity, and sensitivity of the urinary mRNA markers. RESULTS: The expression of CDC20, MDK, UPK1B, FOXM1, KRT17, and KRT20 was up-regulated in samples obtained from low- and high-grade pathological grades of NMIBC compared to that measured in healthy subjects. Notably, MDK and KRT17 mRNA levels in the low- and high-grade cases were substantially higher than in normal and CUD groups. The AUC of the KRT17 and MDK combination in diagnosing NMIBC was 0.92, surpassing that of single genes. The sensitivity and specificity of the KRT17 and MDK combination were 74% and 94%, respectively. In diagnosing low-grade from healthy and CUD groups, analysis of the KRT17 and MDK combination yielded AUCs of 0.94 and 0.95, respectively, with sensitivities of 85% and 97%, and specificities of 93% and 85%. CONCLUSION: The findings of this study revealed that KRT17 and MDK together are potential urine-based biomarkers for early diagnosis of NMIBC.


Assuntos
Biomarcadores Tumorais , Queratina-17 , RNA Mensageiro , Neoplasias da Bexiga Urinária , Humanos , Neoplasias da Bexiga Urinária/urina , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/diagnóstico , Neoplasias da Bexiga Urinária/patologia , Queratina-17/genética , Queratina-17/urina , Masculino , Feminino , RNA Mensageiro/urina , RNA Mensageiro/genética , Pessoa de Meia-Idade , Biomarcadores Tumorais/urina , Biomarcadores Tumorais/genética , Idoso , Regulação Neoplásica da Expressão Gênica , Adulto , Neoplasias não Músculo Invasivas da Bexiga
4.
Clin Chim Acta ; 561: 119750, 2024 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-38885756

RESUMO

BACKGROUND: Renin-angiotensin system inhibitors (RASi) treatment is the basic therapy for IgA nephropathy (IgAN) patients. However, there is few of biomarker that can predict the efficacy of RASi. This study aimed to find urinary exosomal mRNAs related to the therapeutic effect of RASi in the treatment of proteinuria in IgAN patients. METHODS: We divided IgAN patients in screening cohort into A1 (proteinuria increase at 3 months), B1 (proteinuria decrease less than 50 % at 3 months), C1 (proteinuria decrease more than 50 % at 3 months) groups according to changes of proteinuria after treatment. The urinary exosomes were collected before biopsy, RNAs were extracted and analyzed with the microarray assay. The candidate genes were screened by differentially expressed genes (DEGs) analysis and then validated by quantitative real-time polymerase chain reaction (qPCR) in a validation cohort. A receiver operating characteristic (ROC) curve was used to evaluate gene performance in predicting therapeutic effect on RASi reducing proteinuria in IgAN patients. RESULTS: ECE1 and PDE1A mRNAs were significantly different among the three groups, and were gradually decreased among A1, B1 and C1 groups. In the validation cohort, the level of urinary exosomal ECE1 and PDE1A mRNAs were also significantly lower in A2 group compared with C2 group(ECE1, P < 0.001;PDE1A, P < 0.01). Besides, the level of ECE1 mRNA was also lower in B2 group compared with C2 group (P < 0.01). The ROC curve verified that urinary exosomal ECE1 and PDE1A gene level predicted RASi efficacy in IgAN patients with area under curve (AUC) 0.68 and 0.63 respectively. CONCLUSION: Urinary exosomal ECE1 and PDE1A mRNAs expression can serve as potential biomarkers for predicting the RASi efficacy to reduce proteinuria in IgAN patients.


Assuntos
Biomarcadores , Exossomos , Glomerulonefrite por IGA , RNA Mensageiro , Sistema Renina-Angiotensina , Humanos , Glomerulonefrite por IGA/tratamento farmacológico , Glomerulonefrite por IGA/urina , Glomerulonefrite por IGA/genética , Masculino , RNA Mensageiro/genética , RNA Mensageiro/urina , Adulto , Feminino , Exossomos/genética , Exossomos/metabolismo , Biomarcadores/urina , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/genética , Pessoa de Meia-Idade , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico
5.
Curr Opin Organ Transplant ; 28(2): 117-125, 2023 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-36757681

RESUMO

PURPOSE OF REVIEW: Because all functioning nephrons contribute to urine formation, we reasoned that urine would be a suitable substitute to kidney allograft biopsy to discern human kidney allograft status. In view of compelling data that ribonucleic acid (RNA) sequencing outperforms microarray-based profiling, we performed RNA sequencing of urinary cells and kidney allograft biopsies to define the transcriptional landscape of allograft rejection. RECENT FINDINGS: Whole genome transcriptome profiling identified unique and shared gene signatures of acute T cell mediated rejection (TCMR) and antibody mediated rejection (AMR). We found that biopsy rejection signatures are enriched in urinary cells and that the immune cellular landscape is more diverse and enriched in urine compared to biopsies. Towards a patient friendly protocol for urinary cell messenger RNA (mRNA) profiling, we developed a filtration-based protocol for the initial processing of urine at home and demonstrated excellent performance characteristics of the filter- based protocol. SUMMARY: Acute rejection signatures are enriched in urinary cells. Urinary cell mRNA profiles are diagnostic and prognostic of acute rejection and could serve as yardsticks of in-vivo immune status. RNA sequencing yields insights into mechanisms of rejection and helps prioritize therapeutic targets. The filtration protocol for home processing of urine may optimize immune surveillance.


Assuntos
Transplante de Rim , Humanos , Transplante de Rim/efeitos adversos , RNA Mensageiro/genética , RNA Mensageiro/urina , Rim/patologia , Transplante Homólogo , Biópsia , Aloenxertos , Rejeição de Enxerto/diagnóstico , Rejeição de Enxerto/genética
6.
Front Endocrinol (Lausanne) ; 12: 774436, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34858345

RESUMO

The clinical manifestations of diabetic kidney disease (DKD) are more heterogeneous than those previously reported, and these observations mandate the need for the recruitment of patients with biopsy-proven DKD in biomarker research. In this study, using the public gene expression omnibus (GEO) repository, we aimed to identify urinary mRNA biomarkers that can predict histological severity and disease progression in patients with DKD in whom the diagnosis and histologic grade has been confirmed by kidney biopsy. We identified 30 DKD-specific mRNA candidates based on the analysis of the GEO datasets. Among these, there were significant alterations in the urinary levels of 17 mRNAs in patients with DKD, compared with healthy controls. Four urinary mRNAs-LYZ, C3, FKBP5, and G6PC-reflected tubulointerstitial inflammation and fibrosis in kidney biopsy and could predict rapid progression to end-stage kidney disease independently of the baseline eGFR (tertile 1 vs. tertile 3; adjusted hazard ratio of 9.68 and 95% confidence interval of 2.85-32.87, p < 0.001). In conclusion, we demonstrated that urinary mRNA signatures have a potential to indicate the pathologic status and predict adverse renal outcomes in patients with DKD.


Assuntos
Nefropatias Diabéticas/diagnóstico , Testes de Função Renal/métodos , RNA Mensageiro/urina , Adulto , Idoso , Biomarcadores/urina , Biópsia , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patologia , Diabetes Mellitus Tipo 2/urina , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/patologia , Nefropatias Diabéticas/urina , Progressão da Doença , Feminino , Taxa de Filtração Glomerular , Humanos , Rim/metabolismo , Rim/patologia , Falência Renal Crônica/diagnóstico , Falência Renal Crônica/genética , Falência Renal Crônica/patologia , Falência Renal Crônica/urina , Masculino , Pessoa de Meia-Idade , Prognóstico , República da Coreia , Transcriptoma
7.
BJU Int ; 128(6): 713-721, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-33793062

RESUMO

OBJECTIVE: To evaluate the performance of the Xpert Bladder Cancer Monitor (Xpert; Cepheid, Sunnyvale, CA, USA) test as a predictor of tumour recurrence in patients with non-muscle-invasive bladder cancer (NMIBC). PATIENTS AND METHODS: Patients (n = 429) undergoing surveillance for NMIBC underwent Xpert, cytology, and UroVysion testing. Patients with a positive Xpert and a negative cystoscopy result (positive-negative [PN] group, n = 66) and a control group of double negative patients (negative Xpert and cystoscopy results [NN] group) were followed for 12 months (±90 days). RESULTS: Histology-confirmed recurrences were detected in 58 patients (13.5%). Xpert had an overall sensitivity of 60.3% and a specificity of 76.5%. The sensitivity for high-grade (HG) cancer was 87% with a negative predictive value (NPV) of 99%. Urine cytology showed an overall sensitivity of 23.2% (47.6% sensitivity for HG tumours) and a specificity of 88.3%. In the PN group, 32% (n = 21) developed a recurrence within 12 months, 11 of which were HG tumours. In the NN control group, 14% (n = 9) developed a recurrence and only two were HG tumours. The hazard ratio for developing recurrence in the PN group was 2.68 for all tumours and 6.84 for HG cancer. CONCLUSIONS: The Xpert test has a high sensitivity for detecting the recurrence of cancer and a high NPV for excluding HG cancer. In addition, the data suggest that patients with a positive Xpert assay in the setting of negative cystoscopy are at high risk for recurrence and need close surveillance.


Assuntos
Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/urina , RNA Mensageiro/urina , Neoplasias da Bexiga Urinária/diagnóstico , Neoplasias da Bexiga Urinária/urina , Adulto , Idoso , Idoso de 80 Anos ou mais , Cistoscopia , Feminino , Seguimentos , Humanos , Hibridização in Situ Fluorescente , Biópsia Líquida , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Músculo Liso/patologia , Gradação de Tumores , Invasividade Neoplásica , Recidiva Local de Neoplasia/patologia , Valor Preditivo dos Testes , Estudos Prospectivos , Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/cirurgia , Urina/química , Urina/citologia
8.
Clin J Am Soc Nephrol ; 16(10): 1565-1577, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-33906907

RESUMO

Immune monitoring of kidney allograft recipients and personalized therapeutics may help reach the aspirational goal of "one transplant for life." The invasive kidney biopsy procedure, the diagnostic tool of choice, has become safer and the biopsy classification more refined. Nevertheless, biopsy-associated complications, interobserver variability in biopsy specimen scoring, and costs continue to be significant concerns. The dynamics of the immune repertoire make frequent assessments of allograft status necessary, but repeat biopsies of the kidney are neither practical nor safe. To address the existing challenges, we developed urinary cell mRNA profiling and investigated the diagnostic, prognostic, and predictive accuracy of absolute levels of a hypothesis-based panel of mRNAs encoding immunoregulatory proteins. Enabled by our refinements of the PCR assay and by investigating mechanistic hypotheses, our single-center studies identified urinary cell mRNAs associated with T cell-mediated rejection, antibody-mediated rejection, interstitial fibrosis and tubular atrophy, and BK virus nephropathy. In the multicenter National Institutes of Health Clinical Trials in Organ Transplantation-04, we discovered and validated a urinary cell three-gene signature of T-cell CD3 ε chain mRNA, interferon gamma inducible protein 10 (IP-10) mRNA, and 18s ribosomal RNA that is diagnostic of subclinical acute cellular rejection and acute cellular rejection and prognostic of acute cellular rejection and graft function. The trajectory of the signature score remained flat and below the diagnostic threshold for acute cellular rejection in the patients with no rejection biopsy specimens, whereas a sharp rise was observed during the weeks before the biopsy specimen that showed acute cellular rejection. Our RNA sequencing and bioinformatics identified kidney allograft biopsy specimen gene signatures of acute rejection to be enriched in urinary cells matched to acute rejection biopsy specimens. The urinary cellular landscape was more diverse and more enriched for immune cell types compared with kidney allograft biopsy specimens. Urinary cell mRNA profile-guided clinical trials are needed to evaluate their value compared with current standard of care.


Assuntos
Perfilação da Expressão Gênica , Rejeição de Enxerto/diagnóstico , Transplante de Rim , RNA Mensageiro/genética , Transcriptoma , Doença Aguda , Animais , Biomarcadores/urina , Biópsia , Complexo CD3/genética , Complexo CD3/urina , Quimiocina CXCL10/genética , Quimiocina CXCL10/urina , Rejeição de Enxerto/genética , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/urina , Sobrevivência de Enxerto , Humanos , Transplante de Rim/efeitos adversos , Valor Preditivo dos Testes , RNA Mensageiro/urina , RNA Ribossômico 18S/genética , RNA Ribossômico 18S/urina , Fatores de Tempo , Resultado do Tratamento , Urinálise
9.
Urol Oncol ; 39(7): 437.e11-437.e19, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33785220

RESUMO

OBJECTIVES: To prospectively investigate the role of a urinary mRNA biomarker (Xpert Test) after initial complete resection of T1 bladder cancer (BC) for the prediction of positive repeat biopsy for malignancy. METHODS: Patients who underwent TURBT for NMIBC between September 2018 and April 2020 were included. Patients with benign pathology, incomplete resection, concomitant CIS/upper tract urothelial tumor or muscle invasive BC, were excluded. 2 to 6 weeks after primary TURBT, voided urine sample was retrieved for Xpert analysis and patients were scheduled for repeat biopsy. The primary outcome was to determine the role of positive Xpert test to predict positive repeat biopsy for malignancy. RESULTS: During the study period, 254 patients met the study inclusion criteria of which 61 (24%) patients had recurrent NMIBC. Complete resection was censured by the presence of detrusor muscle in the specimen with documented T1 disease in all study participants. Xpert test was positive in 128 patients; of whom 85 (66.4%) showed positive repeat biopsy (HR=6.2, 95%CI=3.46-9.4, P = 0.002). The sensitivity, specificity, positive and negative predictive values of Xpert test for repeat biopsy were 85.9% (95%CI: 82-89), 72.3% (95%CI: 68-76), 66.4% (95%CI: 62-71) and 88.9% (95%CI: 85-94), respectively. On median (range) follow up of 12(3-25) months, tumor recurrence was encountered in 84 (35%) patients. On multivariate Cox regression analysis, Xpert test was significantly associated with tumor recurrence (HR= 9.7, 95%CI=5-18, P <0.001). CONCLUSIONS: Positive Xpert test after primary complete resection of T1 BC is significantly associated with positive repeat biopsy for malignancy. In addition, Xpert test is an independent predictor of early tumor recurrence. Xpert test might be applied after initial complete resection of NMIBC to minimize unnecessary repeat biopsy with potential saving of healthcare costs and reduction in patient morbidity.


Assuntos
Biomarcadores Tumorais/urina , Cistectomia , RNA Mensageiro/urina , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/urina , Idoso , Biópsia , Cistectomia/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos Prospectivos , Neoplasias da Bexiga Urinária/cirurgia
10.
Urol Oncol ; 39(8): 497.e9-497.e15, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33766467

RESUMO

OBJECTIVES: The risk of bladder cancer (BCa) diagnosis and recurrence necessitates cystoscopy. Improved risk stratification may inform personalized triage and surveillance strategies. We aim to develop a urinary mRNA biomarker panel for risk stratification in patients undergoing BCa screening and surveillance. METHODS AND MATERIALS: Urine samples were collected from patients undergoing cystoscopy for BCa screening or surveillance. In patients who underwent transurethral resection of bladder tumor, urine samples were categorized based on tumor histopathology, size, and focality. Subjects with intermediate and high-risk BCa based on American Urological Association (AUA) guideline for non-muscle invasive bladder cancer were classified as "increased-risk"; those with no cancer and AUA low-risk BCa were classified as "low-risk". Urine was evaluated for ROBO1, WNT5A, CDC42BPB, ABL1, CRH, IGF2, ANXA10, and UPK1B expression. A diagnostic model to detect "increased-risk" BCa was created using forward logistic regression analysis of cycle threshold values. Model validation was performed with ten-fold cross-validation. Sensitivity and specificity for detection of "increased-risk" BCa was determined and net benefit analysis performed. RESULTS: Urine samples (n = 257) were collected from 177 patients (95 screening, 76 surveillance, 6 both). There were 65 diagnoses of BCa (12 low, 22 intermediate, 31 high risk). ROBO1, CRH, and IGF2 expression correlated with "increased-risk" disease yielding sensitivity of 92.5% (95% CI, 84.9%-98.1%) and specificity of 73.5% (95% CI, 67.7-79.9%). The overall calculated standardized net benefit of the model was 0.81 (95%CI, 0.71-0.90). CONCLUSIONS: A 3-marker urinary mRNA panel allows for non-invasive identification of "increased-risk" BCa and with further validation may prove to be a tool to reduce the need for cystoscopies in low-risk patients.


Assuntos
Biomarcadores Tumorais/urina , Cistoscopia/métodos , RNA Mensageiro/urina , Medição de Risco/métodos , Neoplasias da Bexiga Urinária/patologia , Idoso , Biomarcadores Tumorais/genética , Feminino , Seguimentos , Humanos , Masculino , Prognóstico , RNA Mensageiro/genética , Taxa de Sobrevida , Triagem , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/cirurgia , Neoplasias da Bexiga Urinária/urina
11.
Methods Mol Biol ; 2292: 57-72, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33651352

RESUMO

Liquid biopsy is gaining importance in the context of analysis of circulating subcellular components, such as exosomes and nucleic acids, and the investigation of biological fluids is increasing because they express features common to the tissue of origin. Particularly, urine has become one of the most attractive biofluids in clinical practice due to its easy collection approach, its availability of large quantities, and its noninvasiveness. Furthermore, a peculiarity is that, compared to serum or plasma, urine is characterized by a simpler composition that improves isolation and identification of biomarkers. Recent studies have been associated with the investigation of mRNAs and microRNAs as potential noninvasive cancer biomarkers in urine, and to date, several approaches for isolating and measuring urinary nucleic acids have been established, despite still developing. This chapter aims at giving some main published evidences on urinary microRNAs and mRNAs, with the intent to consider their potential translational use in clinical practice.


Assuntos
MicroRNAs/urina , Neoplasias/urina , RNA Mensageiro/urina , Biomarcadores Tumorais/urina , Humanos , Biópsia Líquida , Neoplasias/diagnóstico , Urinálise
12.
Urol Oncol ; 39(1): 77.e9-77.e16, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32800441

RESUMO

OBJECTIVES: To assess the clinical performance characteristics of Xpert Monitor test for recurrence detection during surveillance of patients with non muscle invasive bladder cancer (NMIBC). PATIENTS AND METHODS: Patient with previous history of NMIBC were included in the study. Voided urine specimens were collected for Xpert monitor analysis and cytology. Office cystoscopy was performed for all study participants with in patient biopsy specimen retrieval for positive or suspicious cases. Test characteristics were calculated based on cystoscopy/biopsy results and compared between Xpert and cytology. RESULTS: Between March 2018 and May 2019, 181 patients including 168 (92.8%) males fulfilled the study criteria with median age 61 years, Primary tumors were low, intermediate, high risk in 2.8%, 22.7% and 74.5% of patients respectively. Biopsy proven recurrence was detected in 19 patients (10.4%). Xpert Monitor had a sensitivity of 73.7% with a negative predictive value (NPV) of 96.3%. Xpert Monitor was positive in all cases with high grade tumors (9 patients). Urine cytology showed sensitivity of 47% and an NPV of 93.2%. During follow up surveillance, out of 162 cystoscopy negative patients (CNP), 9.3% developed recurrence within 8 months. Xpert Monitor was found to be an independent predictor of early recurrence in CNP (HR=2.8, 95%CI=1.1-7.2, p=0.01). CONCLUSIONS: Xpert Monitor urine test has a superior diagnostic performance for recurrence detection in NMIBC patients compared to urine cytology. It might be a helpful tool not only for excluding bladder cancer recurrence in those patients, but also for prediction of possible future early recurrence.


Assuntos
Recidiva Local de Neoplasia/urina , RNA Mensageiro/urina , Urinálise/métodos , Neoplasias da Bexiga Urinária/urina , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Vigilância da População/métodos , Estudos Prospectivos , Neoplasias da Bexiga Urinária/patologia
13.
Investig Clin Urol ; 62(1): 1-13, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33381926

RESUMO

Although prostate-specific antigen (PSA) remains the most used test to detect prostate cancer (PCa), the limited specificity and an elevated rate of overdiagnosis are the main problems associated with PSA testing. Over the last three decades, a large body of evidence has indicated that PSA screening methods for PCa are problematic, although PSA screening significantly reduces PCa-specific mortality. A number of novel biomarkers have been introduced to overcome these limitations of PSA in the clinical setting. These biomarkers have demonstrated an increased ability to select patients for biopsy and identify men at risk for clinically significant PCa. Although a number of assays require further validation, initial data are promising. Forthcoming results will ultimately determine the clinical utility and commercial availability of these assays. Extensive efforts have recently been made to identify and commercialize novel PCa biomarkers for more effective detection of PCa, either alone or in combination with currently available clinical tools. This review highlights the role of existing and promising serum and urinary biomarkers for the detection and prognostication of PCa before prostate biopsy.


Assuntos
Antígenos de Neoplasias/urina , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/sangue , Neoplasias da Próstata/diagnóstico , RNA Mensageiro/urina , Proteína da Polipose Adenomatosa do Colo/genética , Fatores Etários , Algoritmos , Antígenos de Neoplasias/genética , Proteínas de Ciclo Celular/genética , Metilação de DNA , Exame Retal Digital , Exossomos , Perfilação da Expressão Gênica , Glutationa S-Transferase pi/genética , Proteínas de Homeodomínio/genética , Humanos , Masculino , Proteínas de Fusão Oncogênica/urina , Isoformas de Proteínas/sangue , Proteínas Proto-Oncogênicas c-ets/genética , Calicreínas Teciduais/sangue , Fatores de Transcrição/genética , Regulador Transcricional ERG/genética , Proteínas Supressoras de Tumor/genética
14.
Sci Rep ; 10(1): 3716, 2020 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-32111915

RESUMO

Sensitive and specific diagnostic and prognostic biomarkers for prostate cancer (PCa) are urgently needed. Urine samples are a non-invasive means to obtain abundant and readily accessible "liquid biopsies". Herein we used urine liquid biopsies to identify and characterize a novel group of urine-enriched RNAs and metabolites in patients with PCa and normal individuals with or without benign prostatic disease. Differentially expressed RNAs were identified in urine samples by deep sequencing and metabolites in urine were measured by mass spectrometry. mRNA and metabolite profiles were distinct in patients with benign and malignant disease. Integrated analysis of urinary gene expression and metabolite signatures unveiled an aberrant glutamate metabolism and tricarboxylic acid (TCA) cycle node in prostate cancer-derived cells. Functional validation supported a role for glutamate metabolism and glutamate oxaloacetate transaminase 1 (GOT1)-dependent redox balance in PCa, which could be exploited for novel biomarkers and therapies. In this study, we discovered cancer-specific changes in urinary RNAs and metabolites, paving the way for the development of sensitive and specific urinary PCa diagnostic biomarkers either alone or in combination. Our methodology was based on single void urine samples (i.e., without prostatic massage). The integrated analysis of metabolomic and transcriptomic data from these liquid biopsies revealed a glutamate metabolism and tricarboxylic acid cycle node that was specific to prostate-derived cancer cells and cancer-specific metabolic changes in urine.


Assuntos
Biomarcadores Tumorais/urina , Neoplasias da Próstata/urina , RNA Mensageiro/urina , Ciclo do Ácido Cítrico , Ácido Glutâmico/metabolismo , Humanos , Biópsia Líquida , Masculino , Próstata/metabolismo , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , RNA Mensageiro/genética
15.
Nat Rev Clin Oncol ; 17(6): 372-381, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32112055

RESUMO

Following detection of high levels of serum prostate-specific antigen, many men are advised to have transrectal ultrasound-guided biopsy in an attempt to locate a cancer. This nontargeted approach lacks accuracy and carries a small risk of potentially life-threatening sepsis. Worse still, it can detect clinically insignificant cancer cells, which are unlikely to be the origin of advanced-stage disease. The detection of these indolent cancer cells has led to overdiagnosis, one of the major problems of contemporary medicine, whereby many men with clinically insignificant disease are advised to undergo unnecessary radical surgery or radiotherapy. Advances in imaging and biomarker discovery have led to a revolution in prostate cancer diagnosis, and nontargeted prostate biopsies should become obsolete. In this Perspective article, we describe the current diagnostic pathway for prostate cancer, which relies on nontargeted biopsies, and the problems linked to this pathway. We then discuss the utility of prebiopsy multiparametric MRI and novel tumour markers. Finally, we comment on how the incorporation of these advances into a new diagnostic pathway will affect the current risk-stratification system and explore future challenges.


Assuntos
Biópsia Guiada por Imagem/métodos , Imageamento por Ressonância Magnética Multiparamétrica , Neoplasias da Próstata/diagnóstico , Fatores Etários , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/urina , Biópsia com Agulha de Grande Calibre , Exame Retal Digital , Proteínas de Homeodomínio/genética , Humanos , Calicreínas/sangue , Masculino , Uso Excessivo dos Serviços de Saúde , Diagnóstico Ausente , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , RNA Mensageiro/urina , Fatores de Transcrição/genética , Ultrassonografia
16.
JCI Insight ; 5(4)2020 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-32102984

RESUMO

BACKGROUNDRNA sequencing (RNA-Seq) is a molecular tool to analyze global transcriptional changes, deduce pathogenic mechanisms, and discover biomarkers. We performed RNA-Seq to investigate gene expression and biological pathways in urinary cells and kidney allograft biopsies during an acute rejection episode and to determine whether urinary cell gene expression patterns are enriched for biopsy transcriptional profiles.METHODSWe performed RNA-Seq of 57 urine samples collected from 53 kidney allograft recipients (patients) with biopsies classified as acute T cell-mediated rejection (TCMR; n = 22), antibody-mediated rejection (AMR; n = 8), or normal/nonspecific changes (No Rejection; n = 27). We also performed RNA-Seq of 49 kidney allograft biopsies from 49 recipients with biopsies classified as TCMR (n = 12), AMR (n = 17), or No Rejection (n = 20). We analyzed RNA-Seq data for differential gene expression, biological pathways, and gene set enrichment across diagnoses and across biospecimens.RESULTSWe identified unique and shared gene signatures associated with biological pathways during an episode of TCMR or AMR compared with No Rejection. Gene Set Enrichment Analysis demonstrated enrichment for TCMR biopsy signature and AMR biopsy signature in TCMR urine and AMR urine, irrespective of whether the biopsy and urine were from the same or different patients. Cell type enrichment analysis revealed a diverse cellular landscape with an enrichment of immune cell types in urinary cells compared with biopsies.CONCLUSIONSRNA-Seq of urinary cells and biopsies, in addition to identifying enriched gene signatures and pathways associated with TCMR or AMR, revealed genomic changes between TCMR and AMR, as well as between allograft biopsies and urinary cells.


Assuntos
Rejeição de Enxerto/genética , Transplante de Rim , RNA Mensageiro/urina , Transcriptoma , Doença Aguda , Aloenxertos , Biópsia , Humanos , Rim/patologia , Análise de Sequência de RNA
17.
Prostate ; 80(6): 500-507, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32077525

RESUMO

BACKGROUND: A 2-gene urine-based molecular test that targets messenger RNAs known to be overexpressed in aggressive prostate cancer (PCa) has been described as a helpful method for detecting clinically significant prostate cancer (grade group [GG] ≥2). We performed an external validation of this test in men undergoing initial prostate biopsy (Bx) within a Spanish opportunistic screening scenario. METHODS: We analyzed archived samples from 492 men who underwent prostate Bx in an opportunistic screening scenario, with prostate-specific antigen (PSA) 3 to 10 ng/mL and/or suspicious digital rectal exploration (DRE) and without previous multi-parametric magnetic resonance imaging (mpMRI). Urinary biomarker measurements were combined with clinical risk factors to determine a risk score, and accuracy for GG ≥ 2 PCa detection was compared with PCA3, European randomized screening in prostate cancer (ERSPC), and prostate biopsy collaborative group (PBCG) risk calculators in a validation workup that included calibration, discrimination, and clinical utility analysis. RESULTS: In our cohort, the detection rates for GG1 and GG ≥ 2 PCa were 20.3% and 14.0%, respectively. The median PSA level was 3.9 ng/mL and 13.4% of subjects had suspicious DRE findings. The median risk score for men with GG ≥ 2 PCa was 21 (interquartile range: 14-28), significantly higher than benign+GG1 PCa (10, 6-18), P < .001, achieving the highest area under the curve among the models tested, 0.749 (95% confidence interval: 0.690-0.807). The urine test was well-calibrated, while ERSPC showed a slight underestimation and PBCG a slight overestimation of risk. Assuming a GG2 non-detection rate of 11% without using mpMRI, use of the urinary biomarker-based clinical model could have helped avoid 37.2% of excess biopsies while delaying the diagnosis of eight patients (1.6% of the entire cohort) with GG ≥ 2 PCa. CONCLUSIONS: In this first evaluation in an opportunistic screening population, the urinary biomarker-based test improved the detection of clinically significant PCa. Facing men with elevated PSA and/or suspicious DRE, it could be a useful tool to help avoid excess initial Bx and to identify patients most likely to benefit from Bx.


Assuntos
Neoplasias da Próstata/urina , RNA Mensageiro/urina , Idoso , Antígenos de Neoplasias/urina , Detecção Precoce de Câncer , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Ensaios Clínicos Controlados Aleatórios como Assunto , Reprodutibilidade dos Testes
18.
World J Urol ; 38(3): 547-554, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30993424

RESUMO

PURPOSE: A number of urine and blood-based biomarker tests have been described for prostate cancer, although to date there has only been a limited exploration of the methodology behind the validation studies that underpin these tests. METHODS: In this review, a selection of commercially available urine and blood-based biomarker tests for prostate cancer are described, and the underlying key validation studies for each test are critically appraised using the Standards for Reporting Diagnostic Accuracy (STARD) 2015 statement. RESULTS: The ExoDx Prostate Intelliscore, SelectMDx, Progensa PCA3, Mi-Prostate Score, 4K Score, and Prostate Health Index (PHI) tests were reviewed. Most of the validation studies supporting these tests perform exploratory analyses to determine cut-off values in a post hoc manner, comprise cohorts that are primarily Caucasian, report receiver operating characteristic curves that combine the biomarker's result with established clinical nomograms and are based on a reference standard (prostate biopsy) that lacks central pathology review. Deficiencies in STARD reporting guidelines include frequent failure to provide a published study protocol, prospective study registration in a registry, a flow diagram, justification for sample size determination, a discussion of adverse events with testing, and information on how missing or indeterminate test results should be managed. CONCLUSIONS: Key validation studies that support many commercially available urine and blood-based biomarkers for prostate cancers have deficiencies in transparency based on STARD reporting guidelines, and limitations in methodology must be considered when deciding when these tests should be applied in clinical practice.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias da Próstata/metabolismo , Antígenos de Neoplasias/urina , Área Sob a Curva , Biópsia , Exossomos , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/urina , Humanos , Calicreínas/sangue , Calicreínas/genética , Calicreínas/urina , Masculino , Gradação de Tumores , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/urina , Antígeno Prostático Específico/sangue , Antígeno Prostático Específico/genética , Antígeno Prostático Específico/urina , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/patologia , Precursores de Proteínas/sangue , RNA Mensageiro/genética , RNA Mensageiro/urina , Curva ROC , Reprodutibilidade dos Testes , Calicreínas Teciduais/sangue , Fatores de Transcrição/genética , Fatores de Transcrição/urina
19.
World J Urol ; 38(9): 2215-2220, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31691083

RESUMO

PURPOSE: To investigate the clinical performance of a new mRNA-based urine test, aiming to avoid unnecessary follow-up cystoscopy in patients under active surveillance (AS) for recurrent NMIBC. METHODS: This is a prospective cohort study enrolling patients with history of low-grade (LG) NMIBC, who developed a recurrence during the follow-up and underwent AS. Their urinary samples were analyzed by Xpert BC Monitor (Cepheid, Sunnyvale, CA, USA). The primary endpoint was to investigate if Xpert BC Monitor could avoid unnecessary cystoscopy during the follow-up period. Its sensitivity, specificity, PPVs and NPVs were calculated. A cutoff of 0.4 "linear discriminant analysis" (LDA) was optimized for the AS setting. RESULTS: The cohort consisted of 106 patients with a mean age of 72 ± 9.52 and a median follow-up from AS start of 8.8 (range 0-56.5) months. No statistically significant difference was found for the mean age, smoker status, lesion size, and number of lesions with a cutoff of 0.4. Of 106 patients, 22 (20.8%) were deemed to require treatment because of cystoscopic changes in size and/or number of lesions during the follow-up period. Using a cutoff value of < 0.4, 34 (33.7%) cystoscopies could be avoided due to low LDA value, missing 2/22 (9%) failures, none with high-grade (HG) NMIBC. Further research on larger population remains mandatory before its clinical use. CONCLUSION: Xpert BC Monitor seems to be a reliable assay, which might avoid unnecessary cystoscopies without missing HG NMIBC when its cutoff is optimized for the AS setting.


Assuntos
Recidiva Local de Neoplasia/urina , RNA Mensageiro/urina , Neoplasias da Bexiga Urinária/urina , Conduta Expectante , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Recidiva Local de Neoplasia/patologia , Estudos Prospectivos , Urinálise/métodos , Neoplasias da Bexiga Urinária/patologia
20.
Radiol Oncol ; 55(2): 196-202, 2020 12 29.
Artigo em Inglês | MEDLINE | ID: mdl-33764701

RESUMO

BACKGROUND: Cystoscopy in complement with urinary cytology represents the gold standard for the follow-up of patients with urinary bladder tumours. Xpert Bladder Cancer Monitor Test (XBC) is a novel mRNA-based urine test for bladder cancer surveillance. The aim of the study was to evaluate the performance of the XBC and voided urinary cytology (VUC) in the follow-up of bladder tumours. PATIENTS AND METHODS: The XBC was performed on stabilized voided urine and VUC was performed on urine samples. The results were compared to cystoscopic findings and histopathological results after transurethral resection of the bladder lesion. RESULTS: For the prediction of malignant histopathological result sensitivity, the specificity and negative predictive value were 76.9%, 9 7.5% and 93.0% for the XBC and 38.4%, 9 7.5% and 83.3%, respectively for VUC. For the prediction of suspicious or positive cystoscopic finding sensitivity, the specificity and negative predictive value were 75.0%, 95.2%, and 93.0% respectively for the XBC and 41.7%, 97.6%, and 85.4% for VUC. The sensitivities for papilary urothelial neoplasms of low malignant potential (PUNLMP), low- and high-grade tumours were 0.0%, 66.7% an d 100.0% for the XBC and 0.0%, 66 .7% and 42.9%, respectively for VUC. CONCLUSIONS: The XBC showed significantly higher overall sensitivity and negative predictive value than VUC and could be used to increase the recommended follow-up cystoscopy time intervals. Complementing the XBC and voided urinary cytology does not improve performance in comparison to the XBC alone.


Assuntos
Carcinoma/urina , Proteínas de Neoplasias/urina , RNA Mensageiro/urina , Neoplasias da Bexiga Urinária/urina , Anexinas/genética , Área Sob a Curva , Carcinoma/diagnóstico , Carcinoma/patologia , Carcinoma/cirurgia , Hormônio Liberador da Corticotropina/genética , Cistoscopia/estatística & dados numéricos , Feminino , Seguimentos , Humanos , Fator de Crescimento Insulin-Like II/genética , Masculino , Proteínas de Neoplasias/genética , Valor Preditivo dos Testes , Proteínas Proto-Oncogênicas c-abl/genética , Curva ROC , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sensibilidade e Especificidade , Neoplasias da Bexiga Urinária/diagnóstico , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/cirurgia , Urina/citologia , Uroplaquina Ib/genética
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