RESUMO
To construct a urine extracellular vesicle long non-coding RNA (lncRNA) classifier that can detect high-grade prostate cancer (PCa) of grade group 2 or greater and estimate the risk of progression during active surveillance, we identify high-grade PCa-specific lncRNAs by combined analyses of cohorts from TAHSY, TCGA, and the GEO database. We develop and validate a 3-lncRNA diagnostic model (Clnc, being made of AC015987.1, CTD-2589M5.4, RP11-363E6.3) that can detect high-grade PCa. Clnc shows higher accuracy than prostate cancer antigen 3 (PCA3), multiparametric magnetic resonance imaging (mpMRI), and two risk calculators (Prostate Cancer Prevention Trial [PCPT]-RC 2.0 and European Randomized Study of Screening for Prostate Cancer [ERSPC]-RC) in the training cohort (n = 350), two independent cohorts (n = 232; n = 251), and TCGA cohort (n = 499). In the prospective active surveillance cohort (n = 182), Clnc at diagnosis remains a powerful independent predictor for overall active surveillance progression. Thus, Clnc is a potential biomarker for high-grade PCa and can also serve as a biomarker for improved selection of candidates for active surveillance.
Assuntos
Neoplasias da Próstata , RNA Longo não Codificante , Masculino , Humanos , RNA Longo não Codificante/genética , Estudos Prospectivos , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Gradação de Tumores , BiomarcadoresRESUMO
BACKGROUND: We aimed to develop and validate a plasma extracellular vesicle circular RNA (circRNA)-based signature that can predict overall survival (OS) in first-line abiraterone therapy for metastatic castration-resistant prostate cancer (mCRPC) patients. METHODS: In total, 582 mCRPC patients undergoing first-line abiraterone therapy from four institutions were sorted by three phases. In the discovery phase, 30 plasma samples from 30 case-matched patients with or without early progression were obtained to generate circRNA expression profiles using RNA sequencing. In the training phase, differentially expressed circRNAs were examined using digital droplet PCR in a training cohort (n = 203). The circRNA signature was constructed using a least absolute shrinkage and selection operator Cox regression to predict OS. In the validation phase, the prognostic ability of this signature was prospectively validated in two external cohorts (Cohort I, n = 183; Cohort II, n = 166). RESULTS: We developed a five-circRNA signature, based on circCEP112, circFAM13A, circBRWD1, circVPS13C and circMACROD2, which successfully stratified patients into high-risk and low-risk groups. The prognostic ability of this signature was prospectively validated in two external cohorts (P < 0.0001, P < 0.0001). Patients with high-risk scores had shorter OS than patients with low-risk scores. CONCLUSION: This five-circRNA signature is a reliable predictor of OS for mCRPC patients undergoing abiraterone.
Assuntos
Neoplasias de Próstata Resistentes à Castração , RNA Circular , Masculino , Humanos , RNA Circular/genética , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Antígeno Prostático Específico , Resultado do Tratamento , Acetato de Abiraterona/efeitos adversosRESUMO
Circular RNAs (circRNAs) have been increasingly linked to cancer progression. However, the detailed biological functions of circRNAs in prostate cancer (PCa) remain unclear. Using high-throughput circRNA sequencing, we previously identified 18 urine extracellular vesicle circRNAs that were increased in patients with PCa compared with those with benign prostatic hyperplasia. Spearman correlation analysis of the expression levels of the 18 circRNAs between the tumor tissue and matched urine extracellular vesicles in 30 PCa patients showed that circSCAF8 had the highest R2 (R2 = 0.635, P < 0.001). The Cox proportional hazards regression model was used to estimate the effect of circSCAF8 on progression-free survival. The in vitro and in vivo functional experiments were implemented to investigate the effects of circSCAF8 on the phenotype of PCa. We found that the knockdown of circSCAF8 in PCa cells suppressed the proliferation, migration, and invasion ability, while overexpression of circSCAF8 had the opposite effects. Similar results were observed in vivo. In a cohort of 85 patients who had undergone radical prostatectomy, circSCAF8 expression in PCa tissues was a powerful predictor of progression-free survival (HR = 2.14, P = 0.022). Mechanistically, circSCAF8 can function by binding to both miR-140-3p and miR-335 to regulate LIF expression and activate the LIF-STAT3 pathway that leads to the growth and metastasis of PCa. Collectively, our findings demonstrate that circSCAF8 contributes to PCa progression through the circSCAF8-miR-140-3p/miR-335-LIF pathway.
Assuntos
MicroRNAs , Neoplasias da Próstata , Linhagem Celular Tumoral , Proliferação de Células/genética , Humanos , Masculino , MicroRNAs/genética , MicroRNAs/metabolismo , Neoplasias da Próstata/patologia , RNA Circular/genéticaRESUMO
To efficiently remove all recurrent lymph nodes (rLNs) and minimize complications, we developed a combination approach that consisted of 68Gallium prostate-specific membrane antigen (PSMA) ligand positron emission tomography (PET)/computed tomography (CT) and integrated indocyanine green (ICG)-guided salvage lymph node dissection (sLND) for rLNs after radical prostatectomy (RP). Nineteen patients were enrolled to receive such treatment. 68Ga-PSMA ligand PET/CT was used to identify rLNs, and 5 mg of ICG was injected into the space between the rectum and bladder before surgery. Fluorescent laparoscopy was used to perform sLND. While extensive LN dissection was performed at level I, another 5 mg of ICG was injected via the intravenous route to intensify the fluorescent signal, and laparoscopy was introduced to intensively target stained LNs along levels I and II, specifically around suspicious LNs, with 68Ga-PSMA ligand PET/CT. Next, both lateral peritonea were exposed longitudinally to facilitate the removal of fluorescently stained LNs at levels III and IV. In total, pathological analysis confirmed that 42 nodes were rLNs. Among 145 positive LNs stained with ICG, 24 suspicious LNs identified with 68Ga-PSMA ligand PET/CT were included. The sensitivity and specificity of 68Ga-PSMA ligand PET/CT for detecting rLNs were 42.9% and 96.6%, respectively. For ICG, the sensitivity was 92.8% and the specificity was 39.1%. At a median follow-up of 15 (interquartile range [IQR]: 6-31) months, 15 patients experienced complete biochemical remission (BR, prostate-specific antigen [PSA] <0.2 ng ml-1), and 4 patients had a decline in the PSA level, but it remained >0.2 ng ml-1. Therefore, 68Ga-PSMA ligand PET/CT integrating ICG-guided sLND provides efficient sLND with few complications for patients with rLNs after RP.
Assuntos
Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Neoplasias da Próstata , Isótopos de Gálio , Radioisótopos de Gálio , Humanos , Verde de Indocianina , Ligantes , Excisão de Linfonodo , Metástase Linfática/diagnóstico por imagem , Masculino , Recidiva Local de Neoplasia/cirurgia , Próstata , Prostatectomia , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/cirurgia , Terapia de SalvaçãoRESUMO
Recently, studies on competing endogenous RNA (ceRNA) networks have become prevalent, and circular RNAs (circRNAs) have crucial implications for the development and progression of carcinoma. However, studies relevant to metastatic prostate cancer (mPCa) are scant. This study aims to discover potential ceRNAs that may be related to the prognosis of mPCa. RNA-Seq data were obtained from the MiOncoCirc database and Gene Expression Omnibus (GEO). Differential expression patterns of RNAs were examined using R packages. Circular RNA Interactome, miRTarBase, miRDB and TargetScan were applied to predict the corresponding relation between circRNAs, miRNAs and mRNAs. The Gene Ontology (GO) annotations were performed to present related GO terms, and Gene Set Enrichment Analysis (GSEA) tools were applied for pathway annotations. Moreover, survival analysis was conducted for the hub genes. We found 820 circRNAs, 81 miRNAs and 179 mRNAs that were distinguishingly expressed between primary prostate cancer (PCa) and mPCa samples. A ceRNA network including 45 circRNAs, 24 miRNAs and 56 mRNAs was constructed. In addition, the protein-protein interaction (PPI) network was built, and 10 hub genes were selected by using the CytoHubba application. Among the 10 hub genes, survival analysis showed that ITGA1, LMOD1, MYH11, MYLK, SORBS1 and TGFBR3 were significantly connected with disease-free survival (DFS). The circRNA-mediated ceRNA network provides potential prognostic biomarkers for metastatic prostate cancer.
Assuntos
Biomarcadores Tumorais/genética , Redes Reguladoras de Genes , MicroRNAs/genética , Neoplasias da Próstata/patologia , Mapas de Interação de Proteínas , RNA Circular/genética , RNA Mensageiro/genética , Biologia Computacional , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Anotação de Sequência Molecular , Metástase Neoplásica , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismoRESUMO
The aim of this study was to identify a urine extracellular vesicle circular RNA (circRNA) classifier that could detect high-grade prostate cancer (PCa) of Grade Group (GG) 2 or greater. For this purpose, we used RNA sequencing to identify candidate circRNAs from urinary extracellular vesicles from 11 patients with high-grade PCa and 11 case-matched patients with benign prostatic hyperplasia. Using ddPCR in a training cohort (n = 263), we built a urine extracellular vesicle circRNA classifier (Ccirc, containing circPDLIM5, circSCAF8, circPLXDC2, circSCAMP1, and circCCNT2), which was evaluated in two independent cohorts (n = 497, n = 505). Ccirc showed higher accuracy than two standard of care risk calculators (RCs) (PCPT-RC 2.0 and ERSPC-RC) in both the training cohort and the validation cohorts. In all three cohorts, this novel urine extracellular vesicle circRNA classifier plus RCs was statistically more predictive than RCs alone for predicting ≥ GG2 PCa. This assay, which does not require precollection digital rectal examination nor special handling, is repeatable, noninvasive, and can be easily implemented as part of the basic clinical workflow.
Assuntos
Biomarcadores Tumorais , Ácidos Nucleicos Livres , Vesículas Extracelulares/metabolismo , Antígeno Prostático Específico/urina , Neoplasias da Próstata/genética , Neoplasias da Próstata/urina , RNA Circular/genética , Biópsia , Perfilação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Gradação de Tumores , Prognóstico , Neoplasias da Próstata/diagnóstico , RNA Circular/metabolismo , Curva ROC , Reprodutibilidade dos TestesRESUMO
BACKGROUND: Metastasis is the major cause of cancer-specific death in patients with prostate cancer (PCa). We previously reported that collapsing response mediator protein-4 (CRMP4) is a PCa metastasis-suppressor gene and the hypermethylation in CRMP4 promoter is responsible for the transcription repression in metastatic PCa. However, the underlying mechanisms remain unknown. In this study, we aimed to investigate the role of calpain-2 in CRMP4 promoter hypermethylation and its functional modulation in PCa metastasis. METHODS: Calpain-2 expression in PCa tissues (n = 87) and its specific mechanisms of functional modulation in CRMP4 expression via limited enzymatic cleavage was investigated. We then focused on the cooperative crosstalk of calpain-2 and NF-κB RelA/p65 in CRMP4 promoter methylation for the initiation of PCa metastasis. Statistical differences between groups were determined using a two-tailed Student's t-test. P < 0.05 indicated statistically significant. RESULTS: Calpain-2 was differentially upregulated in metastatic PCa compared with localized PCa. Moreover, calpain-2 cleaved CRMP4 into the N-terminally fragment which promoted migration and invasion in PCa cells via nuclear translocation and activation of E2F1-mediated DNA methyltransferase 1 (DNMT1) expression. NF-κB RelA/p65 recruited DNMT1 to bind to and methylate CRMP4 promoter in which Serine276 phosphorylation of p65 was essential. Furthermore, CRMP4 exhibited anti-metastatic function via inhibiting the expression of VEGFC through Semaphorin3B-Neuropilin2 signaling. CONCLUSION: Calpain-2 may contribute to the promoter methylation of CRMP4 to repress its transcription, leading to the metastasis of PCa via enhancing VEGFC expression.
Assuntos
Calpaína/biossíntese , DNA (Citosina-5-)-Metiltransferase 1/metabolismo , Proteínas Musculares/metabolismo , Metástase Neoplásica/fisiopatologia , Neoplasias da Próstata/metabolismo , Fator de Transcrição RelA/metabolismo , Idoso , Linhagem Celular Tumoral , Ilhas de CpG , DNA (Citosina-5-)-Metiltransferase 1/biossíntese , Metilação de DNA , Regulação Neoplásica da Expressão Gênica/fisiologia , Genes Supressores de Tumor/fisiologia , Humanos , Masculino , Glicoproteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Proteínas Musculares/biossíntese , Metástase Neoplásica/genética , Neuropilina-2/metabolismo , Fosforilação , Regiões Promotoras Genéticas/fisiologia , Hiperplasia Prostática/metabolismo , Neoplasias da Próstata/patologia , Neoplasias da Próstata/secundário , Neoplasias de Próstata Resistentes à Castração/metabolismo , Neoplasias de Próstata Resistentes à Castração/secundário , Receptor Cross-Talk/fisiologia , Estudos Retrospectivos , Semaforinas/metabolismo , Transdução de Sinais , Regulação para Cima , Fator C de Crescimento do Endotélio Vascular/biossínteseRESUMO
Background: For patients with prostate cancer (PCa), the presence of pelvic lymph node metastasis (LNM) is a strong predictor of poor outcome. However, the approaches with promising sensitivity and specificity to detect LNM are still lacking. We investigated the value of collapsin response mediator protein 4 (CRMP4) promoter methylation in biopsies as a predictor for LNM. Methods: CRMP4 promoter methylation at two previously identified CpG sites was determined in 80 case-matched biopsy samples (the training set) using bisulfite pyrosequencing. The predictive cutoff value was independently validated using cohort I of 339 PCa patients (Southern China) and cohort II of 328 case patients (Germany, across China). Mann-Whitney U test, the receiver operating characteristic curve, McNemar's test, and logistic regression were used to assess data. All statistical tests were two-sided. Results: In the training set, CRMP4 promoter methylation (≥15.0% methylated) was statistically significantly associated with LNM (P < 001). Successful validations were achieved in both cohorts I and II (sensitivity = 92.3%, 95% confidence interval [CI] = 79.3 to 97.9, and sensitivity = 92.2%, 95% CI = 81.1 to 97.8, respectively; specificity = 92.7%, 95% CI = 80.2 to 99.1, and specificity = 91.3%, 95% CI = 87.4 to 94.4, respectively). The sensitivity of CRMP4 promoter methylation is superior to conventional MRI (cohort I: 92.3% vs 26.2%, P < 001; cohort II: 92.2% vs 33.3%, P < 001). CRMP4 promoter methylation is an independent predictor of LNM (cohort I: hazard ratio [HR] = 8.35, 95% CI = 5.64 to 12.35, P < 001; cohort II: HR = 12.46, 95% CI = 5.82 to 26.70, P < 001) in a multivariable analysis model. Conclusion: CRMP4 promoter methylation in diagnostic biopsies could be a robust biomarker for LNM in PCa.
Assuntos
Metilação de DNA , Proteínas Musculares/genética , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Idoso , Área Sob a Curva , Biomarcadores Tumorais/genética , Biópsia , Estudos de Casos e Controles , Ilhas de CpG , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Proteínas Musculares/metabolismo , Valor Preditivo dos Testes , Regiões Promotoras Genéticas , Estudos Prospectivos , Próstata/patologia , Curva ROCRESUMO
Prostate cancer is the most commonly diagnosed non-cutaneous cancer and one of the leading causes of cancer death for North American men. Whereas localized prostate cancer can be cured, there is currently no cure for metastatic prostate cancer. Here we report a novel approach that utilizes designed chimeric transcription activator-like effectors (dTALEs) to control prostate cancer metastasis. Transfection of dTALEs of DNA methyltransferase or demethylase induced artificial, yet active locus-specific CpG and subsequent histone modifications. These manipulations markedly altered expression of endogenous CRMP4, a metastasis suppressor gene. Remarkably, locus-specific CpG demethylation of the CRMP4 promoter in metastatic PC3 cells abolished metastasis, whereas locus-specific CpG methylation of the promoter in non-metastatic 22Rv1 cells induced metastasis. CRMP4-mediated metastasis suppression was found to require activation of Akt/Rac1 signaling and down-regulation of MMP-9 expression. This proof-of-concept study with dTALEs for locus-specific epigenomic manipulation validates the selected CpG methylation of CRMP4 gene as an independent biomarker for diagnosis and prognosis of prostate cancer metastasis and opens up a novel avenue for mechanistic research on cancer biology.
Assuntos
Metilases de Modificação do DNA/genética , Proteínas Musculares/genética , Proteínas do Tecido Nervoso/genética , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/metabolismo , Animais , Células COS , Linhagem Celular Tumoral , Chlorocebus aethiops , Metilação de DNA , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Metástase Neoplásica , Prognóstico , Regiões Promotoras Genéticas , Neoplasias de Próstata Resistentes à Castração/patologia , TransfecçãoRESUMO
Metastasis is the main cause of death from muscle-invasive urothelial carcinoma of the bladder (UCB), and the metastatic potential of tumors is often unpredictable. The role of Dachshund homolog 2 gene (DACH2) in tumorigenesis remains unexplored. We aimed to investigate whether DACH2 can be used as a biomarker to predict metastasis and prognosis of muscle-invasive UCB in a sequential training and validation fashion. For the training set (n = 40), compared with UCB patients without lymph node (LN) metastasis, both DACH2 protein and mRNA expression were greatly increased in case-matched patients with LN metastasis. For the independent validation set (n = 243), patients with primary UCB that did not express DACH2 had a longer metastasis-free survival (MFS) and overall survival (OS) than did those with tumors expressing DACH2 (5-year MFS: 88% [95% CI 80-96] versus 19% [95% CI 7-31], p < 0.001; 5-year OS: 93% [95% CI 87-99] versus 37% [95% CI 23-51], p < 0.001). Multivariable analysis of DACH2 status showed hazard ratios of 7.34 (95% CI 3.15-11.87, p < 0.001) for MFS and 3.96 (95% CI 2.04-7.16, p < 0.001) for OS which were much higher than hazard ratios associated with other independent risk factors. Collectively, DACH2 is an independent prognostic marker that can be used at initial diagnosis of UCB to identify patients who have a high potential to develop metastasis.
Assuntos
Biomarcadores Tumorais/metabolismo , Proteínas Nucleares/metabolismo , Fatores de Transcrição/metabolismo , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/secundário , Adulto , Idoso , Biomarcadores Tumorais/genética , Proteínas de Ligação a DNA , Feminino , Humanos , Estimativa de Kaplan-Meier , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Músculos/patologia , Invasividade Neoplásica/patologia , Proteínas Nucleares/genética , Prognóstico , Estudos Prospectivos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Neoplásico/genética , RNA Neoplásico/metabolismo , Fatores de Risco , Fatores de Transcrição/genética , Neoplasias da Bexiga Urinária/genéticaRESUMO
The aim of this study was to compare the intraoperative difference in anatomic details between loupe-assisted and microscopic varicocelectomy within the same spermatic cord. Between April 2011 and August 2011, 26 men with 33 sides containing grade 2-3 varicocele were enrolled in this study. First, one surgeon performed the open inguinal varicocelectomy under × 3.5 loupe magnification. The presumed vascular channels and lymphatics were isolated and marked without ligation. Another surgeon then microsurgically dissected and checked the same spermatic cord using an operating microscope to judge the results in terms of the ligation of the internal spermatic veins and the preservation of the arteries and lymphatics. There were significant differences in the average number of internal spermatic arteries (1.51 vs 0.97), internal spermatic veins (5.70 vs 4.39) and lymphatics (3.52 vs 1.61) between the microscope and loupe-assisted procedures (P < 0.001, P < 0.001, P < 0.001, respectively). Meanwhile, in varicocele repair with loupe magnification, an average of 1.30 ± 1.07 (43/33) internal spermatic veins per side were missed, among the overlooked veins, 1.12 ± 0.93 (37/33) were adhered to the preserved testicular artery, as well as 0.55 ± 0.79 lymphatics and 0.36 ± 0.55 arteries that were to be ligated. In conclusion, microscopic varicocelectomy could preserve more internal spermatic arteries and lymphatics and could ligate more veins than the loupe-assisted procedure. To some degree, loupe magnification is inadequate for the reliable identification and dissection of the tiny vessels of the spermatic cord, as most of the overlooked veins were adhered to the preserved testicular artery.
Assuntos
Microcirurgia/métodos , Procedimentos Cirúrgicos Urogenitais/métodos , Varicocele/cirurgia , Humanos , Ligadura , Vasos Linfáticos/cirurgia , Masculino , Cordão Espermático/irrigação sanguínea , Instrumentos Cirúrgicos , Testículo/irrigação sanguínea , Procedimentos Cirúrgicos Urogenitais/instrumentação , Procedimentos Cirúrgicos VascularesRESUMO
OBJECTIVE: To report a novel technique for performing single-port transvesical laparoscopic radical prostatectomy (STLRP) and to evaluate the oncological and functional outcomes in 16 patients with organ-confined prostate cancer. PATIENTS AND METHODS: In total, 16 consecutive patients with clinical stage T1-2aN0M0 were scheduled for STLRP, and their continence and erectile status were investigated preoperatively. The patients' mean age was 62 years, mean prostate volume 42 mL and mean prostate-specific antigen (PSA) 7.5 ng/mL. The STLRP procedures were performed by a single surgeon, and all the operating procedures were conducted transvesically and laparoscopically. Intra-operative and postoperative complications, assessed according to the modified Clavien system, were recorded and peri-operative and functional outcome data were analysed. All patients were followed up for a minimum of 12 months postoperatively through PSA detection, daily pads, the International Index of Erectile Function (IIEF)-6 score and urography. RESULTS: All of the 16 STLRP procedures were successfully completed. The mean (range) operation duration was 105 (75-180) min, and the mean (range) estimated blood loss was 130 (75-500) mL. No patients had positive surgical margins. Postoperative complications occurred in five patients, including three cases of urinary infection and two cases of haematuria (grade II). Catheters were removed after a mean (range) time of 11.2 (9-14) days with cystography. The mean (range) hospital stay was 12.7 (10-15) days. Of the 16 patients, 13 were immediately continent (0 pads/day), and three had mild incontinence (2-3 pads/day) after catheter removal. All patients were observed as continent 3 months postoperatively. In total, 10/16 and 12/16 patients achieved a satisfactory erection at 6 and 12 months follow-up postoperatively, respectively, with an IIEF-6 score ≥ 18. The mean postoperative PSA levels at 3, 6 and 12 months were 0.015 ng/mL, 0.017 ng/mL and 0.016 ng/mL, respectively. No patients were identified with biochemical recurrence in this series. No patients demonstrated vesico-urethral stricture during follow-up for 12-24 months. CONCLUSIONS: We conclude that STLRP is technically feasible for patients with low-risk organ-confined prostate cancer and demonstrates promising functional outcomes regarding continence and potency.
Assuntos
Laparoscopia/métodos , Prostatectomia/métodos , Neoplasias da Próstata/cirurgia , Idoso , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Antígeno Prostático Específico , Neoplasias da Próstata/patologia , Resultado do TratamentoRESUMO
PURPOSE: We aimed to analyze whether ERG rearrangement in biopsies could be used to assess subsequent cancer diagnosis in high-grade prostatic intraepithelial neoplasia (HGPIN) and the risk of lymph node metastasis in early prostate cancer. EXPERIMENTAL DESIGN: Samples from 523 patients (361 with early prostate cancer and 162 with HGPIN) were collected prospectively. On the basis of the cutoff value established previously, the 162 patients with HGPIN were stratified to two groups: one with an ERG rearrangements rate ≥1.6% (n = 59) and the other with an ERG rearrangements rate <1.6% (n = 103). For the 361 prostate cancer cases undergoing radical prostatectomy, 143 had pelvic lymph node dissection (node-positive, n = 56 and node-negative, n = 87). All ERG rearrangement FISH data were validated with ERG immunohistochemistry. RESULTS: A total of 56 (of 59, 94.9%) HGPIN cases with an ERG rearrangements rate ≥1.6% and 5 (of 103, 4.9%) HGPIN cases with an ERG rearrangements rate <1.6% were diagnosed with prostate cancer during repeat biopsy follow-ups (P < 0.001). There were significant differences in ERG rearrangement rates between lymph node-positive and -negative prostate cancer (P < 0.001). The optimal cutoff value to predict lymph node metastasis by ERG rearrangement was established, being 2.6% with a sensitivity at 80.4% [95% confidence interval (CI), 67.6-89.8] and a specificity at 85.1% (95% CI, 75.8-91.8). ERG protein expression by immunohistochemistry was highly concordant with ERG rearrangement by FISH. CONCLUSIONS: The presence of ERG rearrangement in HGPIN lesions detected on initial biopsy warrants repeat biopsies and measuring ERG rearrangement could be used for assessing the risk of lymph node metastasis in early prostate cancer.
Assuntos
Rearranjo Gênico , Neoplasia Prostática Intraepitelial/genética , Neoplasias da Próstata/genética , Transativadores/genética , Idoso , Idoso de 80 Anos ou mais , Biópsia , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Prognóstico , Prostatectomia/métodos , Neoplasia Prostática Intraepitelial/diagnóstico , Neoplasia Prostática Intraepitelial/patologia , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/patologia , Medição de Risco , Fatores de Risco , Sensibilidade e Especificidade , Transativadores/metabolismo , Regulador Transcricional ERGRESUMO
OBJECTIVE: To investigate the expressions of CD4+ CD25(high) regulatory T cells, TGF-beta 1 and COX-2 in the peripheral blood of prostate cancer (PCa) patients, and analyze the role of CD4+ CD25(high) regulatory T cells in the pathogenesis of PCa and their relationship with TGF-beta 1 and COX-2. METHODS: We used flow cytometry to calculate the percentage of CD4+ CD25(high) regulatory T cells in the CD4+ T cells in the peripheral blood mononuclear cells (PBMC) from 30 PCa patients (11 localized and 19 non-localized cases) and 20 healthy volunteer controls, determined the expressions of TGF-beta 1 and COX-2 in the serum by ELISA, and analyzed their correlation with the CD4+ CD25(high) regulatory T cells in the PCa patients as well as the differences between the localized and non- localized cases. RESULTS: CD4+ CD25(high) regulatory T cells accounted for (18.32 +/- 7.49) % in the CD4+ T cells in PBMCs from the PCa patients, significantly higher than (7.77 +/- 1.86) % from the controls (P < 0.05), but with no statistically significant difference between pre- and post-treatment in the PCa patients (P > 0.05). The expressions of TGF-beta 1 and COX-2 in the peripheral blood were (215.97 +/- 55.16) ng/ml and (6.88 +/- 5.14) ng/ml in the PCa patients, in comparison with (149.75 +/- 47.11) ng/ml (P < 0.05) and (6.88 +/- 5.14) ng/ml (P > 0.05) in the controls. Multiple linear regression analysis showed no significant correlation between the expression of CD4+ CD25(high) regulatory T cells in PBMCs and those of TGF-beta 1 and COX-2 in the peripheral blood of the PCa patients. There were no significant differences between the localized and non-localized PCa groups in the expressions of CD4+ CD25(high) regulatory T cells, TGF-beta 1 and COX-2 (P > 0.05). CONCLUSION: CD4+ CD25(high) regulatory T cells in in PBMCs are involved in the pathogenesis of PCa. The proliferation of CD4+ CD25(high) regulatory T cells is not significantly correlated to the expressions of TGF-beta 1 and COX-2 in the peripheral blood, but maybe to the tumor itself and the local tumor microenvironment.
Assuntos
Ciclo-Oxigenase 2/sangue , Neoplasias da Próstata/sangue , Linfócitos T Reguladores/metabolismo , Fator de Crescimento Transformador beta1/sangue , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Citometria de Fluxo , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Fusion of the prostate-specific and androgen-regulated transmembrane-serine protease gene (TMPRSS2) with the erythroblast transformation-specific (ETS) family members is the most common genetic alteration in prostate cancer. However, the biological and clinical role of TMPRSS2-ETS fusions in prostate cancer, especially in problematic prostate needle core biopsies, has not been rigorously evaluated. We randomly collected 85 specimens including 50 archival prostate cancer tissue blocks, 15 normal prostate specimens, and 20 benign prostatic hyperplasia specimens for TMPRSS2-ETS fusion analyses. Moreover, the fusion status in an additional 20 patients with initial negative biopsies who progressed to biopsy-positive prostate cancer at subsequent follow-ups was also characterized. Fluorescently labeled probes specific for ERG-related rearrangements involving the TMPRSS2-ERG fusion as well as TMPRSS2-ETV1 and TMPRSS2-ETV4 were used to assess samples for gene rearrangements indicative of malignancy under a design of sequential trial. Rearrangements involving TMPRSS2-ETS fusions were detected in 90.0% of the 50 postoperative prostate cancer samples. The positive rate for the rearrangements in the initial prostate cancer-negative biopsies of 20 patients who eventually progressed to prostate cancer was 60.0% (12/20). Our preliminary study demonstrates that the clinical utility of TMPRSS2-ETS fusion detection as a biomarker and ancillary diagnostic tool for the early diagnosis of prostate cancer is promising, given this approach shows significant high sensitivity and specificity in detection.
Assuntos
Hibridização in Situ Fluorescente/métodos , Neoplasias da Próstata/diagnóstico , Proteínas Proto-Oncogênicas c-ets/genética , Serina Endopeptidases/genética , Idoso , Idoso de 80 Anos ou mais , Biópsia por Agulha , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologiaRESUMO
INTRODUCTION: Erectile dysfunction (ED) represents a common quality-of-life issue of any treatment used for prostate cancer, including high-intensity focused ultrasound (HIFU) and targeted cryoablation of the prostate (TCAP). There is a paucity of comparative studies regarding the difference in the erectile function and penile size of patients undergoing HIFU or TCAP. AIM: The aim of this study is to compare the erectile function and penile size of patients undergoing HIFU or TCAP. METHODS: Patients with a preoperative erectile function domain of the International Index of Erectile Function (IIEF-EF) score ≥ 26 were prospectively included. All patients were preoperatively evaluated by IIEF-EF and penile color Doppler ultrasound. Penile length and circumference were measured in flaccidity and at maximum erection. At 6, 12, 18, 24, 36 months after surgery, patients were assessed with the same protocol. MAIN OUTCOME MEASURES: IIEF-EF score, penile color Doppler ultrasound, penile length, and circumference at different time points. RESULTS: There were 55 patients in the HIFU group and 47 in the TCAP group. At each time point, there were significant differences in mean IIEF-EF scores and penile color Doppler results between the two groups. At 36 months, TCAP patients experienced lower erectile function recovery rate compared with HIFU patients (TCAP=46.8%; HIFU=65.5%; P=0.021). No significant decreases in penile length and circumference were found in the two groups (all P values ≥ 0.05). CONCLUSIONS: Our data demonstrate TCAP caused significantly decreased erectile function than HIFU. We found no change in penile size after HIFU or TCAP. The option of HIFU may be more attractive to the patient who wants to avoid ED afterward, to maintain their quality of life.
Assuntos
Criocirurgia , Ablação por Ultrassom Focalizado de Alta Intensidade , Ereção Peniana , Pênis/anatomia & histologia , Pênis/diagnóstico por imagem , Neoplasias da Próstata/terapia , Velocidade do Fluxo Sanguíneo , Humanos , Masculino , Pessoa de Meia-Idade , Pênis/irrigação sanguínea , Projetos Piloto , Estudos Prospectivos , Ultrassonografia Doppler em Cores , Ultrassonografia Doppler DuplaRESUMO
Current predictive tools and imaging modalities are not accurate enough for preoperative diagnosis of lymph node metastatic prostate cancer (LNM PCa). Proteomic analysis is introduced to screen potential biomarkers for early detection of LNM PCa. In our initial study, protein samples from localized and LNM PCa as well as benign prostatic hyperplasia tissues were analyzed using two-dimensional fluorescence difference in gel electrophoresis (2-D DIGE) coupled with MALDI-TOF/TOF MS. We identified 58 proteins that were differentially expressed in the LNM PCa group relative to the localized PCa group. Six of these proteins, e-FABP5, MCCC2, PPA2, Ezrin, SLP2, and SM22, are functionally relevant to cancer metastasis. Expression of these proteins was therefore further validated in tissue samples from the original cohort and also from a larger, independent cohort of patients using real time PCR, Western blotting, and immunohistochemistry staining. In addition, the serum levels of e-FABP5 were also examined by ELISA. Relative to localized PCa tissues, LNM PCa tissues had increased expression of e-FABP5, MCCC2, PPA2, Ezrin, and SLP2 and decreased expression of SM22. Patients with LNM PCa had significantly higher levels of serum e-FABP5. This study presents evidence that increased expression of e-FABP5, MCCC2, PPA2, Ezrin, and SLP2 and decreased expression of SM22 are useful diagnostic markers for the existence of LNM PCa.
Assuntos
Biomarcadores Tumorais/metabolismo , Eletroforese em Gel Bidimensional/métodos , Proteínas de Neoplasias/metabolismo , Neoplasias da Próstata/metabolismo , Proteômica/métodos , Idoso , Análise de Variância , Western Blotting , Proteínas de Ligação a Ácido Graxo/sangue , Humanos , Imuno-Histoquímica , Linfonodos/metabolismo , Linfonodos/patologia , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Hiperplasia Prostática/metabolismo , Neoplasias da Próstata/patologia , Reprodutibilidade dos Testes , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Espectrometria de Massas em TandemRESUMO
OBJECTIVES: To determine the systemic response to percutaneous nephrolithotomy (PCNL) and mini-PCNL (MPCNL) and evaluate whether MPCNL is less invasive than PCNL, as experimental studies suggest that the acute-phase reaction is proportional to surgery-induced tissue damage. METHODS: In all, 165 consecutive patients who had undergone MPCNL (93) or PCNL (72) were prospectively assessed. Blood samples were collected 24 hours before; during surgery; at the end of anesthesia; and 12, 24, and 36 hours after surgery. The extent of the systemic response to surgery-induced tissue trauma was measured, by assessing the levels of acute-phase markers tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), IL-10, C-reactive protein (CRP), and serum amyloid A (SAA), at all sampling times in all patients. RESULTS: No significant differences were observed between the 2 groups in preoperative variables. Baseline levels of TNF-alpha, IL-6, IL-10, CRP, and SAA were comparable in both groups. An increase was noted in TNF-alpha, IL-6, CRP, and SAA after surgery but no significant differences were assessed between MPCNL and PCNL during the entire period. IL-10 did not change at the different sampling times. CONCLUSIONS: Our data fail to demonstrate significant advantages of MPCNL in terms of reduced surgical trauma and associated invasiveness compared with standard PCNL based on the variables objectively measured in this study.
Assuntos
Cálculos Renais/cirurgia , Nefrostomia Percutânea/métodos , Adulto , Idoso , Proteína C-Reativa/análise , Feminino , Humanos , Interleucina-6/sangue , Cálculos Renais/sangue , Masculino , Pessoa de Meia-Idade , Nefrostomia Percutânea/efeitos adversos , Estudos Prospectivos , Proteína Amiloide A Sérica/análise , Fator de Necrose Tumoral alfa/sangue , Adulto JovemRESUMO
In this study we evaluate the oncological and functional results of the largest cohort of patients in China treated by laparoscopic radical prostatectomy (LRP) and with at least 3 years of follow-up. 126 inconsecutive patients (range 56-78 years, median 62.5) who had an LRP were retrospectively analyzed. The mean prostate specific antigen level and Gleason score was 13.4 ng mL(-1) and 6.4, respectively. Twenty-seven patients had unilateral or bilateral nerve preservation and 29 had pelvic lymphadenectomy. Multivariate analysis was used to adjust for differences in clinical and pathological features when comparing the risk for biochemical progression-free survival (bPFS). Urinary continence was assessed by incontinence questionnaire and erectile function by the Sexual Health Inventory for Men score. The mean operative duration was 250 min and blood loss 354 mL. Five patients received blood transfusion and nine had complications, including rectal injury (two), ureteral injury (one), active bleeding (one), bladder neck stenosis (two), paralytic ileus (one), subcutaneous hematoma (one) and port-site hernia (one). The overall positive surgical margin rate was 20.6% and correlated with pathological stage and Gleason score respectively (P = 0.03, P < 0.001 respectively). All patients had >or= 3 years of follow-up (range 3-6.75 years, mean 4.6, median 4.75). At 3 years of follow-up, the overall survival rate was 100% and the bPFS was 81.0% in all patients; 124 patients (98.4%) were continent; 22 of 27 patients (81.5%) who underwent nerve preservation retained erectile function. Our series confirms that LRP is an effective, safe and precise technique at Chinese institution.