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1.
Anticancer Res ; 41(9): 4395-4400, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34475059

RESUMO

BACKGROUND/AIM: The aim of this study was to evaluate the cancer detection rate (CDR) using magnetic resonance imaging-transrectal ultrasound (MRI-TRUS) fusion-guided transperineal targeted biopsy (TB). PATIENTS AND METHODS: We included 401 consecutive patients, of which 161 were biopsy-naïve. All underwent prebiopsy bi-parametric MRI; patients with positive MRI [prostate imaging reporting and data system (PI-RADS≥3)] underwent TB. Biopsy-naïve patients with positive MRI underwent TB and systematic biopsies (SBs). MRI-negative patients underwent SBs. Clinically significant prostate cancer (csPCa) was defined as ISUP ≥2. The added value of SB was defined as an upgrade from a negative biopsy or ISUP of 1 in TB to csPCa in SB. RESULTS: The median (interquartile range) age was 69 (range=63-74) years, and PSA was 6.9 (range=4.5-11) ng/ml. The overall CDR was 65%, with csPCa occurring in 48%. In cases of PI-RADS 5, CDR was 91%, and csPCa was 77%. The added value of SB was 2%. CONCLUSION: Transperineal TB biopsies using MRI-TRUS fusion yield a high CDR.


Assuntos
Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico/métodos , Imageamento por Ressonância Magnética Multiparamétrica/métodos , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/patologia , Idoso , Humanos , Masculino , Pessoa de Meia-Idade , Imagem Multimodal , Estudos Prospectivos , Antígeno Prostático Específico/metabolismo , Neoplasias da Próstata/metabolismo , Sensibilidade e Especificidade
2.
Anticancer Res ; 41(9): 4443-4446, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34475067

RESUMO

BACKGROUND: Androgen deprivation therapy (ADT) is one of the most effective treatments for advanced prostate cancer (PCa). However, it has been reported that the use of ADT is significantly associated with an increased risk of acute kidney injury (AKI) among patients with newly diagnosed non-metastatic PCa. We investigated changes in renal function that occurred in Japanese patients with PCa after ADT was discontinued. PATIENTS AND METHODS: Among 121 patients who underwent prostate biopsies, were pathologically diagnosed with PCa, and received ADT for ≥6 months at our Institution between 2009 and 2014, 60 patients who underwent radiotherapy for stage B or C PCa were eligible for inclusion in this retrospective study. Renal function was assessed using the estimated glomerular filtration rate (eGFR) before treatment and at 1, 3, 6, 9, and 12 months after the initiation of ADT and the rate of change in the eGFR (ΔeGFR) during ADT and after the discontinuation of ADT was investigated. We divided patients into two groups: Group 1 received ADT for 6 months, and group 2 received ADT for 12 months. Age; ΔeGFR; prostate-specific antigen, testosterone and hemoglobin levels; clinical stage; Gleason score; comorbidities; body mass index; heart rate; and the cardiothoracic ratio were analyzed. RESULTS: A total of 60 patients (group 1: n=23, group 2: n=37) were analyzed. The Gleason score of group 2 was higher than that of group 1 (p=0.0011). Regarding clinical stage, group 1 had more patients with stage B disease, and group 2 had more with stage C (p<0.0001). The eGFR decreased with the duration of ADT treatment. At 12 months, renal function had started to recover in group 1, while it had continued to decrease in group 2. CONCLUSION: Discontinuation of ADT tended to result in improvements in renal function. Furthermore, this study indicated that renal dysfunction caused by 6 months of ADT is transient. Normalization of the serum testosterone level seen after the discontinuation of ADT may be associated with improvements in renal function. Thus, intermittent ADT may be a useful treatment for PCa, as it would help to preserve renal function.


Assuntos
Antagonistas de Androgênios/efeitos adversos , Taxa de Filtração Glomerular/efeitos dos fármacos , Rim/fisiopatologia , Neoplasias da Próstata/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Antagonistas de Androgênios/uso terapêutico , Humanos , Japão , Rim/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/sangue , Neoplasias da Próstata/patologia , Estudos Retrospectivos , Testosterona/sangue , Fatores de Tempo , Suspensão de Tratamento
3.
Acta Biomed ; 92(4): e2021214, 2021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-34487080

RESUMO

The use of multiparametric prostate magnetic resonance imaging (mpMRI) is recommended, in the European Association of Urology (EAU) guidelines, for local staging of patients with prostate cancer (PCa). Systemic staging is recommended only for patients with unfavourable intermediate and high-risk disease; with bone and lymph node assessments usually being performed using bone scan (BS) and computed tomography (CT), respectively. Magnetic resonance imaging (MRI) is the imaging technique with the highest sensitivity for the detection of bone metastases and has shown promising results also for lymph node assessments. In this report we illustrate how MRI provided a comprehensive assessment of local disease as well as bone and lymph node metastases in a patient with PCa. (www.actabiomedica.it).


Assuntos
Neoplasias da Próstata , Humanos , Linfonodos/diagnóstico por imagem , Linfonodos/patologia , Metástase Linfática/diagnóstico por imagem , Imageamento por Ressonância Magnética , Masculino , Estadiamento de Neoplasias , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/patologia
4.
Medicine (Baltimore) ; 100(36): e27094, 2021 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-34516499

RESUMO

ABSTRACT: Epigenetic changes are implicated in prostate cancer (PCa) progression and resistance to therapy. Arginine residue methylation is an understudied histone post-translational modification that is increasingly associated with cancer progression and is catalyzed by enzymes called protein arginine methyltransferases (PRMTs). The molecular consequences of aberrant expression of PRMTs in PCa and the relationship between PRMTs and PCa progression are largely unknown. Using immunohistochemistry, we examined the expression of PRMT1 and CARM1, two of the best-studied PRMTs, in 288 patients across the spectrum of PCa and correlated them with markers of androgen receptor (AR) signaling, and milestones of carcinogenesis. Our findings indicate that PRMT1 and CARM1 are upregulated early in PCa progression, and that CARM1 is further upregulated after therapy. In addition, a correlation of CARM1 with AR post-translational modifications was noted in the setting of therapy resistance, highlighting CARM1 as one of the adaptation mechanisms of PCa cells in an androgen-depleted environment. Finally, CARM1 correlated with markers of cell cycle regulation, and both CARM1 and PRMT1 correlated with markers of epithelial-to-mesenchymal transition signaling. Taken together these findings indicate that an epigenetic network drives PCa progression through enhancement of milestone pathways including AR signaling, the cell cycle, and epithelial-to-mesenchymal transition.


Assuntos
Neoplasias da Próstata/metabolismo , Proteína-Arginina N-Metiltransferases/metabolismo , Adulto , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Metástase Neoplásica , Neoplasias da Próstata/patologia , Regulação para Cima
5.
Int J Mol Sci ; 22(16)2021 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-34445612

RESUMO

Prostate cancer is a common cause of death worldwide. Here, we isolated cancer stem cells (CSCs) from four adenocarcinomas of the prostate (Gleason scores from 3 + 3 up to 4 + 5). CSCs were characterized by the expression of the stem cell markers TWIST, the epithelial cell adhesion molecule (EPCAM), the transcription factors SNAI1 (SNAIL) and SNAI2 (SLUG) and cancer markers such as CD44 and prominin-1 (CD133). All investigated CSC populations contained a fraction highly positive for aldehyde dehydrogenase (ALDH) function and displayed robust expressions of programmed cell death 1 (PD-1) ligands. Furthermore, we investigated immunotherapeutic approaches but had no success even with the clinically used PD-1 inhibitor pembrolizumab. In addition, we studied another death-inducing pathway via interferon gamma signaling and detected high-level upregulations of human leukocyte antigen A (HLA-A) and beta 2-microglobulin (B2M) with only moderate killing efficacy. To examine further killing mechanisms in prostate cancer stem cells (PCSCs), we analyzed NF-κB signaling. Surprisingly, two patient-specific populations of PCSCs were found: one with canonical NF-κB signaling and another one with blunted NF-κB activation, which can be efficiently killed by tumor necrosis factor (TNF). Thus, culturing of PCSCs and analysis of respective NF-κB induction potency after surgery might be a powerful tool for optimizing patient-specific treatment options, such as the use of TNF-inducing chemotherapeutics and/or NF-κB inhibitors.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células Matadoras Naturais/patologia , NF-kappa B/metabolismo , Células-Tronco Neoplásicas/patologia , Neoplasias da Próstata/patologia , Fator de Necrose Tumoral alfa/farmacologia , Antineoplásicos Imunológicos/farmacologia , Apoptose , Proliferação de Células , Humanos , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/metabolismo , Masculino , NF-kappa B/genética , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Células Tumorais Cultivadas
6.
Lancet Oncol ; 22(9): 1240-1249, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34391509

RESUMO

BACKGROUND: Screening for prostate cancer using prostate-specific antigen (PSA) reduces prostate cancer mortality but can lead to adverse outcomes. We aimed to compare a traditional screening approach with a diagnostic strategy of blood-based risk prediction combined with MRI-targeted biopsies. METHODS: We did a prospective, population-based, randomised, open-label, non-inferiority trial (STHLM3-MRI) in Stockholm county, Sweden. Men aged 50-74 years were randomly selected by Statistics Sweden and invited by mail to participate in screening; those with an elevated risk of prostate cancer, defined as either a PSA of 3 ng/mL or higher or a Stockholm3 score of 0·11 or higher were eligible for randomisation. Men with a previous prostate cancer diagnosis, who had undergone a prostate biopsy within 60 days before the invitation to participate, with a contraindication for MRI, or with severe illness were excluded. Eligible participants were randomly assigned (2:3) using computer-generated blocks of five, stratified by clinically significant prostate cancer risk, to receive either systematic prostate biopsies (standard group) or biparametric MRI followed by MRI-targeted and systematic biopsy in MRI-positive participants (experimental group). The primary outcome was the detection of clinically significant prostate cancer at prostate biopsy, defined as a Gleason score of 3 + 4 or higher. We used a margin of 0·78 to assess non-inferiority for the primary outcome. Key secondary outcome measures included the proportion of men with clinically insignificant prostate cancer (defined as a Gleason score of 3 + 3), and the number of any prostate MRI and biopsy procedures done. We did two comparisons: Stockholm3 (using scores of 0·11 and 0·15 as cutoffs) versus PSA in the experimental group (paired analyses) and PSA plus standard biopsy versus Stockholm3 plus MRI-targeted and systematic biopsy (unpaired, randomised analyses). All analyses were intention to treat. This study is registered with ClinicalTrials.gov, NCT03377881. FINDINGS: Between Feb 5, 2018, and March 4, 2020, 49 118 men were invited to participate, of whom 12 750 were enrolled and provided blood specimens, and 2293 with elevated risk were randomly assigned to the experimental group (n=1372) or the standard group (n=921). The area under the receiver-operating characteristic curve for detection of clinically significant prostate cancer was 0·76 (95% CI 0·72-0·80) for Stockholm3 and 0·60 (0·54-0·65) for PSA. In the experimental group, a Stockholm3 of 0·11 or higher was non-inferior to a PSA of 3 ng/mL or higher for detection of clinically significant prostate cancer (227 vs 192; relative proportion [RP] 1·18 [95% CI 1·09-1·28], p<0·0001 for non-inferiority), and also detected a similar number of low-grade prostate cancers (50 vs 41; 1·22 [0·96-1·55], p=0·053 for superiority) and was associated with more MRIs and biopsies. Compared with PSA of 3 ng/mL or higher, a Stockholm3 of 0·15 or higher provided identical sensitivity to detect clinically significant cancer, and led to fewer MRI procedures (545 vs 846; 0·64 [0·55-0·82]) and fewer biopsy procedures (311 vs 338; 0·92 (0·86-1·03). Compared with screening using PSA and systematic biopsies, a Stockholm3 of 0·11 or higher combined with MRI-targeted and systematic biopsies was associated with higher detection of clinically significant cancers (227 [3·0%] men tested vs 106 [2·1%] men tested; RP 1·44 [95% CI 1·15-1·81]), lower detection of low-grade cancers (50 [0·7%] vs 73 [1·4%]; 0·46 [0·32-0·66]), and led to fewer biopsy procedures. Patients randomly assigned to the experimental group had a lower incidence of prescription of antibiotics for infection (25 [1·8%] of 1372 vs 41 [4·4%] of 921; p=0·0002) and a lower incidence of admission to hospital (16 [1·2%] vs 31 [3·4%]; p=0·0003) than those in the standard group. INTERPRETATION: The Stockholm3 test can inform risk stratification before MRI and targeted biopsies in prostate cancer screening. Combining the Stockholm3 test with an MRI-targeted biopsy approach for prostate cancer screening decreases overdetection while maintaining the ability to detect clinically significant cancer. FUNDING: The Swedish Cancer Society, the Swedish Research Council, and Stockholm City Council.


Assuntos
Detecção Precoce de Câncer/métodos , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/patologia , Idoso , Biomarcadores Tumorais/sangue , Humanos , Biópsia Guiada por Imagem , Análise de Intenção de Tratamento , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estudos Prospectivos , Próstata/diagnóstico por imagem , Próstata/patologia , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/sangue , Curva ROC , Distribuição Aleatória , Medição de Risco , Suécia/epidemiologia
7.
Nat Commun ; 12(1): 5066, 2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34417456

RESUMO

Prostate cancer (PCa) shows strong dependence on the androgen receptor (AR) pathway. Here, we show that squalene epoxidase (SQLE), an enzyme of the cholesterol biosynthesis pathway, is overexpressed in advanced PCa and its expression correlates with poor survival. SQLE expression is controlled by micro-RNA 205 (miR-205), which is significantly downregulated in advanced PCa. Restoration of miR-205 expression or competitive inhibition of SQLE led to inhibition of de novo cholesterol biosynthesis. Furthermore, SQLE was essential for proliferation of AR-positive PCa cell lines, including abiraterone or enzalutamide resistant derivatives, and blocked transactivation of the AR pathway. Inhibition of SQLE with the FDA approved antifungal drug terbinafine also efficiently blocked orthotopic tumour growth in mice. Finally, terbinafine reduced levels of prostate specific antigen (PSA) in three out of four late-stage PCa patients. These results highlight SQLE as a therapeutic target for the treatment of advanced PCa.


Assuntos
Colesterol/biossíntese , Regulação para Baixo/genética , Regulação Neoplásica da Expressão Gênica , MicroRNAs/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Esqualeno Mono-Oxigenase/antagonistas & inibidores , Idoso , Idoso de 80 Anos ou mais , Animais , Sequência de Bases , Linhagem Celular Tumoral , Proliferação de Células/genética , Sobrevivência Celular , Estudos de Coortes , Simulação por Computador , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Masculino , Camundongos , Camundongos SCID , MicroRNAs/genética , Pessoa de Meia-Idade , Invasividade Neoplásica , Metástase Neoplásica , Estadiamento de Neoplasias , Antígeno Prostático Específico/metabolismo , Neoplasias da Próstata/patologia , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/patologia , Receptores Androgênicos/metabolismo , Esqualeno Mono-Oxigenase/genética , Esqualeno Mono-Oxigenase/metabolismo , Terbinafina/farmacologia , Ativação Transcricional/genética
8.
Radiol Clin North Am ; 59(5): 801-811, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34392920

RESUMO

The role of PET imaging with 11C-choline and 18F-fluciclovine in evaluating patients with prostate cancer (PCa) has become more important over the years and has been incorporated into the NCCN guidelines. A new generation of PET radiotracers targeting the prostate-specific membrane antigen (PSMA) is widely used outside the United States to evaluate patients with primary PCa and PCa recurrence. PET imaging influences treatment planning and demonstrates a significantly higher disease detection rate than conventional imaging such as computed tomography and MR imaging. Early data indicate that using PET radiotracers such as 18F-fluciclovine and PSMA improves patient outcomes. 68-Ga-PSMA-11 and 18F-DCFPyL-PET/CT were recently approved by the US Food & Drug Administration (FDA) for clinical use. Other PSMA radiotracers, including fluorinated variants, will likely gain FDA approval in the not-too-distant future.


Assuntos
Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/tendências , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/patologia , Ácidos Carboxílicos , Ciclobutanos , Humanos , Masculino , Recidiva Local de Neoplasia/diagnóstico por imagem , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Antígeno Prostático Específico , Compostos Radiofarmacêuticos
9.
Radiologe ; 61(9): 818-824, 2021 Sep.
Artigo em Alemão | MEDLINE | ID: mdl-34351430

RESUMO

CLINICAL/METHODOLOGICAL ISSUE: Prostate cancer is the most common malignancy and the second leading cause of cancer-related death in men. Accurate imaging diagnosis and staging are crucial for patient management and treatment. The role of nuclear medicine in the diagnosis of prostate cancer has evolved rapidly in recent years due to the availability of hybrid imaging with radiopharmaceuticals targeting the prostate-specific membrane antigen (PSMA). STANDARD RADIOLOGICAL PROCEDURES: Hybrid imaging provides higher diagnostic accuracy compared to conventional imaging and has a significant impact on clinical management. Numerous radiotracers have been used in clinical applications, with PSMA ligands being the most commonly used. METHODOLOGICAL INNOVATIONS: Hybrid imaging provides higher diagnostic accuracy for lymph node and bone metastases compared to conventional imaging and has a significant impact on clinical management. PERFORMANCE: The high accuracy for primary staging in high-risk prostate cancer using PSMA ligands has led to the inclusion of PSMA positron emission tomography (PET)/computed tomography (CT) in the new German S3 guideline for primary staging of prostate cancer. PURPOSE: The aim of this article is to provide an overview of the use of PET imaging in the primary diagnosis of prostate cancer, to present the most commonly used radiotracers, and to highlight the results of recent studies.


Assuntos
Neoplasias da Próstata , Humanos , Imageamento por Ressonância Magnética , Masculino , Estadiamento de Neoplasias , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Tomografia por Emissão de Pósitrons , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/patologia , Compostos Radiofarmacêuticos , Tomografia Computadorizada por Raios X
10.
Medicine (Baltimore) ; 100(31): e26833, 2021 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-34397848

RESUMO

ABSTRACT: To compare the outcomes of patients with high-risk prostate cancer treated by primary radical prostatectomy (RP) and primary androgen deprivation therapy (ADT).The study included patients with high-risk or very high-risk prostate cancer. Patients treated with definitive radiation therapy and those with clinical N1 and M1 disease were excluded. The RP group was divided into sub-cohorts of patients treated with ADT and those who received ADT after biochemical recurrence post-RP. Cancer-specific survival (CSS) and overall survival (OS) were analyzed using the Kaplan-Meier method and the Cox proportional hazards model.The study analyzed 859 patients divided into the RP group (n = 654) and ADT group (n = 205). Castration-resistant prostate cancer was detected in 23 (3.5%) patients in the RP group and 43 (21.0%) patients in the ADT group. Mortality cases included 63 (9.6%) patients in the RP group and 91 (44.4%) patients in the ADT group. CSS (P = .0002) and OS (P < .0001) were significantly higher in the RP group than in the ADT group. In the sub-cohort, CSS did not differ significantly between the RP and ADT groups, whereas OS was significantly higher in the RP group than in the ADT group (P < .0001). In the multivariate analysis, primary ADT increased CSS (hazard ratio, 2.068; P = .0498) and OS (hazard ratio, 3.218; P < .0001) compared with RP.In clinically localized high-risk prostate cancer patients, primary RP was associated with better CSS and OS than primary ADT. Comprehensive counseling in this cohort of patients will help the selection of treatment.


Assuntos
Antagonistas de Androgênios/uso terapêutico , Prostatectomia , Neoplasias da Próstata , Radioterapia , Idoso , Biomarcadores Tumorais/sangue , Terapia Combinada/métodos , Humanos , Estimativa de Kaplan-Meier , Masculino , Estadiamento de Neoplasias , Avaliação de Processos e Resultados em Cuidados de Saúde , Seleção de Pacientes , Modelos de Riscos Proporcionais , Antígeno Prostático Específico/sangue , Prostatectomia/efeitos adversos , Prostatectomia/métodos , Neoplasias da Próstata/sangue , Neoplasias da Próstata/mortalidade , Neoplasias da Próstata/patologia , Neoplasias da Próstata/terapia , Neoplasias de Próstata Resistentes à Castração/diagnóstico , Neoplasias de Próstata Resistentes à Castração/epidemiologia , Radioterapia/efeitos adversos , Radioterapia/métodos , República da Coreia/epidemiologia , Medição de Risco
11.
Medicine (Baltimore) ; 100(34): e26985, 2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34449467

RESUMO

BACKGROUND: The management of aspirin before transrectal prostate puncture-guided biopsy continues to be controversial. The conclusions in newly published studies differ from the published guideline. Therefore, an updated meta-analysis was performed to assess the safety of continuing to take aspirin when undergoing a transrectal ultrasound-guided prostate biopsy (TRUS-PB). METHODS: We searched the following databases for relevant literature from their inception to October 30, 2020: PubMed, EMBASE, Cochrane Central Register of Controlled Trials, Medline, Web of Science, Sinomed, Chinese National Knowledge Internet, and WANGFANG. Studies that compared the bleeding rates between aspirin that took aspirin and non-aspirin groups were included. The quality of all included studies was evaluated using the Newcastle-Ottawa Scale. Revman Manger version 5.2 software was employed to complete the meta-analysis to assess the risk of hematuria, hematospermia, and rectal bleeding. RESULTS: Six articles involving 3373 patients were included in this meta-analysis. Our study revealed that compared with the non-aspirin group, those taking aspirin exhibited a higher risk of rectal bleeding after TRUS-PB (risk ratio [RR] = 1.27, 95% confidence interval [CI] [1.09-1.49], P = .002). Also, the meta-analysis results did not reveal any significant difference between the 2 groups for the risk of hematuria (RR = 1.02, 95%CI [0.91-1.16], P = .71) and hematospermia (RR = 0.93, 95%CI [0.82-1.06], P = .29). CONCLUSION: Taking aspirin does not increase the risk of hematuria and hematospermia after TRUS-PB. However, the risk of rectal bleeding, which was slight and self-limiting, did increase. We concluded that it was not necessary to stop taking aspirin before undergoing TRUS-PB.


Assuntos
Aspirina/efeitos adversos , Biópsia por Agulha/efeitos adversos , Inibidores da Agregação Plaquetária/efeitos adversos , Aspirina/administração & dosagem , Ensaios Clínicos como Assunto , Hemorragia Gastrointestinal/induzido quimicamente , Hemorragia Gastrointestinal/etiologia , Hematúria/induzido quimicamente , Hematúria/etiologia , Hemospermia/induzido quimicamente , Hemospermia/etiologia , Humanos , Masculino , Inibidores da Agregação Plaquetária/administração & dosagem , Próstata/patologia , Neoplasias da Próstata/patologia , Ultrassonografia de Intervenção
12.
Pan Afr Med J ; 39: 20, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34394811

RESUMO

Introduction: incidental prostate cancer findings reflect the great burden of prostatic cancer across the globe. Our 10 year retrospective analysis aimed to identify the incidence and clinic-pathologic features of prostate cancer incidentally detected in patients undergoing transurethral resection of the prostate (TURP) for benign prostatic hyperplasia (BPH), and to estimate the clinical value of pathologic review of all TURP specimens. Methods: after excluding patients with a known diagnosis of prostate cancer prior to TURP a total of 2,386 men (ages 25-98) were identified by pathology (TURP) specimens. Yearly incidences, Gleason score, grade, pathologic stage were recorded for all incidental prostate cancer patients. Results: a total of 256 (10.7%) patients were found to have prostate cancer. Mean Age was 68.51±9.22 years. T1a and T1b stage prostatic carcinoma was found in 9.9% and 90.1% of these patients respectively. Forty-nine percent (49%) patients had higher Gleason scores (>7). After subtracting average incidences between 5-year intervals, a statistical rise of almost 4% was found. Conclusion: our analysis concludes that a large proportion (10.7%) of patients had incidental prostate cancer and the incidence was increasing in recent years in Pakistan and in comparison, to Asian countries. In Pakistan there is a scarcity of updated national cancer registries. The growing incidence of high Gleason scores requires keen and prompt attention. The diverse ethnic and socioeconomic background of patients propels their propensity towards loss of follow up with already limited tertiary healthcare institutes in Pakistan. This pathologic review of TURP specimens is valuable for Asiatic and non-Asiatic populations.


Assuntos
Hiperplasia Prostática/cirurgia , Neoplasias da Próstata/diagnóstico , Ressecção Transuretral da Próstata , Adulto , Idoso , Idoso de 80 Anos ou mais , Humanos , Incidência , Achados Incidentais , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Paquistão , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/patologia , Estudos Retrospectivos , Centros de Atenção Terciária
13.
J Enzyme Inhib Med Chem ; 36(1): 1839-1859, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34338119

RESUMO

A series of [1]benzothieno[2,3-c]pyridines was synthesised. Most compounds were chosen by NCI-USA to evaluate their anticancer activity. Compounds 5a-c showed prominent growth inhibition against most cell lines. 5c was selected at five dose concentration levels. It exhibited potent broad-spectrum anticancer activity with a GI50 of 4 nM-37 µM. Cytotoxicity of 5a-c was further evaluated against prostate, renal, and breast cancer cell lines. 5c showed double and quadruple the activity of staurosporine and abiraterone, respectively, against the PC-3 cell line with IC50 2.08 µM. The possible mechanism of anti-prostate cancer was explored via measuring the CYP17 enzyme activity in mice prostate cancer models compared to abiraterone. The results revealed that 5c suppressed the CYP17 enzyme to 15.80 nM. Moreover, it was found to be equipotent to abiraterone in testosterone production. Cell cycle analysis and apoptosis were performed. Additionally, the ADME profile of compound 5c demonstrated both good oral bioavailability and metabolic stability.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Piridinas/química , Piridinas/farmacologia , Esteroide 17-alfa-Hidroxilase/antagonistas & inibidores , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Antineoplásicos/farmacocinética , Disponibilidade Biológica , Linhagem Celular Tumoral , Simulação por Computador , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Humanos , Masculino , Camundongos , Neoplasias da Próstata/patologia , Piridinas/síntese química , Piridinas/farmacocinética , Análise Espectral/métodos , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Int J Mol Sci ; 22(15)2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34360875

RESUMO

Single prostate stem cells can generate stem and progenitor cells to form prostaspheres in 3D culture. Using a prostasphere-based label retention assay, we recently identified keratin 13 (KRT13)-enriched prostate stem cells at single-cell resolution, distinguishing them from daughter progenitors. Herein, we characterized the epithelial cell lineage hierarchy in prostaspheres using single-cell RNA-seq analysis. Keratin profiling revealed three clusters of label-retaining prostate stem cells; cluster I represents quiescent stem cells (PSCA, CD36, SPINK1, and KRT13/23/80/78/4 enriched), while clusters II and III represent active stem and bipotent progenitor cells (KRT16/17/6 enriched). Gene set enrichment analysis revealed enrichment of stem and cancer-related pathways in cluster I. In non-label-retaining daughter progenitor cells, three clusters were identified; cluster IV represents basal progenitors (KRT5/14/6/16 enriched), while clusters V and VI represent early and late-stage luminal progenitors, respectively (KRT8/18/10 enriched). Furthermore, MetaCore analysis showed enrichment of the "cytoskeleton remodeling-keratin filaments" pathway in cancer stem-like cells from human prostate cancer specimens. Along with common keratins (KRT13/23/80/78/4) in normal stem cells, unique keratins (KRT10/19/6C/16) were enriched in cancer stem-like cells. Clarification of these keratin profiles in human prostate stem cell lineage hierarchy and cancer stem-like cells can facilitate the identification and therapeutic targeting of prostate cancer stem-like cells.


Assuntos
Queratinas/metabolismo , Células-Tronco Neoplásicas , Neoplasias da Próstata , RNA/metabolismo , Adulto , Células Cultivadas , Humanos , Masculino , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Cultura Primária de Células , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Análise de Célula Única , Adulto Jovem
15.
Nat Commun ; 12(1): 5049, 2021 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-34413304

RESUMO

Preclinical testing is a crucial step in evaluating cancer therapeutics. We aimed to establish a significant resource of patient-derived xenografts (PDXs) of prostate cancer for rapid and systematic evaluation of candidate therapies. The PDX collection comprises 59 tumors collected from 30 patients between 2012-2020, coinciding with availability of abiraterone and enzalutamide. The PDXs represent the clinico-pathological and genomic spectrum of prostate cancer, from treatment-naïve primary tumors to castration-resistant metastases. Inter- and intra-tumor heterogeneity in adenocarcinoma and neuroendocrine phenotypes is evident from bulk and single-cell RNA sequencing data. Organoids can be cultured from PDXs, providing further capabilities for preclinical studies. Using a 1 x 1 x 1 design, we rapidly identify tumors with exceptional responses to combination treatments. To govern the distribution of PDXs, we formed the Melbourne Urological Research Alliance (MURAL). This PDX collection is a substantial resource, expanding the capacity to test and prioritize effective treatments for prospective clinical trials in prostate cancer.


Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Organoides/patologia , Neoplasias da Próstata/patologia , Animais , Modelos Animais de Doenças , Genoma , Humanos , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Mutação , Metástase Neoplásica , Organoides/metabolismo , Estudos Prospectivos , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Bancos de Tecidos , Transcriptoma , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Int J Mol Sci ; 22(16)2021 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-34445387

RESUMO

Prostate cancer (PCa) is the leading cause of cancer-associated mortality in men, and new biomarkers are still needed. The expression pattern and protein tissue localization of proteoglycans of the syndecan family (SDC 1-4) and syntenin-1 (SDCBP) were determined in normal and prostatic tumor tissue from two genetically engineered mouse models and human prostate tumors. Studies were validated using SDC 1-4 and SDCBP mRNA levels and patient survival data from The Cancer Genome Atlas and CamCAP databases. RNAseq showed increased expression of Sdc1 in Pb-Cre4/Ptenf/f mouse Pca and upregulation of Sdc3 expression and downregulation of Sdc2 and Sdc4 when compared to the normal prostatic tissue in Pb-Cre4/Trp53f/f-;Rb1f/f mouse tumors. These changes were confirmed by immunohistochemistry. In human PCa, SDC 1-4 and SDCBP immunostaining showed variable localization. Furthermore, Kaplan-Meier analysis showed that patients expressing SDC3 had shorter prostate-specific survival than those without SDC3 expression (log-rank test, p = 0.0047). Analysis of the MSKCC-derived expression showed that SDC1 and SDC3 overexpression is predictive of decreased biochemical recurrence-free survival (p = 0.0099 and p = 0.045, respectively), and SDC4 overexpression is predictive of increased biochemical recurrence-free survival (p = 0.035). SDC4 overexpression was associated with a better prognosis, while SDC1 and SDC3 were associated with more aggressive tumors and a worse prognosis.


Assuntos
Perfilação da Expressão Gênica/métodos , Neoplasias da Próstata/patologia , Sindecana-1/genética , Sindecana-3/genética , Sindecana-4/genética , Idoso , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Transplante de Neoplasias , Prognóstico , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Análise Serial de Proteínas , Análise de Sequência de RNA , Análise de Sobrevida , Sindecana-1/metabolismo , Sindecana-3/metabolismo , Sindecana-4/metabolismo , Sinteninas/genética , Sinteninas/metabolismo
17.
Lancet Oncol ; 22(8): e348-e357, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34339655

RESUMO

In patients with prostate cancer who have a high risk of pelvic nodal disease, the use of elective whole pelvis radiotherapy is still controversial. Two large, randomised, controlled trials (RTOG 9413 and GETUG-01) did not show a benefit of elective whole pelvis radiotherapy over prostate-only radiotherapy. In 2020, the POP-RT trial established the role of elective whole pelvis radiotherapy in patients who have more than a 35% risk of lymph node invasion (known as the Roach formula). POP-RT stressed the importance of patient selection. In patients with cN1 (clinically node positive) disease or pN1 (pathologically node positive) disease, the addition of whole pelvis radiotherapy to androgen deprivation therapy significantly improved survival compared with androgen deprivation therapy alone, as shown in large, retrospective studies. This patient population might increase in the future because use of the more sensitive prostate-specific membrane antigen PET-CT will become the standard staging procedure. Additionally, the SPORTT trial suggested a benefit of whole pelvis radiotherapy in biochemical recurrence-free survival in the salvage setting. A correct definition of the upper field border, which should include the bifurcation of the abdominal aorta, is key in the use of pelvic radiotherapy. As a result of using modern radiotherapy technology, severe late urinary and intestinal toxic effects are rare and do not seem to increase compared with prostate-only radiotherapy.


Assuntos
Metástase Linfática/radioterapia , Neoplasias da Próstata/patologia , Neoplasias da Próstata/radioterapia , Humanos , Masculino
18.
Theranostics ; 11(16): 7779-7796, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34335964

RESUMO

Rationale: The progression of prostate cancer (PCa) to castration-resistant PCa (CRPC) despite continuous androgen deprivation therapy is a major clinical challenge. Over 90% of patients with CRPC exhibit sustained androgen receptor (AR) signaling. KDM4B that removes the repressive mark H3K9me3/2 is a transcriptional activator of AR and has been implicated in the development of CRPC. However, the mechanisms of KDM4B involvement in CRPC remain largely unknown. Here, we sought to demonstrate the molecular pathway mediated by KDM4B in CRPC and to provide proof-of-concept evidence that KDM4B is a potential CRPC target. Methods: CRPC cells (C4-2B or CWR22Rv1) depleted with KDM4B followed by cell proliferation (in vitro and xenograft), microarray, qRT-PCR, Seahorse Flux, and metabolomic analyses were employed to identify the expression and metabolic profiles mediated by KDM4B. Immunoprecipitation was used to determine the KDM4B-c-Myc interaction region. Reporter activity assay and ChIP analysis were used to characterize the KDM4B-c-Myc complex-mediated mechanistic actions. The clinical relevance between KDM4B and c-Myc was determined using UCSC Xena analysis and immunohistochemistry. Results: We showed that KDM4B knockdown impaired CRPC proliferation, switched Warburg to OXPHOS metabolism, and suppressed gene expressions including those targeted by c-Myc. We further demonstrated that KDM4B physically interacted with c-Myc and they were co-recruited to the c-Myc-binding sequence on the promoters of metabolic genes (LDHA, ENO1, and PFK). Importantly, KDM4B and c-Myc synergistically promoted the transactivation of the LDHA promoter in a demethylase-dependent manner. We also provided evidence that KDM4B and c-Myc are co-expressed in PCa tissue and that high expression of both is associated with worse clinical outcome. Conclusions: KDM4B partners with c-Myc and serves as a coactivator of c-Myc to directly enhance c-Myc-mediated metabolism, hence promoting CRPC progression. Targeting KDM4B is thus an alternative therapeutic strategy for advanced prostate cancers driven by c-Myc and AR.


Assuntos
Histona Desmetilases com o Domínio Jumonji/metabolismo , Neoplasias de Próstata Resistentes à Castração/metabolismo , Antagonistas de Androgênios , Animais , Linhagem Celular Tumoral , Proliferação de Células/genética , Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/genética , Xenoenxertos , Humanos , Histona Desmetilases com o Domínio Jumonji/fisiologia , Masculino , Camundongos Endogâmicos BALB C , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/patologia , Receptores Androgênicos/metabolismo , Transdução de Sinais/genética , Fatores de Transcrição/metabolismo
19.
Nat Commun ; 12(1): 4217, 2021 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-34244513

RESUMO

The functional consequences of genetic variants within 5' untranslated regions (UTRs) on a genome-wide scale are poorly understood in disease. Here we develop a high-throughput multi-layer functional genomics method called PLUMAGE (Pooled full-length UTR Multiplex Assay on Gene Expression) to quantify the molecular consequences of somatic 5' UTR mutations in human prostate cancer. We show that 5' UTR mutations can control transcript levels and mRNA translation rates through the creation of DNA binding elements or RNA-based cis-regulatory motifs. We discover that point mutations can simultaneously impact transcript and translation levels of the same gene. We provide evidence that functional 5' UTR mutations in the MAP kinase signaling pathway can upregulate pathway-specific gene expression and are associated with clinical outcomes. Our study reveals the diverse mechanisms by which the mutational landscape of 5' UTRs can co-opt gene expression and demonstrates that single nucleotide alterations within 5' UTRs are functional in cancer.


Assuntos
Regiões 5' não Traduzidas/genética , Análise Mutacional de DNA/métodos , Regulação Neoplásica da Expressão Gênica , Genômica/métodos , Neoplasias da Próstata/genética , Linhagem Celular Tumoral , Células HEK293 , Ensaios de Triagem em Larga Escala , Humanos , Masculino , Mutação Puntual , Próstata/patologia , Neoplasias da Próstata/patologia , Biossíntese de Proteínas/genética , RNA-Seq
20.
Int J Mol Sci ; 22(12)2021 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-34207601

RESUMO

The current statistics on cancer show that 90% of all human cancers originate from epithelial cells. Breast and prostate cancer are examples of common tumors of epithelial origin that would benefit from improved drug treatment strategies. About 90% of preclinically approved drugs fail in clinical trials, partially due to the use of too simplified in vitro models and a lack of mimicking the tumor microenvironment in drug efficacy testing. This review focuses on the origin and mechanism of epithelial cancers, followed by experimental models designed to recapitulate the epithelial cancer structure and microenvironment, such as 2D and 3D cell culture models and animal models. A specific focus is put on novel technologies for cell culture of spheroids, organoids, and 3D-printed tissue-like models utilizing biomaterials of natural or synthetic origins. Further emphasis is laid on high-content imaging technologies that are used in the field to visualize in vitro models and their morphology. The associated technological advancements and challenges are also discussed. Finally, the review gives an insight into the potential of exploiting nanotechnological approaches in epithelial cancer research both as tools in tumor modeling and how they can be utilized for the development of nanotherapeutics.


Assuntos
Bioimpressão , Neoplasias da Mama , Modelos Biológicos , Neoplasias Epiteliais e Glandulares , Organoides , Impressão Tridimensional , Neoplasias da Próstata , Animais , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Feminino , Humanos , Masculino , Nanotecnologia , Neoplasias Epiteliais e Glandulares/diagnóstico por imagem , Neoplasias Epiteliais e Glandulares/metabolismo , Neoplasias Epiteliais e Glandulares/patologia , Organoides/diagnóstico por imagem , Organoides/metabolismo , Organoides/patologia , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Engenharia Tecidual
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