Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 15.336
Filtrar
1.
Theranostics ; 11(16): 7640-7657, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34335955

RESUMO

Background: Since primary prostate cancer (PCa) can advance to the life-threatening metastatic PCa, exploring the molecular mechanisms underlying PCa metastasis is crucial for developing the novel targeted preventive strategies for decreasing the mortality of PCa. RNA N6-methyladenosine (m6A) is an emerging regulatory mechanism for gene expression and its specific roles in PCa progression remains elusive. Methods: Western blotting, quantitative real-time PCR and immunohistochemical analyses were used to detect target gene expression in PCa cells in vitro and prostate tissues from patients. RNA immunoprecipitation was conducted to analyze the specific binding of mRNA to the target protein. Migration and invasion assays were used to assess the migratory capacities of cancer cells. The correlation between target gene expression and survival rate of PCa patients was analyzed based the TCGA database. Results: We found that total RNA N6-methyladenosine (m6A) modification levels were markedly upregulated in human PCa tissues due to increased expression of methyltransferase like 3 (METTL3). Further studies revealed that the migratory and invasive capacities of PCa cells were markedly suppressed upon METTL3 knockdown. Mechanistically, METTL3 mediates m6A modification of USP4 mRNA at A2696, and m6A reader protein YTHDF2 binds to and induces degradation of USP4 mRNA by recruiting RNA-binding protein HNRNPD to the mRNA. Decrease of USP4 fails to remove the ubiquitin group from ELAVL1 protein, resulting in a reduction of ELAVL1 protein. Lastly, downregulation of ELAVL1 in turn increases ARHGDIA expression, promoting migration and invasion of PCa cells. Conclusions: Our findings highlight the role of METTL3 in modulating invasion and metastasis of PCa cells, providing insight into promising therapeutic strategies for hindering PCa progressing to deadly metastases.


Assuntos
Metiltransferases/genética , Neoplasias da Próstata/metabolismo , Adenosina/análogos & derivados , Adenosina/genética , Adenosina/metabolismo , Movimento Celular/genética , Proliferação de Células/genética , Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/genética , Inativação Gênica/fisiologia , Humanos , Masculino , Metiltransferases/metabolismo , Invasividade Neoplásica/genética , Metástase Neoplásica/genética , Próstata/metabolismo , Próstata/patologia , Neoplasias da Próstata/genética , RNA Mensageiro/genética , Proteínas de Ligação a RNA/metabolismo , Proteases Específicas de Ubiquitina/genética
2.
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
3.
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
4.
Clin Adv Hematol Oncol ; 19(7): 460-467, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34236345

RESUMO

Oligometastatic prostate cancer is a subtype of metastatic disease that generally is defined by the presence of 5 or fewer metastatic lesions. Metastatic prostate cancer currently is treated with androgen deprivation therapy and additional systemic therapy, such as novel antiandrogen medications or chemotherapy. The management of metastatic prostate cancer is evolving, however, with the notion that some patients with low-burden metastatic disease may benefit from both local and systemic therapy. Local therapy of the prostate in the setting of oligometastatic prostate cancer is a new concept. Evidence from retrospective studies suggests that cytoreductive therapy, including radical prostatectomy, can improve overall survival in these patients. Ongoing randomized trials are comparing cytoreductive therapy with standard-of-care treatment options. Local therapy in the form of radiation has also been investigated in phase 2 randomized trials. In this review, we discuss the biological and clinical rationales for local therapy, review the current evidence for local therapy, and compare the clinical designs of various ongoing trials.


Assuntos
Neoplasias da Próstata/terapia , Antagonistas de Androgênios/uso terapêutico , Animais , Ensaios Clínicos como Assunto , Gerenciamento Clínico , Humanos , Masculino , Metástase Neoplásica/patologia , Metástase Neoplásica/radioterapia , Metástase Neoplásica/terapia , Próstata/efeitos dos fármacos , Próstata/patologia , Próstata/efeitos da radiação , Próstata/cirurgia , Prostatectomia , Neoplasias da Próstata/patologia , Neoplasias da Próstata/radioterapia
5.
Genes (Basel) ; 12(5)2021 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-34069563

RESUMO

Castration-resistant prostate cancer (CRPC) is an advanced stage of prostate cancer that can progress rapidly even in patients treated with castration. Previously, we found that tumor-associated macrophages (TAM) can be recruited by CSF-1 secreted by docetaxel-treated prostate cancer cells and promote the survival of cancer cells in response to chemotherapy. The inhibition of CSF-1R can impede this effect and significantly prolong survival in xenograft mice. However, the actual mechanism of how TAM improves cancer cell survival still remains elusive and controversial. Here, for the first time, we found that the enhanced survival of cancer cells achieved by TAM was mainly mediated by CXCR4 activation from the increased secretion of CXCL12 from CSF-1 activated TAM. This finding helps to clarify the mechanism of chemoresistance for second-line chemotherapy using docetaxel, facilitating the development of novel drugs to overcome immune tolerance in castration-resistant prostate cancer.


Assuntos
Sobrevivência Celular/genética , Quimiocina CXCL12/genética , Fator Estimulador de Colônias de Macrófagos/genética , Neoplasias de Próstata Resistentes à Castração/genética , Receptores CXCR4/genética , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Macrófagos Associados a Tumor/patologia , Animais , Antineoplásicos/farmacologia , Linhagem Celular , Linhagem Celular Tumoral , Docetaxel/farmacologia , Humanos , Masculino , Camundongos , Células PC-3 , Próstata/patologia , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/patologia , Células RAW 264.7 , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Macrófagos Associados a Tumor/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Eur J Radiol ; 141: 109804, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34062473

RESUMO

PURPOSE: To compare biparametric MRI (bpMRI) with multiparametric MRI (mpMRI) staging accuracy in assessing extracapsular extension (ECE) and seminal vesicle invasion (SVI). METHOD: Biopsy-naïve patients undergoing 3 T-MRI before radical prostatectomy for clinically significant prostate cancer were included in this single-centre retrospective study. Two uroradiologists separately evaluated bpMRI and mpMRI for presence of ECE and SVI using a 5-point Likert scale (1: ECE/SVI highly unlikely, 5: ECE/SVI highly likely). RESULTS: 110 men of median age 63 years and PSA 8.5 ng/mL were included. ECE and SVI was confirmed histologically in 71/110 (64.5 %) and 18/110 (16.4 %) patients, respectively. Sensitivity and specificity of bpMRI versus mpMRI for predicting ECE was 59.1 % and 87.2 % versus 66.2 % and 84.6 %, respectively. For SVI detection, the sensitivity and specificity for bpMRI versus mpMRI was 66.7 % and 92.4 % versus 83.3 % and 97.8 %, respectively. At an optimal cut-off Likert score ≥3 for ECE prediction, mpMRI area under the receiver operating curve (AUC) was 0.80 (95 % confidence interval (CI) 0.72-0.87) versus 0.78 (95 % CI 0.69-0.86) for bpMRI (p = 0.52) and for SVI, mpMRI AUC was 0.91 (95 % CI 0.84-0.96) versus 0.86 (95 % CI 0.78-0.92) for bpMRI (p = 0.02), respectively. Inter-reader agreement for both ECE and SVI prediction was substantial, with a marginally higher k-value for mpMRI (k range, 0.67-0.75) than bpMRI (k range, 0.65-0.69). CONCLUSIONS: Diagnostic performance of bpMRI and mpMRI was comparable for detection of ECE, however, mpMRI with contrast was superior for SVI detection and improved the inter-reader agreement.


Assuntos
Imageamento por Ressonância Magnética Multiparamétrica , Neoplasias da Próstata , Biópsia , Extensão Extranodal , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Próstata/diagnóstico por imagem , Próstata/patologia , Prostatectomia , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/patologia , Neoplasias da Próstata/cirurgia , Estudos Retrospectivos , Glândulas Seminais/diagnóstico por imagem , Glândulas Seminais/patologia
7.
Front Endocrinol (Lausanne) ; 12: 677701, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34122351

RESUMO

Background: Angiotensin-converting enzyme II (ACE2), a receptor for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) to enter host cells, is widely expressed in testes and prostate tissues. The testis and prostate produce semen. At present, there are contradictory reports about whether SARS-CoV-2 can exist in the semen of infected men. Objective: To provide a comprehensive overview of the topic of whether COVID-19 can impact on male reproductive system. Methods: We reviewed the relevant publications on the possible impact of Coronavirus Disease 2019 (COVID-19) on male reproductive system and summarized the latest and most important research results so far. Literature published in English from December 2019 to January 31, 2021 regarding the existence of SARS-CoV-2 in semen, testis, and prostatic fluid and the effects of COVID-19 on male reproductive were included. Results: We identified 28 related studies, only one of which reported the presence of SARS-CoV-2 in semen. The study found that the semen quality of patients with moderate infection was lower than that of patients with mild infection and healthy controls. The impaired semen quality may be related to fever and inflammation. Pathological analysis of the testis/epididymis showed that SARS-CoV-2 viral particles were positive in 10 testicular samples, and the spermatogenic function of the testis was impaired. All 94 expressed prostatic secretion (EPS) samples were negative for SARS-CoV-2 RNA. Conclusion: The likelihood of SARS-CoV-2 in the semen of COVID-19 patients is very small, and semen should rarely be regarded as a carrier of SARS-CoV-2 genetic material. However, COVID-19 may cause testicular spermatogenic dysfunction via immune or inflammatory reactions. Long-term follow-up is needed for COVID-19 male patients and fetuses conceived during the father's infection period.


Assuntos
COVID-19/fisiopatologia , Genitália Masculina/virologia , SARS-CoV-2/fisiologia , COVID-19/complicações , COVID-19/patologia , Genitália Masculina/patologia , Genitália Masculina/fisiologia , História do Século XXI , Humanos , Inflamação/complicações , Inflamação/patologia , Inflamação/virologia , Masculino , Próstata/patologia , Próstata/fisiologia , Próstata/virologia , Sêmen/virologia , Análise do Sêmen , Disfunções Sexuais Fisiológicas/patologia , Disfunções Sexuais Fisiológicas/virologia , Testículo/patologia , Testículo/fisiologia , Testículo/virologia
8.
Nat Commun ; 12(1): 3372, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34099734

RESUMO

Despite advances in the development of highly effective androgen receptor (AR)-directed therapies for the treatment of men with advanced prostate cancer, acquired resistance to such therapies frequently ensues. A significant subset of patients with resistant disease develop AR-negative tumors that lose their luminal identity and display neuroendocrine features (neuroendocrine prostate cancer (NEPC)). The cellular heterogeneity and the molecular evolution during the progression from AR-positive adenocarcinoma to AR-negative NEPC has yet to be characterized. Utilizing a new genetically engineered mouse model, we have characterized the synergy between Rb1 loss and MYCN (encodes N-Myc) overexpression which results in the formation of AR-negative, poorly differentiated tumors with high metastatic potential. Single-cell-based approaches revealed striking temporal changes to the transcriptome and chromatin accessibility which have identified the emergence of distinct cell populations, marked by differential expression of Ascl1 and Pou2f3, during the transition to NEPC. Moreover, global DNA methylation and the N-Myc cistrome are redirected following Rb1 loss. Altogether, our data provide insight into the progression of prostate adenocarcinoma to NEPC.


Assuntos
Adenocarcinoma/genética , Carcinoma Neuroendócrino/genética , Regulação Neoplásica da Expressão Gênica , Próstata/metabolismo , Neoplasias da Próstata/genética , Receptores Androgênicos/genética , Adenocarcinoma/metabolismo , Animais , Carcinoma Neuroendócrino/metabolismo , Linhagem Celular Tumoral , Progressão da Doença , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Proteína Proto-Oncogênica N-Myc/genética , Proteína Proto-Oncogênica N-Myc/metabolismo , Técnicas de Cultura de Órgãos/métodos , Prognóstico , Próstata/patologia , Neoplasias da Próstata/metabolismo , Receptores Androgênicos/metabolismo , Proteína do Retinoblastoma/genética , Proteína do Retinoblastoma/metabolismo
9.
J Urol ; 206(3): 623-629, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34003011

RESUMO

PURPOSE: There were 3 recent U.S. Food and Drug Administration approvals for drugs to be used in nonmetastatic castration resistant prostate cancer, a state that arises from the unproven start of continuous androgen deprivation therapy (ADT) for biochemical recurrent prostate cancer (BCR), before metastatic disease is evident. This report examines the outcome of men with BCR who defer ADT until time of metastasis. MATERIALS AND METHODS: Retrospective review of men diagnosed with clinically localized prostate cancer who underwent radical prostatectomy at Johns Hopkins Hospital and Walter Reed National Military Medical Center and developed BCR with a prostate specific antigen doubling time of not more than 10 months (806 patients). The primary end points were metastasis-free survival and overall survival from time of local treatment among men who delayed ADT until time of metastasis. RESULTS: The median metastasis-free survival of men with BCR and a prostate specific antigen doubling time <6 months and 10 months who delay ADT until metastasis is 144 months (95% CI 48-not reached) and 192 months (95% CI 72-not reached), respectively, with a median overall survival of 168 months (95% CI 96-276 months) and 204 months (95% CI 120-276), respectively. CONCLUSIONS: Metastasis-free survival and overall survival of men with BCR who delay hormone therapy is long. This underscores the need to reevaluate when to start primary ADT in this patient population.


Assuntos
Antagonistas de Androgênios/uso terapêutico , Calicreínas/sangue , Recidiva Local de Neoplasia/tratamento farmacológico , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/terapia , Tempo para o Tratamento/estatística & dados numéricos , Idoso , Quimioterapia Adjuvante/métodos , Tomada de Decisão Clínica , Progressão da Doença , Intervalo Livre de Doença , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/sangue , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/epidemiologia , Guias de Prática Clínica como Assunto , Próstata/patologia , Próstata/cirurgia , Prostatectomia , Neoplasias da Próstata/sangue , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/mortalidade , Estudos Retrospectivos , Fatores de Tempo , Tempo para o Tratamento/normas
10.
Adv Anat Pathol ; 28(4): 276-287, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33990497

RESUMO

Intraductal carcinoma of the prostate gland (IDCP) is characterized by an expansile, architecturally, and cytologically atypical proliferation of prostatic epithelial cells within preexisting prostatic ducts and acini. There has been a wider recognition of IDCP by practicing pathologists since its recognition as a separate category in the World Health Organization (WHO) 2016 classification of tumours of the prostate gland. However, there is also a lack of clarity regarding the diagnosis and reporting of IDCP, which has been compounded by divergent expert recommendations regarding the grading of invasive prostate cancers associated with an intraductal component. The International Society of Urological Pathologists (ISUP) recommends that the IDCP component should be incorporated into the Gleason score, while the Genitourinary Pathology Society (GUPS) recommends excluding it when grading prostate cancer. This review seeks to clarify some of these issues and outline a pragmatic approach to reporting IDCP, particularly in needle biopsies. Diagnostic issues and terminology for lesions falling short of IDCP but exceeding that of high-grade prostatic intraepithelial neoplasia are discussed. The management of patients whose prostate biopsies show only IDCP without an associated invasive component is controversial. Some experts recommend radical therapy, while others recommend prompt repeat biopsy. An alternative clinicopathologic approach that takes into consideration the extent, histomorphology, and location (with respect to a radiologic abnormality) of IDCP, as well as radiologic features, is outlined.


Assuntos
Carcinoma Intraductal não Infiltrante/patologia , Próstata/patologia , Neoplasias da Próstata/patologia , Humanos , Masculino , Gradação de Tumores
11.
BMC Cancer ; 21(1): 501, 2021 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-33947348

RESUMO

BACKGROUND: The objective of this study is to investigate the clinical significance and risk factors of upgrading in the International Society of Urological Pathology (ISUP) Grade Group System in men undergoing robot-assisted radical prostatectomy (RARP) for prostate cancer. METHODS: A total of 583 patients diagnosed with prostate cancer by systematic biopsy were treated with RARP without neoadjuvant therapy from November 2011 to December 2018. Clinicopathological data were obtained from our clinical records. ISUP grade upgrading (IGU) was defined as 'ISUP grade in prostatectomy specimen determined to be higher than that in the biopsy specimen'. Clinicopathological factors, including age, PSA, prostate volume at biopsy (PV), PSA density, clinical stage, body mass index (BMI), interval from biopsy to prostatectomy, maximum percentage of cancer involvement per core (%CI), total number of biopsy cores, percentage of cancer positive biopsy cores (%PC), and sampling density were analyzed to detect potential risk factors of IGU. Biochemical recurrence (BCR) rates were calculated to analyze the effect of IGU on cancer prognosis. RESULTS: In univariate analysis, BMI was a positive predictor of IGU, while %CI, %PC, and sampling density were negative predictors of IGU. BMI and %PC were statistically significant predictors of IGU in multivariate analysis. For cases diagnosed as ISUP grade group 2 or higher at biopsy, there was a significant difference in BCR rates between cases with and without IGU. CONCLUSIONS: The results from our cohort showed that elements of both high-grade cancer risk (such as BMI) and sampling efficiency (such as %PC) contribute to IGU. Excluding cases diagnosed as ISUP grade group 1 at biopsy, BCR-free rates were significantly worse in cases with IGU, highlighting the need for more accurate pathological diagnosis at biopsy.


Assuntos
Prostatectomia/métodos , Neoplasias da Próstata/patologia , Neoplasias da Próstata/cirurgia , Procedimentos Cirúrgicos Robóticos/métodos , Idoso , Análise de Variância , Biópsia por Agulha , Índice de Massa Corporal , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Próstata/patologia , Antígeno Prostático Específico/análise , Prostatectomia/estatística & dados numéricos , Neoplasias da Próstata/química , Fatores de Risco , Procedimentos Cirúrgicos Robóticos/estatística & dados numéricos , Sociedades Médicas , Urologia
12.
Urologiia ; (2): 100-105, 2021 May.
Artigo em Russo | MEDLINE | ID: mdl-33960167

RESUMO

An analysis of domestic and foreign literature on the predictors of prostate cancer recurrence are presented in the article. A deep analysis of both pathological and histological risk factors for progression was provided, as well as of laboratory and clinical predictors.


Assuntos
Antígeno Prostático Específico , Neoplasias da Próstata , Humanos , Masculino , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Próstata/patologia , Prostatectomia , Neoplasias da Próstata/patologia , Neoplasias da Próstata/cirurgia
14.
Cancer Med ; 10(10): 3427-3436, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33932111

RESUMO

The three oncogenic PIM family kinases have been implicated in the development of prostate cancer (PCa). The aim of this study was to examine the mRNA and protein expression levels of PIM1, PIM2, and PIM3 in PCa and their associations with the MYC and ERG oncogenes. We utilized prostate tissue specimens of normal, benign prostatic hyperplasia (BPH), prostatic intraepithelial neoplasia (PIN), untreated PCa, and castration-resistant prostate cancer (CRPC) for immunohistochemical (IHC) analysis. In addition, we analyzed data from publicly available mRNA expression and chromatin immunoprecipitation sequencing (ChIP-Seq) datasets. Our data demonstrated that PIM expression levels are significantly elevated in PCa compared to benign samples. Strikingly, the expression of both PIM1 and PIM2 was further increased in CRPC compared to PCa. We also demonstrated a significant association between upregulated PIM family members and both the ERG and MYC oncoproteins. Interestingly, ERG directly binds to the regulatory regions of all PIM genes and upregulates their expression. Furthermore, ERG suppression with siRNA reduced the expression of PIM in PCa cells. These results provide evidence for cooperation of PIM and the MYC and ERG oncoproteins in PCa development and progression and may help to stratify suitable patients for PIM-targeted therapies.


Assuntos
Neoplasias da Próstata/genética , Proteínas Proto-Oncogênicas c-pim-1/genética , Idoso , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Masculino , Pessoa de Meia-Idade , Próstata/patologia , Hiperplasia Prostática/genética , Hiperplasia Prostática/patologia , Neoplasias da Próstata/patologia , RNA Mensageiro/genética , RNA Interferente Pequeno/genética , Regulador Transcricional ERG/genética , Regulação para Cima/genética
15.
J Urol ; 206(3): 604-612, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33878887

RESUMO

PURPOSE: Targeted biopsy improves prostate cancer diagnosis. Accurate prostate segmentation on magnetic resonance imaging (MRI) is critical for accurate biopsy. Manual gland segmentation is tedious and time-consuming. We sought to develop a deep learning model to rapidly and accurately segment the prostate on MRI and to implement it as part of routine magnetic resonance-ultrasound fusion biopsy in the clinic. MATERIALS AND METHODS: A total of 905 subjects underwent multiparametric MRI at 29 institutions, followed by magnetic resonance-ultrasound fusion biopsy at 1 institution. A urologic oncology expert segmented the prostate on axial T2-weighted MRI scans. We trained a deep learning model, ProGNet, on 805 cases. We retrospectively tested ProGNet on 100 independent internal and 56 external cases. We prospectively implemented ProGNet as part of the fusion biopsy procedure for 11 patients. We compared ProGNet performance to 2 deep learning networks (U-Net and holistically-nested edge detector) and radiology technicians. The Dice similarity coefficient (DSC) was used to measure overlap with expert segmentations. DSCs were compared using paired t-tests. RESULTS: ProGNet (DSC=0.92) outperformed U-Net (DSC=0.85, p <0.0001), holistically-nested edge detector (DSC=0.80, p <0.0001), and radiology technicians (DSC=0.89, p <0.0001) in the retrospective internal test set. In the prospective cohort, ProGNet (DSC=0.93) outperformed radiology technicians (DSC=0.90, p <0.0001). ProGNet took just 35 seconds per case (vs 10 minutes for radiology technicians) to yield a clinically utilizable segmentation file. CONCLUSIONS: This is the first study to employ a deep learning model for prostate gland segmentation for targeted biopsy in routine urological clinical practice, while reporting results and releasing the code online. Prospective and retrospective evaluations revealed increased speed and accuracy.


Assuntos
Aprendizado Profundo , Processamento de Imagem Assistida por Computador/métodos , Próstata/diagnóstico por imagem , Neoplasias da Próstata/diagnóstico , Conjuntos de Dados como Assunto , Estudos de Viabilidade , Humanos , Biópsia Guiada por Imagem/métodos , Imagem por Ressonância Magnética Intervencionista , Masculino , Imagem Multimodal/métodos , Imageamento por Ressonância Magnética Multiparamétrica , Estudo de Prova de Conceito , Estudos Prospectivos , Próstata/patologia , Neoplasias da Próstata/patologia , Reprodutibilidade dos Testes , Estudos Retrospectivos , Software , Fatores de Tempo , Ultrassonografia de Intervenção/métodos
16.
J Urol ; 206(3): 586-594, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33881932

RESUMO

PURPOSE: NonHispanic Black (NHB) and Hispanic/Afro-Caribbean men have the highest risk of prostate cancer (PCa) compared to nonHispanic White (NHW) men. However, ethnicity-specific outcomes of targeted fusion biopsy (FB) for the detection of PCa are poorly characterized. We compared the outcomes of FB by Prostate Imaging Reporting and Data System (PI-RADS®) score and race/ethnicity among a diverse population. MATERIALS AND METHODS: We evaluated all men who underwent image-guided FB for suspicious lesions on prostate magnetic resonance imaging (≥PI-RADS 3) over a 2-year period. We examined associations of race/ethnicity and PI-RADS score with risk of PCa or clinically significant PCa (cs-PCa, Gleason Group ≥2) on FB using mixed-effects logistic regression models. RESULTS: A total of 410 men with 658 lesions were analyzed, with 201 (49.0%) identified as NHB and 125 (30.5%) identified as Hispanic. NHB men had a twofold increase in the odds of detecting cs-PCa (OR=2.7, p=0.045), while Hispanic men had similar odds of detecting cs-PCa compared to NHW men. With regard to all PCa, NHB men had a similar increase in the odds of detecting all PCa (OR=2.4, p=0.050), which was borderline statistically significant compared to NHW men on FB. When we excluded men on active surveillance, NHB men had even stronger associations with detection of cs-PCa (OR=3.10, p=0.047) or all PCa (OR=2.77, p=0.032) compared to NHW men. CONCLUSIONS: NHB men have higher odds for overall PCa and cs-PCa on FB compared to NHW men. Further work may clarify differences per PI-RADS score. Clinicians should interpret prostate magnetic resonance imaging lesions with more caution in NHB men.


Assuntos
Imagem por Ressonância Magnética Intervencionista/estatística & dados numéricos , Próstata/patologia , Neoplasias da Próstata/epidemiologia , Afro-Americanos/estatística & dados numéricos , Idoso , Grupo com Ancestrais do Continente Europeu/estatística & dados numéricos , Hispano-Americanos/estatística & dados numéricos , Humanos , Biópsia Guiada por Imagem/métodos , Biópsia Guiada por Imagem/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Próstata/diagnóstico por imagem , Neoplasias da Próstata/diagnóstico , Estudos Retrospectivos , Medição de Risco/estatística & dados numéricos
17.
J Urol ; 206(3): 638-645, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33890485

RESUMO

PURPOSE: We assessed whether prostate cancer (PCa) location might affect oncologic outcomes after focal therapy (FT) for PCa. MATERIALS AND METHODS: We identified 274 men receiving FT for PCa using either high intensity focused ultrasound (HIFU) or cryotherapy at a high volume center between 2009 and 2018. Survival analyses using Kaplan-Meier method were used to assess any additional treatment and radical treatment rates according to PCa location. Propensity-score match analysis was used to compare oncologic outcomes of HIFU vs cryotherapy according to PCa location. Covariates were prostate specific antigen, clinical stage, prostate volume, Gleason score, maximum cancer core length, percentage of positive cores and treatment modality. RESULTS: A total of 166 and 108 men received FT with HIFU and cryotherapy, respectively. Overall, 39% (106) and 31% (85) received at least an additional treatment and a radical treatment after FT, respectively, with a median followup of 51 months. At 36 months' followup, the rates of any additional treatment-free survival were 71%, 75%, and 69% for patients with basal, mid-prostate and apical disease, respectively (p=0.7). At multivariable logistic regression analysis, PCa location was not significantly associated with higher risk of either any additional treatment or radical treatment (all p >0.4). After matching, there was no difference between HIFU vs cryotherapy in terms of any additional treatment rates according to PCa location. CONCLUSIONS: The PCa location does not significantly affect the rate of failure after FT. The presence of an apical lesion should not be considered an exclusion criteria for FT. Both HIFU and cryotherapy likely achieve similar medium-term oncologic results regardless of PCa location.


Assuntos
Criocirurgia , Neoplasias da Próstata/cirurgia , Ultrassom Focalizado Transretal de Alta Intensidade , Idoso , Biópsia com Agulha de Grande Calibre , Seguimentos , Humanos , Calicreínas/sangue , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Imageamento por Ressonância Magnética Multiparamétrica , Gradação de Tumores , Estadiamento de Neoplasias , Próstata/diagnóstico por imagem , Próstata/patologia , Próstata/efeitos da radiação , Próstata/cirurgia , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/sangue , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/mortalidade , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do Tratamento
18.
J Urol ; 206(3): 630-637, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33904759

RESUMO

PURPOSE: We aimed to explore the association between genomic status and clinical outcome of platinum-based chemotherapy among patients with metastatic castration-resistant prostate cancer (mCRPC). MATERIALS AND METHODS: We conducted a retrospective study of 55 patients with mCRPC who received platinum-based chemotherapy after the progression to docetaxel chemotherapy and underwent genomic profiling of 14 homologous recombination (HR) pathway genes. Progression-free survival (PFS) was analyzed using the Kaplan-Meier method. RESULTS: Of 55 patients, 23 harbored genomic defects in HR pathway genes. Median prostate specific antigen (PSA)-PFS for the HR defect group was 6.7 months compared with 2.6 months for the no HR defect group (p=0.001). The patients harboring somatic HR defect displayed shorter PSA-PFS than those harboring germline HR defect (4.5 months vs not available; p=0.066). The PSA50 (patients who survived for 12 weeks and had a PSA decline over 50% from baseline) response rate displayed higher in patients harboring BRCA2 or ATM defect (6/8, 75.0%) than in those harboring CDK12 defect (2/9, 22.2%; p=0.06). Patients harboring BRCA2 or ATM defect displayed prolonged PSA-PFS, compared with those harboring CDK12 defect and those harboring other HR defect (p=0.038). In multivariate Cox regression analysis, HR defect and BRCA2 or ATM defect were independent significant factors associated with superior PAS-PFS to platinum-based chemotherapy. CONCLUSIONS: The patients with mCRPC harboring alterations in different HR genes displayed distinct response to platinum-based chemotherapy. Patients with mCRPC harboring genomic defects in crucial HR genes either in the germline or somatic, especially BRCA2 and ATM, might experience superior outcomes to platinum-based chemotherapy, compared with those harboring CDK12 defect.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/genética , Carboplatina/uso terapêutico , Cisplatino/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteína BRCA2/genética , Biópsia , Carboplatina/farmacologia , Cisplatino/farmacologia , Quinases Ciclina-Dependentes/genética , Análise Mutacional de DNA , Docetaxel/farmacologia , Docetaxel/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Recombinação Homóloga/genética , Humanos , Calicreínas/sangue , Masculino , Pessoa de Meia-Idade , Mutação , Intervalo Livre de Progressão , Próstata/patologia , Antígeno Prostático Específico/sangue , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/mortalidade , Neoplasias de Próstata Resistentes à Castração/secundário , Estudos Retrospectivos
19.
J Urol ; 206(3): 706-714, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33905262

RESUMO

PURPOSE: To determine if benign glandular tissue at the surgical margin (BGM) is associated with detectable prostate specific antigen (PSA) and/or biochemical recurrence (BCR) after radical prostatectomy (RP). MATERIALS AND METHODS: Participants underwent RP for localized prostate cancer between 2004 and 2018. Regression analysis was used to identify demographic, clinical and surgical factors associated with the likelihood of BGM presence on surgical pathology. Oncologic outcomes included detectable PSA (>0.03 ng/ml), BCR (≥0.2 ng/ml) and progression to BCR or salvage treatment after detectable PSA. Life tables and Cox proportional hazards regression models were used to determine the association of BGM and risk of oncologic outcomes. RESULTS: A total of 1,082 men underwent RP for localized prostate cancer with BGM reported on surgical pathology and an undetectable postoperative PSA. BGM was present on 249 (23%) specimens. Younger age, bilateral nerve sparing surgery and robotic approach were associated with presence of BGM while malignancy at the surgical margin (MSM) was not. At 7 years after RP, 29% experienced detectable PSA and 11% had BCR. In the subgroup of men who reached detectable PSA, 79% had progression within 7 years. On multivariate Cox proportional hazards regression, BGM status was not independently associated with detectable PSA, BCR and/or progression from detectable PSA to BCR or salvage treatment. CONCLUSIONS: The presence of BGM at RP was not associated with increased risk of MSM, detectable PSA, BCR or progression after detectable PSA.


Assuntos
Calicreínas/sangue , Recidiva Local de Neoplasia/diagnóstico , Antígeno Prostático Específico/sangue , Próstata/patologia , Neoplasias da Próstata/cirurgia , Idoso , Progressão da Doença , Seguimentos , Humanos , Masculino , Margens de Excisão , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/sangue , Neoplasia Residual , Período Pós-Operatório , Estudos Prospectivos , Prostatectomia , Neoplasias da Próstata/sangue , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/patologia , Fatores de Risco , Resultado do Tratamento
20.
J Urol ; 206(3): 646-654, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33908799

RESUMO

PURPOSE: Radiation refractory prostate cancer (RRPCa) is common and salvage cryotherapy for RRPCa is emerging as a viable local treatment option. However, there is a paucity of long-term data. The purpose of this study is to determine long-term outcomes following salvage cryotherapy for RRPca. MATERIALS AND METHODS: Patients undergoing salvage cryotherapy for biopsy-proven, localized RRPCa from 1992 through 2004 were prospectively accrued at two centers. Preoperative characteristics, perioperative morbidity and postoperative data were reviewed from our database. The primary outcomes were overall survival (OS) and disease-specific survival (DSS). The secondary outcomes were freedom from castration-resistant prostate cancer (CRPC) and freedom from androgen deprivation therapy (ADT). RESULTS: A total of 268 patients were identified with a median followup of 10.3 years. A total of 223 complication events were recorded; of them, 168 were Clavien I-II events and 55 Clavien III events. At 10 years, 69% had freedom from ADT and 76% had freedom from CRPC. The 10-year DSS rate was 81%, and the 10-year OS rate was 77%. A pre-salvage prostate specific antigen level of >10 ng/ml was associated with an increased risk of developing CRPC and initiation of ADT but was not associated with DSS or OS. The use of neoadjuvant ADT was associated with improved OS and DSS but did not affect freedom from CRPC or adjuvant ADT. CONCLUSIONS: Salvage cryotherapy for RRPCa provides excellent long-term freedom from ADT, CRPC and DSS with acceptable morbidity. OS at 10 years was 77%. Prospective trials are required for validation.


Assuntos
Criocirurgia/efeitos adversos , Terapia Neoadjuvante/métodos , Recidiva Local de Neoplasia/terapia , Complicações Pós-Operatórias/epidemiologia , Neoplasias de Próstata Resistentes à Castração/terapia , Terapia de Salvação/efeitos adversos , Idoso , Antagonistas de Androgênios/farmacologia , Antagonistas de Androgênios/uso terapêutico , Quimioterapia Adjuvante/estatística & dados numéricos , Seguimentos , Humanos , Calicreínas/sangue , Masculino , Terapia Neoadjuvante/estatística & dados numéricos , Recidiva Local de Neoplasia/sangue , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/mortalidade , Complicações Pós-Operatórias/etiologia , Estudos Prospectivos , Próstata/patologia , Próstata/efeitos da radiação , Próstata/cirurgia , Antígeno Prostático Específico/sangue , Neoplasias de Próstata Resistentes à Castração/sangue , Neoplasias de Próstata Resistentes à Castração/diagnóstico , Neoplasias de Próstata Resistentes à Castração/mortalidade , Tolerância a Radiação , Radioterapia Adjuvante/estatística & dados numéricos , Estudos Retrospectivos , Terapia de Salvação/métodos , Taxa de Sobrevida , Resultado do Tratamento
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...