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1.
BMJ ; 371: m3503, 2020 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-33028540

RESUMO

OBJECTIVE: To assess treatment related changes in quality of life up to 15 years after diagnosis of localised prostate cancer. DESIGN: Population based, prospective cohort study with follow-up over 15 years. SETTING: New South Wales, Australia. PARTICIPANTS: 1642 men with localised prostate cancer, aged less than 70, and 786 controls randomly recruited from the New South Wales electoral roll into the New South Wales Prostate Cancer Care and Outcomes Study (PCOS). MAIN OUTCOME MEASURES: General health and disease specific quality of life were self-reported at seven time points over a 15 year period, using the 12-item Short Form Health Survey scale, University of California, Los Angeles prostate cancer index, and expanded prostate cancer index composite short form (EPIC-26). Adjusted mean differences were calculated with controls as the comparison group. Clinical significance of adjusted mean differences was assessed by the minimally important difference, defined as one third of the standard deviation (SD) from the baseline score. RESULTS: At 15 years, all treatment groups reported high levels of erectile dysfunction, depending on treatment (62.3% (active surveillance/watchful waiting, n=33/53) to 83.0% (non-nerve sparing radical prostatectomy, n=117/141)) compared with controls (42.7% (n=44/103)). Men who had external beam radiation therapy or high dose rate brachytherapy or androgen deprivation therapy as primary treatment reported more bowel problems. Self-reported urinary incontinence was particularly prevalent and persistent for men who underwent surgery, and an increase in urinary bother was reported in the group receiving androgen deprivation therapy from 10 to 15 years (year 10: adjusted mean difference -5.3, 95% confidence interval -10.8 to 0.2; year 15: -15.9; -25.1 to -6.7). CONCLUSIONS: Patients receiving initial active treatment for localised prostate cancer had generally worse long term self-reported quality of life than men without a diagnosis of prostate cancer. Men treated with radical prostatectomy faired especially badly, particularly in relation to long term sexual outcomes. Clinicians and patients should consider these long term quality of life outcomes when making treatment decisions.


Assuntos
Antagonistas de Androgênios , Braquiterapia , Efeitos Adversos de Longa Duração , Prostatectomia , Neoplasias da Próstata , Qualidade de Vida , Idoso , Antagonistas de Androgênios/efeitos adversos , Antagonistas de Androgênios/uso terapêutico , Austrália/epidemiologia , Braquiterapia/efeitos adversos , Braquiterapia/métodos , Estudos de Coortes , Disfunção Erétil/epidemiologia , Disfunção Erétil/etiologia , Humanos , Efeitos Adversos de Longa Duração/epidemiologia , Efeitos Adversos de Longa Duração/etiologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos Prospectivos , Prostatectomia/efeitos adversos , Prostatectomia/métodos , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/patologia , Neoplasias da Próstata/psicologia , Neoplasias da Próstata/terapia , Risco Ajustado , Incontinência Urinária/epidemiologia , Incontinência Urinária/etiologia
2.
Nat Commun ; 11(1): 5070, 2020 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-33033260

RESUMO

The evolutionary progression from primary to metastatic prostate cancer is largely uncharted, and the implications for liquid biopsy are unexplored. We infer detailed reconstructions of tumor phylogenies in ten prostate cancer patients with fatal disease, and investigate them in conjunction with histopathology and tumor DNA extracted from blood and cerebrospinal fluid. Substantial evolution occurs within the prostate, resulting in branching into multiple spatially intermixed lineages. One dominant lineage emerges that initiates and drives systemic metastasis, where polyclonal seeding between sites is common. Routes to metastasis differ between patients, and likely genetic drivers of metastasis distinguish the metastatic lineage from the lineage that remains confined to the prostate within each patient. Body fluids capture features of the dominant lineage, and subclonal expansions that occur in the metastatic phase are non-uniformly represented. Cerebrospinal fluid analysis reveals lineages not detected in blood-borne DNA, suggesting possible clinical utility.


Assuntos
Linhagem da Célula , Biópsia Líquida , Neoplasias da Próstata/patologia , Líquidos Corporais/metabolismo , Cromossomos Humanos Par 8/genética , Células Clonais , Variações do Número de Cópias de DNA/genética , DNA de Neoplasias/genética , Loci Gênicos , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Filogenia
3.
MMWR Morb Mortal Wkly Rep ; 69(41): 1473-1480, 2020 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-33056955

RESUMO

Among U.S. men, prostate cancer is the second leading cause of cancer-related death (1). Past studies documented decreasing incidence of prostate cancer overall since 2000 but increasing incidence of distant stage prostate cancer (i.e., signifying spread to parts of the body remote from the primary tumor) starting in 2010 (2,3). Past studies described disparities in prostate cancer survival by stage, age, and race/ethnicity using data covering ≤80% of the U.S. population (4,5). To provide recent data on incidence and survival of prostate cancer in the United States, CDC analyzed data from population-based cancer registries that contribute to U.S. Cancer Statistics (USCS).* Among 3.1 million new cases of prostate cancer recorded during 2003-2017, localized, regional, distant, and unknown stage prostate cancer accounted for 77%, 11%, 5%, and 7% of cases, respectively, but the incidence of distant stage prostate cancer significantly increased during 2010-2017. During 2001-2016, 10-year relative survival for localized stage prostate cancer was 100%. Overall, 5-year survival for distant stage prostate cancer improved from 28.7% during 2001-2005 to 32.3% during 2011-2016; for the period 2001-2016, 5-year survival was highest among Asian/Pacific Islanders (API) (42.0%), followed by Hispanics (37.2%), American Indian/Alaska Natives (AI/AN) (32.2%), Black men (31.6%), and White men (29.1%). Understanding incidence and survival differences by stage, race/ethnicity, and age can guide public health planning related to screening, treatment, and survivor care. Future research into differences by stage, race/ethnicity, and age could inform interventions aimed at improving disparities in outcomes.


Assuntos
Neoplasias da Próstata/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Grupos de Populações Continentais/estatística & dados numéricos , Grupos Étnicos/estatística & dados numéricos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias/estatística & dados numéricos , Neoplasias da Próstata/etnologia , Neoplasias da Próstata/mortalidade , Neoplasias da Próstata/patologia , Análise de Sobrevida , Estados Unidos/epidemiologia
4.
Urol Clin North Am ; 47(4): 443-456, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33008495

RESUMO

Cancer vaccines, cytokines, and checkpoint inhibitors are immunotherapeutic agents that act within the cancer immunity cycle. Prostate cancer has provided unique opportunities for, and challenges to, immunotherapy drug development, including low tumor mutational burdens, limited expression of PD-L1, and minimal T-cell intratumoral infiltrates. Nevertheless, efforts are ongoing to help prime prostate tumors by turning a "cold" prostate cancer "hot" and thus rendering them more susceptible to immunotherapy. Combination treatments, use of molecular biomarkers, and use of new immunotherapeutic agents provide opportunities to enhance the immune response to prostate tumors.


Assuntos
Vacinas Anticâncer/uso terapêutico , Fatores Imunológicos/uso terapêutico , Imunoterapia/métodos , Neoplasias da Próstata/patologia , Neoplasias da Próstata/terapia , Idoso , Biomarcadores Tumorais/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Prognóstico , Neoplasias da Próstata/mortalidade , Medição de Risco , Análise de Sobrevida , Resultado do Tratamento
5.
Urol Clin North Am ; 47(4): 457-467, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33008496

RESUMO

Biochemically recurrent prostate cancer represents a stage of prostate cancer where conventional (continued on next page) computed tomography and technetium Tc 99m bone scan imaging are unable to detect disease after curative intervention despite rising prostate-specific antigen. There is no clear standard of care and no systemic therapy has been shown to improve survival. Immunotherapy-based treatments potentially are attractive options relative to androgen deprivation therapy due to the generally more favorable side-effect profile. Biochemically recurrent prostate cancer patients have a low tumor burden and likely lymph node-based disease, which may make them more likely to respond to immunotherapy.


Assuntos
Antagonistas de Androgênios/uso terapêutico , Imunoterapia/métodos , Recidiva Local de Neoplasia/terapia , Neoplasias da Próstata/patologia , Idoso , Terapia Combinada , Intervalo Livre de Doença , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/diagnóstico por imagem , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Seleção de Pacientes , Prognóstico , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/mortalidade , Neoplasias da Próstata/terapia , Medição de Risco , Papel (figurativo) , Análise de Sobrevida , Tomografia Computadorizada por Raios X/métodos , Resultado do Tratamento
6.
Urol Clin North Am ; 47(4): 475-485, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33008498

RESUMO

Cancer is a highly complex and heterogeneous disease and immunotherapy has shown promise as a therapeutic approach. The increased resolution afforded by single-cell analysis offers the hope of finding and characterizing previously underappreciated populations of cells that could prove useful in understanding cancer progression and treatment. Urologic and prostate cancers are inherently heterogeneous diseases, and the potential for single-cell analysis to help understand and develop immunotherapeutic approaches to treat these diseases is very exciting. In this review, we view cancer immunotherapy through a single-cell lens and discuss the state-of-the-art technologies that enable advances in this field.


Assuntos
Imunoterapia/métodos , Terapia de Alvo Molecular/métodos , Neoplasias da Próstata/genética , Neoplasias da Próstata/terapia , Microambiente Tumoral/efeitos dos fármacos , Feminino , Previsões , Humanos , Masculino , Terapia de Alvo Molecular/tendências , Prognóstico , Neoplasias da Próstata/patologia , Medição de Risco , Análise de Sequência de DNA , Análise de Sequência de RNA , Análise de Célula Única , Resultado do Tratamento , Microambiente Tumoral/genética , Neoplasias Urológicas/genética , Neoplasias Urológicas/patologia , Neoplasias Urológicas/terapia
7.
Urol Clin North Am ; 47(4): 487-510, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33008499

RESUMO

The advent of immunotherapy has revolutionized cancer treatment. Prostate cancer has an immunosuppressive microenvironment and a low tumor mutation burden, resulting in low neoantigen expression. The consensus was that immunotherapy would be less effective in prostate cancer. However, recent studies have reported that prostate cancer does have a high number of DNA damage and repair gene defects. Immunotherapies that have been tested in prostate cancer so far have been mainly vaccines and checkpoint inhibitors. A combination of genomically targeted therapies, with approaches to alleviate immune response and thereby make the tumor microenvironment immunologically hot, is promising.


Assuntos
Produtos Biológicos/administração & dosagem , Vacinas Anticâncer/administração & dosagem , Imunoterapia/métodos , Neoplasias da Próstata/patologia , Neoplasias da Próstata/terapia , Microambiente Tumoral/efeitos dos fármacos , Idoso , Animais , Antígenos de Neoplasias/efeitos dos fármacos , Antígenos de Neoplasias/imunologia , Previsões , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Terapia de Alvo Molecular/métodos , Invasividade Neoplásica/patologia , Metástase Neoplásica/genética , Metástase Neoplásica/imunologia , Estadiamento de Neoplasias , Neoplasias da Próstata/genética , Resultado do Tratamento , Microambiente Tumoral/genética
9.
Lancet Oncol ; 21(10): 1331-1340, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33002437

RESUMO

BACKGROUND: Adjuvant radiotherapy has been shown to halve the risk of biochemical progression for patients with high-risk disease after radical prostatectomy. Early salvage radiotherapy could result in similar biochemical control with lower treatment toxicity. We aimed to compare biochemical progression between patients given adjuvant radiotherapy and those given salvage radiotherapy. METHODS: We did a phase 3, randomised, controlled, non-inferiority trial across 32 oncology centres in Australia and New Zealand. Eligible patients were aged at least 18 years and had undergone a radical prostatectomy for adenocarcinoma of the prostate with pathological staging showing high-risk features defined as positive surgical margins, extraprostatic extension, or seminal vesicle invasion; had an Eastern Cooperative Oncology Group performance status of 0-1, and had a postoperative prostate-specific antigen (PSA) concentration of 0·10 ng/mL or less. Patients were randomly assigned (1:1) using a minimisation technique via an internet-based, independently generated allocation to either adjuvant radiotherapy within 6 months of radical prostatectomy or early salvage radiotherapy triggered by a PSA of 0·20 ng/mL or more. Allocation sequence was concealed from investigators and patients, but treatment assignment for individual randomisations was not masked. Patients were stratified by radiotherapy centre, preoperative PSA, Gleason score, surgical margin status, and seminal vesicle invasion status. Radiotherapy in both groups was 64 Gy in 32 fractions to the prostate bed without androgen deprivation therapy with real-time review of plan quality on all cases before treatment. The primary endpoint was freedom from biochemical progression. Salvage radiotherapy would be deemed non-inferior to adjuvant radiotherapy if freedom from biochemical progression at 5 years was within 10% of that for adjuvant radiotherapy with a hazard ratio (HR) for salvage radiotherapy versus adjuvant radiotherapy of 1·48. The primary analysis was done on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, NCT00860652. FINDINGS: Between March 27, 2009, and Dec 31, 2015, 333 patients were randomly assigned (166 to adjuvant radiotherapy; 167 to salvage radiotherapy). Median follow-up was 6·1 years (IQR 4·3-7·5). An independent data monitoring committee recommended premature closure of enrolment because of unexpectedly low event rates. 84 (50%) patients in the salvage radiotherapy group had radiotherapy triggered by a PSA of 0·20 ng/mL or more. 5-year freedom from biochemical progression was 86% (95% CI 81-92) in the adjuvant radiotherapy group versus 87% (82-93) in the salvage radiotherapy group (stratified HR 1·12, 95% CI 0·65-1·90; pnon-inferiority=0·15). The grade 2 or worse genitourinary toxicity rate was lower in the salvage radiotherapy group (90 [54%] of 167) than in the adjuvant radiotherapy group (116 [70%] of 166). The grade 2 or worse gastrointestinal toxicity rate was similar between the salvage radiotherapy group (16 [10%]) and the adjuvant radiotherapy group (24 [14%]). INTERPRETATION: Salvage radiotherapy did not meet trial specified criteria for non-inferiority. However, these data support the use of salvage radiotherapy as it results in similar biochemical control to adjuvant radiotherapy, spares around half of men from pelvic radiation, and is associated with significantly lower genitourinary toxicity. FUNDING: New Zealand Health Research Council, Australian National Health Medical Research Council, Cancer Council Victoria, Cancer Council NSW, Auckland Hospital Charitable Trust, Trans-Tasman Radiation Oncology Group Seed Funding, Cancer Research Trust New Zealand, Royal Australian and New Zealand College of Radiologists, Cancer Institute NSW, Prostate Cancer Foundation Australia, and Cancer Australia.


Assuntos
Adenocarcinoma/radioterapia , Prostatectomia , Neoplasias da Próstata/radioterapia , Terapia de Salvação , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Adulto , Idoso , Austrália , Progressão da Doença , Intervalo Livre de Doença , Fracionamento da Dose de Radiação , Humanos , Masculino , Doenças Urogenitais Masculinas/epidemiologia , Doenças Urogenitais Masculinas/etiologia , Pessoa de Meia-Idade , Nova Zelândia , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/patologia , Neoplasias da Próstata/cirurgia , Radioterapia Adjuvante/efeitos adversos , Terapia de Salvação/efeitos adversos , Resultado do Tratamento
10.
Lancet Oncol ; 21(10): 1341-1352, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33002438

RESUMO

BACKGROUND: Adjuvant radiotherapy reduces the risk of biochemical progression in prostate cancer patients after radical prostatectomy. We aimed to compare adjuvant versus early salvage radiotherapy after radical prostatectomy, combined with short-term hormonal therapy, in terms of oncological outcomes and tolerance. METHODS: GETUG-AFU 17 was a randomised, open-label, multicentre, phase 3 trial done at 46 French hospitals. Men aged at least 18 years who had an Eastern Cooperative Oncology Group performance status of 1 or less, localised adenocarcinoma of the prostate treated with radical prostatectomy, who had pathologically-staged pT3a, pT3b, or pT4a (with bladder neck invasion), pNx (without pelvic lymph nodes dissection), or pN0 (with negative lymph nodes dissection) disease, and who had positive surgical margins were eligible for inclusion in the study. Eligible patients were randomly assigned (1:1) to either immediate adjuvant radiotherapy or delayed salvage radiotherapy at the time of biochemical relapse. Random assignment, by minimisation, was done using web-based software and stratified by Gleason score, pT stage, and centre. All patients received 6 months of triptorelin (intramuscular injection every 3 months). The primary endpoint was event-free survival. Efficacy and safety analyses were done on the intention-to-treat population. The trial is registered with ClinicalTrials.gov, NCT00667069. FINDINGS: Between March 7, 2008, and June 23, 2016, 424 patients were enrolled. We planned to enrol 718 patients, with 359 in each study group. However, on May 20, 2016, the independent data monitoring committee recommended early termination of enrolment because of unexpectedly low event rates. At database lock on Dec 19, 2019, the overall median follow-up time from random assignment was 75 months (IQR 50-100), 74 months (47-100) in the adjuvant radiotherapy group and 78 months (52-101) in the salvage radiotherapy group. In the salvage radiotherapy group, 115 (54%) of 212 patients initiated study treatment after biochemical relapse. 205 (97%) of 212 patients started treatment in the adjuvant group. 5-year event-free survival was 92% (95% CI 86-95) in the adjuvant radiotherapy group and 90% (85-94) in the salvage radiotherapy group (HR 0·81, 95% CI 0·48-1·36; log-rank p=0·42). Acute grade 3 or worse toxic effects occurred in six (3%) of 212 patients in the adjuvant radiotherapy group and in four (2%) of 212 patients in the salvage radiotherapy group. Late grade 2 or worse genitourinary toxicities were reported in 125 (59%) of 212 patients in the adjuvant radiotherapy group and 46 (22%) of 212 patients in the salvage radiotherapy group. Late genitourinary adverse events of grade 2 or worse were reported in 58 (27%) of 212 patients in the adjuvant radiotherapy group versus 14 (7%) of 212 patients in the salvage radiotherapy group (p<0·0001). Late erectile dysfunction was grade 2 or worse in 60 (28%) of 212 in the adjuvant radiotherapy group and 17 (8%) of 212 in the salvage radiotherapy group (p<0·0001). INTERPRETATION: Although our analysis lacked statistical power, we found no benefit for event-free survival in patients assigned to adjuvant radiotherapy compared with patients assigned to salvage radiotherapy. Adjuvant radiotherapy increased the risk of genitourinary toxicity and erectile dysfunction. A policy of early salvage radiotherapy could spare men from overtreatment with radiotherapy and the associated adverse events. FUNDING: French Health Ministry and Ipsen.


Assuntos
Adenocarcinoma/radioterapia , Antagonistas de Androgênios/administração & dosagem , Prostatectomia , Neoplasias da Próstata/radioterapia , Terapia de Salvação , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Idoso , Progressão da Doença , França , Humanos , Masculino , Doenças Urogenitais Masculinas/epidemiologia , Doenças Urogenitais Masculinas/etiologia , Sobremedicalização/prevenção & controle , Pessoa de Meia-Idade , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Neoplasias da Próstata/cirurgia , Radioterapia Adjuvante/efeitos adversos , Terapia de Salvação/efeitos adversos , Análise de Sobrevida , Resultado do Tratamento
11.
Medicine (Baltimore) ; 99(39): e22336, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32991446

RESUMO

Over the past decades, the incidence of prostate cancer in Taiwan kept rising. Many possible factors including the utility of prostate specific antigen tests, lifestyle remodeling, and patient's comorbidities may contribute to the increasing of incidence or prostate cancer. We aim to use the nationwide Health and Welfare Database (HWD) to investigate possible associated factors.We used HWD, a nationwide database of medical information, to assess the incidence of prostate cancer, utilization of prostate-specific antigen (PSA) test, and underlying diseases of patients and to evaluate whether there was a common trend among these factors.In total, 32,508 patients with newly diagnosed prostate cancer from 2006 to 2013 were identified. The incidence rate of prostate cancer per 100,000 men increased from 35.47 in 2006 to 52.87 in 2012. The number of patients with prostate cancer and underlying diseases related to metabolic syndrome increased every year. The number of total PSA tests and patients undergoing PSA testing, as well as average times of PSA testing per person in the whole population, increased every year. The average PSA test times of patients with newly diagnosed prostate cancer within 3 years before the diagnosis of prostate cancer also increased every year. There was a high correlation between the average PSA test times and the number of patients with newly diagnosed prostate cancer (r = 0.9734).The trends of incidence of prostate cancer, utilization of PSA testing, and underlying diseases related to metabolic syndrome at the diagnoses of cancer were similar, increasing every year in the study period. The results suggested that increasing use of PSA tests may increase the diagnosis of prostate cancers. Underlying diseases related to metabolic syndrome might also affect the incidence of prostate cancer.


Assuntos
Programas de Rastreamento/métodos , Síndrome Metabólica/epidemiologia , Antígeno Prostático Específico/normas , Neoplasias da Próstata/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Comorbidade/tendências , Bases de Dados Factuais , Humanos , Incidência , Estilo de Vida , Masculino , Síndrome Metabólica/complicações , Pessoa de Meia-Idade , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/patologia , Taiwan/epidemiologia
13.
Mol Cell ; 79(6): 1008-1023.e4, 2020 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-32871104

RESUMO

TMPRSS2-ERG gene fusion occurs in approximately 50% of cases of prostate cancer (PCa), and the fusion product is a key driver of prostate oncogenesis. However, how to leverage cellular signaling to ablate TMPRSS2-ERG oncoprotein for PCa treatment remains elusive. Here, we demonstrate that DNA damage induces proteasomal degradation of wild-type ERG and TMPRSS2-ERG oncoprotein through ERG threonine-187 and tyrosine-190 phosphorylation mediated by GSK3ß and WEE1, respectively. The dual phosphorylation triggers ERG recognition and degradation by the E3 ubiquitin ligase FBW7 in a manner independent of a canonical degron. DNA damage-induced TMPRSS2-ERG degradation was abolished by cancer-associated PTEN deletion or GSK3ß inactivation. Blockade of DNA damage-induced TMPRSS2-ERG oncoprotein degradation causes chemotherapy-resistant growth of fusion-positive PCa cells in culture and in mice. Our findings uncover a previously unrecognized TMPRSS2-ERG protein destruction mechanism and demonstrate that intact PTEN and GSK3ß signaling are essential for effective targeting of ERG protein by genotoxic therapeutics in fusion-positive PCa.


Assuntos
Proteínas de Ciclo Celular/genética , Glicogênio Sintase Quinase 3 beta/genética , Proteínas de Fusão Oncogênica/genética , PTEN Fosfo-Hidrolase/genética , Neoplasias da Próstata/genética , Proteínas Tirosina Quinases/genética , Animais , Carcinogênese/genética , Linhagem Celular Tumoral , Dano ao DNA/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Tratamento Farmacológico , Proteína 7 com Repetições F-Box-WD/genética , Xenoenxertos , Humanos , Masculino , Camundongos , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Proteólise/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
14.
Medicine (Baltimore) ; 99(36): e20755, 2020 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-32898989

RESUMO

Ga-PSMA-11 positron emission computed tomography /computed tomography (PET/CT) is more sensitive than magnetic resonance imaging (MRI) in detecting prostate cancer (PCa). We evaluated the value of Ga-PSMA-11 PET/CT with MRI in treatment-naive PCa.This retrospective study was approved by the hospital ethics committee. The MRI and Ga-PSMA-11 PET/CT imaging data of 63 cases of highly suspected PCa were enrolled in this study. The SUVmax and apparent diffusion coefficient (ADC), and their ratio, were assessed as diagnostic markers to distinguish PCa from benign disease.There were 107 prostate lesions detected in 63 cases. Forty cases with 64 malignant primary lesions were confirmed PCa, whereas 23 cases had 43 benign lesions. PSMA-avid lesions correlated with hypointense signal on ADC maps and hyperintense signal on diffusion-weighted imaging. The ADC of PCa was lower than that of benign lesions, and SUVmax and SUVmax/ADC of PCa was higher than that of benign lesions (P < .01). ADC had significant negative correlation with Gleason score (GS) and SUVmax, SUVmax, and SUVmax/ADC positively correlated with GS. From ROC analysis, we established cutoff values of ADC, SUVmax, and SUVmax/ADC at 1.02 × 10mm/s, 11.72, and 12.35, respectively, to differentiate PCa from benign lesions. The sensitivity, specificity, and AUC were 90.6%, 58.1%, and 0.816 for ADC, 67.2%, 97.7%, and 0.905 for SUVmax, and 81.2%, 88.4%, and 0.929 for SUVmax/ADC, respectively.Ga-PSMA-11 PET/CT combined with MRI offers higher diagnostic efficacy in the detection of PCa than either modality alone.


Assuntos
Espectroscopia de Ressonância Magnética/métodos , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons/métodos , Antígeno Prostático Específico/análise , Neoplasias da Próstata/patologia , Idoso , Idoso de 80 Anos ou mais , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias da Próstata/diagnóstico por imagem , Estudos Retrospectivos
15.
Medicine (Baltimore) ; 99(37): e22059, 2020 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-32925739

RESUMO

Magnetic resonance imaging (MRI) targeted biopsy (TBx) of the prostate demonstrated to improve detection rate (DR) of clinically significant prostate cancer (csPCa) in biopsy-naive patients achieving strong level of evidence. Nevertheless, the csPCa yield for TBx alone versus TBx plus systematic biopsy (SBx) after accounting for overlapping of SBx cores with TBx cores, in prior-negative or active surveillance (AS) patients has not been well established.The objective of the study was to investigate benefits in terms of detection rate and pathological stratification of prostate cancer (PCa) using contextual SBx during MRI-TBx.Patients previously submitted to negative-SBx (cohort A) and those enrolled in an AS program (cohort B) who showed at least 1 suspicious area with a PIRADSv2 score ≥ 3 were prospectively and randomly assigned to only TBx strategy versus TBx plus SBx strategy. SBx locations could not encompass the TBx sites, so that the results of each type of biopsy were independent and did not overlap.A total of 312 patients were included in the 2 cohorts (cohort A: 213 cases; cohort B: 99 cases). No significant differences were found in terms of overall PCa-DR (77.6% vs 69.6% respectively; P = .36) and csPCa-DR (48.2% vs 60.9 respectively; P = .12). The MRI-TBx alone cohort showed higher csPCa/PCa ratio (87.5% vs 62.2%; P = .03). The MRI-TBx plus SBx group subanalysis showed significantly higher csPCa-DR obtained at the MRI-TBx cores when compared with the SBx cores (43.7% vs 24.1%, respectively; P = .01). Independently to age, prostatic-specific antigen and prostate imaging-reporting and data system score, either in rebiopsy (OR 0.43, 0.21-0.97) or AS (OR 0.46, 0.32-0.89) setting, SBx cores were negatively associated with the csPCa-DR when combined to TBx cores.MRI-TBx should be considered the elective method to perform prostate biopsy in patients with previous negative SBx and those considered for an AS program. Adding SBx samples to MRI-TBx did not improve detection rate of csPCa.


Assuntos
Biópsia Guiada por Imagem/métodos , Próstata/patologia , Neoplasias da Próstata/patologia , Idoso , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Ultrassonografia , Conduta Expectante
16.
Nat Commun ; 11(1): 4498, 2020 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-32908142

RESUMO

The androgen receptor (AR) is the master regulator of prostate cancer (PCa) development, and inhibition of AR signalling is the most effective PCa treatment. AR is expressed in PCa cells and also in the PCa-associated stroma, including infiltrating macrophages. Macrophages have a decisive function in PCa initiation and progression, but the role of AR in macrophages remains largely unexplored. Here, we show that AR signalling in the macrophage-like THP-1 cell line supports PCa cell line migration and invasion in culture via increased Triggering Receptor Expressed on Myeloid cells-1 (TREM-1) signalling and expression of its downstream cytokines. Moreover, AR signalling in THP-1 and monocyte-derived macrophages upregulates IL-10 and markers of tissue residency. In conclusion, our data suggest that AR signalling in macrophages may support PCa invasiveness, and blocking this process may constitute one mechanism of anti-androgen therapy.


Assuntos
Macrófagos/metabolismo , Neoplasias da Próstata/patologia , Receptores Androgênicos/metabolismo , Receptor Gatilho 1 Expresso em Células Mieloides/metabolismo , Idoso , Antagonistas de Androgênios/farmacologia , Antagonistas de Androgênios/uso terapêutico , Anilidas/farmacologia , Anilidas/uso terapêutico , Biópsia , Buffy Coat/citologia , Estudos de Casos e Controles , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/imunologia , Quimioterapia Adjuvante , Técnicas de Cocultura , Intervalo Livre de Doença , Humanos , Macrófagos/imunologia , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Invasividade Neoplásica/imunologia , Invasividade Neoplásica/prevenção & controle , Nitrilos/farmacologia , Nitrilos/uso terapêutico , Intervalo Livre de Progressão , Próstata/patologia , Próstata/cirurgia , Prostatectomia , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/mortalidade , Neoplasias da Próstata/terapia , Procedimentos Cirúrgicos Robóticos , Transdução de Sinais/imunologia , Análise de Célula Única , Células THP-1 , Compostos de Tosil/farmacologia , Compostos de Tosil/uso terapêutico
17.
Nat Commun ; 11(1): 4301, 2020 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-32879317

RESUMO

Copy-number aberrations (CNAs) and whole-genome duplications (WGDs) are frequent somatic mutations in cancer but their quantification from DNA sequencing of bulk tumor samples is challenging. Standard methods for CNA inference analyze tumor samples individually; however, DNA sequencing of multiple samples from a cancer patient has recently become more common. We introduce HATCHet (Holistic Allele-specific Tumor Copy-number Heterogeneity), an algorithm that infers allele- and clone-specific CNAs and WGDs jointly across multiple tumor samples from the same patient. We show that HATCHet outperforms current state-of-the-art methods on multi-sample DNA sequencing data that we simulate using MASCoTE (Multiple Allele-specific Simulation of Copy-number Tumor Evolution). Applying HATCHet to 84 tumor samples from 14 prostate and pancreas cancer patients, we identify subclonal CNAs and WGDs that are more plausible than previously published analyses and more consistent with somatic single-nucleotide variants (SNVs) and small indels in the same samples.


Assuntos
Neoplasias da Mama/genética , Variações do Número de Cópias de DNA , Duplicação Gênica , Neoplasias Pancreáticas/genética , Neoplasias da Próstata/genética , Neoplasias da Mama/patologia , Conjuntos de Dados como Assunto , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mutação INDEL , Masculino , Taxa de Mutação , Metástase Neoplásica/genética , Neoplasias Pancreáticas/patologia , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/patologia , Análise de Célula Única , Sequenciamento Completo do Exoma
18.
Urologiia ; (4): 79-83, 2020 Sep.
Artigo em Russo | MEDLINE | ID: mdl-32897659

RESUMO

OBJECTIVE: To study the survival rate of patients without biochemical recurrence according to the Stuttgart and Phoenix criteria in terms of their correlation with four different PSA nadir values as predictors of clinical recurrence in patients with localized prostate cancer who underwent total HIFU prostate ablation. MATERIAL AND METHODS: The object of the study was patients with morphologically proven localized RP by biopsy results, who were treated with prostate cancer by HIFU ablation on the Ablatherm Integrated Imaging apparatus (EDAP TMS, France). The study included 658 patients in whom HIFU ablation was used as primary treatment of localized prostate cancer (stages T1 - T2) without previous use of other methods (hormonal, radiation therapy) For the analysis, a continuous sample of patients was selected, which were divided into four groups depending on the PSA nadir level: less or equal 0.2 ng / ml (1 group), 0.21-0.5 ng / ml (group 2), 0.51-1 ng / ml (group 3) and> 1 ng / ml (group 4). sensitivity, specificity, predictive value, and 5-year biochemical relapse-free survival according to the Stuttgart definition and the Phoenix definition in the PSA nadir groups. RESULTS: The median (range) of the observation period for the patients was 5.3 (3-7) years, the mean time to reaching PSA nadir was 14.5+/-2.6 weeks. PSA nadirs less or equal 0.2, 0.21-0.5, 0.51-1.0 and > 1 ng/ml were achieved in 231 (35.1%), 132 (20.0%), 105 (15, 9%) and 190 (28.8%) patients, respectively. Survival without biochemical relapse in accordance with the Stuttgart definition in the four groups allocated for the PSA nadir was 82, 65, 43 and 32%, respectively (p<0.001), according to the Phoenix definition - 94, 74, 66 and 47% (p<0.001) respectively. According to the results of the control biopsy, 601 (91.3%) patients in the 1st and 2nd groups had a negative oncological status (approximately 85%). CONCLUSION: This study confirms that PSA nadir after HIFU ablation predicts biochemical recurrence-free survival and is a reliable marker that is easy to integrate into routine clinical practice.


Assuntos
Antígeno Prostático Específico/sangue , Neoplasias da Próstata/terapia , Ultrassom Focalizado Transretal de Alta Intensidade , Intervalo Livre de Doença , Seguimentos , Humanos , Masculino , Recidiva Local de Neoplasia , Neoplasias da Próstata/patologia , Resultado do Tratamento
19.
Rev Saude Publica ; 54: 87, 2020.
Artigo em Português, Inglês | MEDLINE | ID: mdl-32876300

RESUMO

OBJECTIVE To estimate the magnitude and identify patterns of change in prostate cancer mortality in the state of São Paulo and in the 17 regional health care networks, according to age groups from 50 years onwards, in the period between 2000 to 2015. METHODS Age-adjusted mortality rates (per 100,000 men) were calculated by the direct method using the Segi world population as standard. Joinpoint regression was used to calculate the average annual percent change (AAPC), with a confidence interval of 95% (95%CI), by regional network and age group (50-59, 60-69, 70-79 and 80 years or more). RESULTS For the state of São Paulo, age-adjusted mortality rates were 15.2, 13.3 and 11.9 per 100,000 men, respectively, in the periods between 2000 to 2005, 2006 to 2010 and 2011 to 2015, with a significant decrease trend (AAPC = -2.10%; 95%CI -2.42 - -1.79) each year. Among the 17 networks, 11 presented significant mean annual reductions, ranging from -1.72% to -3.05%. From the age of 50 onwards, there was a sharper reduction in the groups from 50 to 59 (AAPC = -2.33%; 95%CI -3.04 - -1.62) and 60 to 69 years (AAPC = -2.84%; 95%CI - 3.25 - -2.43). CONCLUSION Although reductions in mortality are still slight, they indicate progress in prostate cancer control actions. Screening actions and changes in therapeutic behaviors in recent decades may be modifying incidence and survival, resulting in changes in the mortality profile. More detailed studies will be useful in understanding the factors that lead to the interregional variations found.


Assuntos
Neoplasias da Próstata/mortalidade , Idoso , Brasil/epidemiologia , Meio Ambiente , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Mortalidade , Neoplasias da Próstata/patologia
20.
Am J Clin Oncol ; 43(9): 628-635, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32889832

RESUMO

OBJECTIVES: Stereotactic body radiation treatment represents an intriguing therapeutic option for patients with early-stage prostate cancer. In this phase II study, stereotactic body radiation treatment was delivered by volumetric modulated arc therapy with flattening filter free beams and was gated using real-time electromagnetic transponder system to maximize precision of radiotherapy and, potentially, to reduce toxicities. MATERIALS AND METHODS: Patients affected by histologically proven prostate adenocarcinoma and National Comprehensive Cancer Network (NCCN) intermediate class of risk were enrolled in this phase II study. Beacon transponders were positioned transrectally within the prostate parenchyma 7 to 10 days before simulation computed tomography scan. The radiotherapy schedule was 38 Gy in 4 fractions delivered every other day. Toxicity assessment was performed according to Common Terminology Criteria for Adverse Events (CTCAE), v4.0. RESULTS: Thirty-six patients were enrolled in this study. Median initial prostate-specific antigen was 7.0 ng/mL (range: 2.3 to 14.0 ng/mL). Median nadir-prostate-specific antigen after treatment was 0.2 ng/mL (range: 0.006 to 4.8 ng/mL). A genitourinary acute toxicity was observed in 21 patients (dysuria grade [G] 1: 41.7%, G2: 16.7%). Gastrointestinal acute toxicity was found in 9 patients (proctitis G1: 19.4%, G2: 5.6%). Late toxicity was mild (genitourinary toxicity G1: 30.6%; G2: 8.3%; gastrointestinal toxicity G1: 13.9%; G2: 19.4%). At a median follow-up time of 41 months, 3 biochemical recurrences were observed (2 local recurrences, 1 distant metastasis). Three-year biochemical recurrence-free survival was 89.8% (International Society of Urologic Pathology Grade Group 2: 100%, Grade Group 3: 77.1%, P=0.042). CONCLUSION: Ultrahypofractionated radiotherapy, delivered with flattening filter free-volumetric modulated arc therapy and gated by electromagnetic transponders, is a valid option for intermediate-risk prostate cancer.


Assuntos
Adenocarcinoma/radioterapia , Recidiva Local de Neoplasia/sangue , Neoplasias da Próstata/radioterapia , Radiocirurgia/métodos , Radioterapia de Intensidade Modulada , Adenocarcinoma/secundário , Idoso , Diarreia/etiologia , Intervalo Livre de Doença , Fracionamento da Dose de Radiação , Disuria/etiologia , Fenômenos Eletromagnéticos , Humanos , Masculino , Pessoa de Meia-Idade , Noctúria/etiologia , Proctite/etiologia , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/patologia , Lesões por Radiação/etiologia , Radiocirurgia/efeitos adversos , Radioterapia de Intensidade Modulada/efeitos adversos
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