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1.
Cell ; 174(3): 576-589.e18, 2018 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-30033361

RESUMO

Genome-wide association studies (GWAS) have identified rs11672691 at 19q13 associated with aggressive prostate cancer (PCa). Here, we independently confirmed the finding in a cohort of 2,738 PCa patients and discovered the biological mechanism underlying this association. We found an association of the aggressive PCa-associated allele G of rs11672691 with elevated transcript levels of two biologically plausible candidate genes, PCAT19 and CEACAM21, implicated in PCa cell growth and tumor progression. Mechanistically, rs11672691 resides in an enhancer element and alters the binding site of HOXA2, a novel oncogenic transcription factor with prognostic potential in PCa. Remarkably, CRISPR/Cas9-mediated single-nucleotide editing showed the direct effect of rs11672691 on PCAT19 and CEACAM21 expression and PCa cellular aggressive phenotype. Clinical data demonstrated synergistic effects of rs11672691 genotype and PCAT19/CEACAM21 gene expression on PCa prognosis. These results provide a plausible mechanism for rs11672691 associated with aggressive PCa and thus lay the ground work for translating this finding to the clinic.


Assuntos
Neoplasias da Próstata/genética , RNA Longo não Codificante/genética , RNA não Traduzido/genética , Adulto , Alelos , Linhagem Celular Tumoral , Cromossomos Humanos Par 19/genética , Estudos de Coortes , Regulação Neoplásica da Expressão Gênica/genética , Frequência do Gene/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Genótipo , Proteínas de Homeodomínio , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Prognóstico
2.
N Engl J Med ; 386(12): 1132-1142, 2022 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-35179323

RESUMO

BACKGROUND: Darolutamide is a potent androgen-receptor inhibitor that has been associated with increased overall survival among patients with nonmetastatic, castration-resistant prostate cancer. Whether a combination of darolutamide, androgen-deprivation therapy, and docetaxel would increase survival among patients with metastatic, hormone-sensitive prostate cancer is unknown. METHODS: In this international, phase 3 trial, we randomly assigned patients with metastatic, hormone-sensitive prostate cancer in a 1:1 ratio to receive darolutamide (at a dose of 600 mg [two 300-mg tablets] twice daily) or matching placebo, both in combination with androgen-deprivation therapy and docetaxel. The primary end point was overall survival. RESULTS: The primary analysis involved 1306 patients (651 in the darolutamide group and 655 in the placebo group); 86.1% of the patients had disease that was metastatic at the time of the initial diagnosis. At the data cutoff date for the primary analysis (October 25, 2021), the risk of death was significantly lower, by 32.5%, in the darolutamide group than in the placebo group (hazard ratio 0.68; 95% confidence interval, 0.57 to 0.80; P<0.001). Darolutamide was also associated with consistent benefits with respect to the secondary end points and prespecified subgroups. Adverse events were similar in the two groups, and the incidences of the most common adverse events (occurring in ≥10% of the patients) were highest during the overlapping docetaxel treatment period in both groups. The frequency of grade 3 or 4 adverse events was 66.1% in the darolutamide group and 63.5% in the placebo group; neutropenia was the most common grade 3 or 4 adverse event (in 33.7% and 34.2%, respectively). CONCLUSIONS: In this trial involving patients with metastatic, hormone-sensitive prostate cancer, overall survival was significantly longer with the combination of darolutamide, androgen-deprivation therapy, and docetaxel than with placebo plus androgen-deprivation therapy and docetaxel, and the addition of darolutamide led to improvement in key secondary end points. The frequency of adverse events was similar in the two groups. (Funded by Bayer and Orion Pharma; ARASENS ClinicalTrials.gov number, NCT02799602.).


Assuntos
Antagonistas de Receptores de Andrógenos/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Pirazóis/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Antagonistas de Androgênios/uso terapêutico , Antagonistas de Receptores de Andrógenos/efeitos adversos , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Docetaxel/efeitos adversos , Docetaxel/uso terapêutico , Quimioterapia Combinada , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica/tratamento farmacológico , Neutropenia/induzido quimicamente , Modelos de Riscos Proporcionais , Neoplasias da Próstata/mortalidade , Neoplasias da Próstata/patologia , Neoplasias de Próstata Resistentes à Castração , Pirazóis/efeitos adversos
3.
Oncologist ; 29(7): 581-588, 2024 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-38394384

RESUMO

BACKGROUND: Patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) are usually asymptomatic and seek treatments that improve survival but have a low risk of adverse events. Darolutamide, a structurally distinct androgen receptor inhibitor (ARi), significantly reduced the risk of metastasis and death versus placebo in ARAMIS. We assessed the extended safety and tolerability of darolutamide and the time-course profile of treatment-emergent adverse events (TEAEs) related to ARis and androgen-suppressive treatment. PATIENTS AND METHODS: Patients with nmCRPC were randomized 2:1 to darolutamide (n = 955) or placebo (n = 554). After trial unblinding, patients could receive open-label darolutamide. Tolerability and TEAEs were assessed every 16 weeks. Time interval-specific new and cumulative event rates were determined during the first 24 months of the double-blind period. RESULTS: Darolutamide remained well tolerated during the double-blind and open-label periods, with 98.8% of patients receiving the full planned dose. The incidence of TEAEs of interest in the darolutamide group was low and ≤2% different from that in the placebo group, except for fatigue. When incidences were adjusted for exposure time, there were minimal differences between the darolutamide double-blind and double-blind plus open-label periods. The rate of initial onset and cumulative incidence of grade 3/4 TEAEs and serious TEAEs were similar for darolutamide and placebo groups over 24 months. CONCLUSION: Extended treatment with darolutamide was well tolerated and no new safety signals were observed. Most ARi-associated and androgen-suppressive treatment-related TEAEs occurred at low incidences with darolutamide, were similar to placebo, and showed minimal increase over time with continued treatment. TRIAL NUMBER: ClinicalTrials.gov identifier NCT02200614.


Assuntos
Neoplasias de Próstata Resistentes à Castração , Pirazóis , Humanos , Masculino , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/patologia , Idoso , Método Duplo-Cego , Pirazóis/uso terapêutico , Pirazóis/efeitos adversos , Antagonistas de Receptores de Andrógenos/uso terapêutico , Antagonistas de Receptores de Andrógenos/efeitos adversos , Antagonistas de Receptores de Andrógenos/farmacologia , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais
4.
Cancer Causes Control ; 35(4): 695-703, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38063980

RESUMO

PURPOSE: We assessed the risk of death from prostate cancer (PCa) in relation to men's screening histories, i.e., screening attendance among men who were offered screening. METHODS: Men in the Finnish Randomized Study of Screening for Prostate Cancer (FinRSPC) screening arm were invited to up to three screening rounds with the serum prostate-specific antigen (PSA) test at 4-year intervals during 1996-2007. Case subjects (n = 330) were men who died from PCa. Each case was matched to five controls (n = 1544) among the men who were free of PCa. Screening history was defined as (1) never/ever attended screening prior to the case diagnosis; (2) attended at the first screening round; and (3) recency of screening, calculated as the time from last screening attendance to the date of case diagnosis. The association between screening history and the risk of death from PCa was estimated by odds ratios (OR) with 95% confidence intervals (CI) using conditional logistic regression. RESULTS: Having ever attended screening versus never attended was associated with a reduced risk of PCa death (OR 0.60, 95% CI 0.45-0.81) and a similar association was found for those attended (versus not attended) the first screening round (OR 0.67, 95% CI 0.51-0.87). The effect by time since last screen for the risk of PCa death was significantly lower 2-7 years since last screen. CONCLUSION: Among men invited to screening, subjects who attended any PSA screening during the previous 19 years had a 40% reduction in PCa mortality compared to non-screened men.


Assuntos
Antígeno Prostático Específico , Neoplasias da Próstata , Humanos , Masculino , Estudos de Casos e Controles , Detecção Precoce de Câncer , Finlândia/epidemiologia , Programas de Rastreamento
5.
BJU Int ; 134(2): 291-299, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38725182

RESUMO

OBJECTIVE: To evaluate whether a subgroup of men can be identified that would benefit more from screening than others. MATERIALS AND METHODS: This retrospective cohort study was based on three European Randomised Study of Screening for Prostate Cancer (ERSPC) centres, Finland, the Netherlands and Sweden. We identified 126 827 men aged 55-69 years in the study who were followed for maximum of 16 years after randomisation. The primary outcome was prostate cancer (PCa) mortality. We analysed three age groups 55-59, 60-64 and 65-69 years and PCa cases within four European Association of Urology (EAU) risk groups: low, intermediate, high risk, and advanced disease. RESULTS: The hazard ratio (HR) for PCa mortality in the screening arm relative to the control arm for men aged 55-59 years was 0.96 (95% confidence interval [CI] 0.75-1.24) in Finland, 0.70 (95% CI 0.44-1.12) in the Netherlands and 0.42 (95% CI 0.24-0.73) in Sweden. The HR for men aged 60-64 years was 1.03 (95% CI 0.77-1.37) in Finland, 0.76 (95% CI 0.50-1.16) in the Netherlands and 0.97 (95% CI 0.64-1.48) in Sweden. The HR for men aged 65-69 years was 0.80 (95% CI 0.62-1.03) in Finland and 0.57 (95% CI 0.38-0.83) in the Netherlands, and this age group was absent in Sweden. In the EAU risk group analysis, PCa mortality rates were materially lower for men with advanced disease at diagnosis in all three countries: 0.67 (95% CI 0.56-0.82) in Finland, 0.28 (95% CI 0.18-0.44) in the Netherlands, and 0.48 (95% CI 0.30-0.78) in Sweden. CONCLUSION: We were unable to unequivocally identify the optimal age group for screening, as mortality reduction differed among centres and age groups. Instead, the screening effect appears to depend on screening duration, and the number and frequency of screening rounds. PCa mortality reduction by screening is largely attributable to stage shift.


Assuntos
Detecção Precoce de Câncer , Neoplasias da Próstata , Humanos , Masculino , Neoplasias da Próstata/mortalidade , Neoplasias da Próstata/diagnóstico , Pessoa de Meia-Idade , Idoso , Estudos Retrospectivos , Finlândia/epidemiologia , Europa (Continente)/epidemiologia , Suécia/epidemiologia
6.
World J Urol ; 42(1): 217, 2024 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-38581590

RESUMO

PURPOSE: Prostate cancer (PCa) histology, particularly the Gleason score, is an independent prognostic predictor in PCa. Little is known about the inter-reader variability in grading of targeted prostate biopsy based on magnetic resonance imaging (MRI). The aim of this study was to assess inter-reader variability in Gleason grading of MRI-targeted biopsy among uropathologists and its potential impact on a population-based randomized PCa screening trial (ProScreen). METHODS: From June 2014 to May 2018, 100 men with clinically suspected PCa were retrospectively selected. All men underwent prostate MRI and 86 underwent targeted prostate of the prostate. Six pathologists individually reviewed the pathology slides of the prostate biopsies. The five-tier ISUP (The International Society of Urological Pathology) grade grouping (GG) system was used. Fleiss' weighted kappa (κ) and Model-based kappa for associations were computed to estimate the combined agreement between individual pathologists. RESULTS: GG reporting of targeted prostate was highly consistent among the trial pathologists. Inter-reader agreement for cancer (GG1-5) vs. benign was excellent (Model-based kappa 0.90, Fleiss' kappa κ = 0.90) and for clinically significant prostate cancer (csPCa) (GG2-5 vs. GG0 vs. GG1), it was good (Model-based kappa 0.70, Fleiss' kappa κ 0.67). CONCLUSIONS: Inter-reader agreement in grading of MRI-targeted biopsy was good to excellent, while it was fair to moderate for MRI in the same cohort, as previously shown. Importantly, there was wide consensus by pathologists in assigning the contemporary GG on MRI-targeted biopsy suggesting high reproducibility of pathology reporting in the ProScreen trial.


Assuntos
Neoplasias da Próstata , Masculino , Humanos , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/patologia , Detecção Precoce de Câncer , Reprodutibilidade dos Testes , Estudos Retrospectivos , Antígeno Prostático Específico , Biópsia , Imageamento por Ressonância Magnética/métodos , Gradação de Tumores , Biópsia Guiada por Imagem
7.
JAMA ; 331(17): 1452-1459, 2024 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-38581254

RESUMO

Importance: Prostate-specific antigen (PSA) screening has potential to reduce prostate cancer mortality but frequently detects prostate cancer that is not clinically important. Objective: To describe rates of low-grade (grade group 1) and high-grade (grade groups 2-5) prostate cancer identified among men invited to participate in a prostate cancer screening protocol consisting of a PSA test, a 4-kallikrein panel, and a magnetic resonance imaging (MRI) scan. Design, Setting, and Participants: The ProScreen trial is a clinical trial conducted in Helsinki and Tampere, Finland, that randomized 61 193 men aged 50 through 63 years who were free of prostate cancer in a 1:3 ratio to either be invited or not be invited to undergo screening for prostate cancer between February 2018 and July 2020. Interventions: Participating men randomized to the intervention underwent PSA testing. Those with a PSA level of 3.0 ng/mL or higher underwent additional testing for high-grade prostate cancer with a 4-kallikrein panel risk score. Those with a kallikrein panel score of 7.5% or higher underwent an MRI of the prostate gland, followed by targeted biopsies for those with abnormal prostate gland MRI findings. Final data collection occurred through June 31, 2023. Main Outcomes and Measures: In descriptive exploratory analyses, the cumulative incidence of low-grade and high-grade prostate cancer after the first screening round were compared between the group invited to undergo prostate cancer screening and the control group. Results: Of 60 745 eligible men (mean [SD] age, 57.2 [4.0] years), 15 201 were randomized to be invited and 45 544 were randomized not to be invited to undergo prostate cancer screening. Of 15 201 eligible males invited to undergo screening, 7744 (51%) participated. Among them, 32 low-grade prostate cancers (cumulative incidence, 0.41%) and 128 high-grade prostate cancers (cumulative incidence, 1.65%) were detected, with 1 cancer grade group result missing. Among the 7457 invited men (49%) who refused participation, 7 low-grade prostate cancers (cumulative incidence, 0.1%) and 44 high-grade prostate cancers (cumulative incidence, 0.6%) were detected, with 7 cancer grade groups missing. For the entire invited screening group, 39 low-grade prostate cancers (cumulative incidence, 0.26%) and 172 high-grade prostate cancers (cumulative incidence, 1.13%) were detected. During a median follow-up of 3.2 years, in the group not invited to undergo screening, 65 low-grade prostate cancers (cumulative incidence, 0.14%) and 282 high-grade prostate cancers (cumulative incidence, 0.62%) were detected. The risk difference for the entire group randomized to the screening invitation vs the control group was 0.11% (95% CI, 0.03%-0.20%) for low-grade and 0.51% (95% CI, 0.33%-0.70%) for high-grade cancer. Conclusions and Relevance: In this preliminary descriptive report from an ongoing randomized clinical trial, 1 additional high-grade cancer per 196 men and 1 low-grade cancer per 909 men were detected among those randomized to be invited to undergo a single prostate cancer screening intervention compared with those not invited to undergo screening. These preliminary findings from a single round of screening should be interpreted cautiously, pending results of the study's primary mortality outcome. Trial Registration: ClinicalTrials.gov Identifier: NCT03423303.


Assuntos
Detecção Precoce de Câncer , Neoplasias da Próstata , Humanos , Masculino , Pessoa de Meia-Idade , Biópsia , Detecção Precoce de Câncer/métodos , Detecção Precoce de Câncer/estatística & dados numéricos , Calicreínas/sangue , Imageamento por Ressonância Magnética , Gradação de Tumores , Próstata/diagnóstico por imagem , Próstata/patologia , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/sangue , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/patologia , Risco , Finlândia/epidemiologia , Populações Escandinavas e Nórdicas/estatística & dados numéricos , Biomarcadores Tumorais/sangue
8.
Int J Cancer ; 152(4): 672-678, 2023 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-36056577

RESUMO

Prostate-specific antigen (PSA)-based screening for prostate cancer (PCa) can reduce PCa mortality, but also involves overdetection of low-risk disease with potential adverse effects. We evaluated PCa incidence among men with PSA below 3 ng/mL and no PCa diagnosis at the first screening round of the Finnish Randomized Study of Screening for PCa. Follow-up started at the first screening attendance and ended at PCa diagnosis, emigration, death or the common closing date (December 2016), whichever came first. Cox regression analysis was used to estimate hazard ratios and their confidence intervals (CI). Among men with PSA <3 ng/mL, cumulative PCa incidence was 9.1% after 17.6 years median follow-up. Cumulative incidence was 3.6% among men with baseline PSA 0 to 0.99 ng/mL, 11.5% in those with PSA 1.0 to 1.99 ng/mL and 25.7% among men with PSA 2 to 2.99 ng/mL (hazard ratio 9.0, 95% CI: 7.9-10.2 for the latter). The differences by PSA level were most striking for low-risk disease based on Gleason score and EAU risk group. PSA values <1 ng/mL indicate a very low 20-year risk, while at PSA 2 to 2.99 ng/mL risks are materially higher, with 4- to 5-fold risk for aggressive disease. Using risk-stratification and appropriate rescreening intervals will reduce screening intensity and overdetection. Using cumulative incidence of clinically significant PCa (csPCa) as the criterion, rescreening intervals could range from approximately 3 years for men with initial PSA 2 to 2.99 ng/mL, 6 years for men with PSA 1 to 1.99 ng/mL to 10 years for men with PSA <1 ng/mL.


Assuntos
Antígeno Prostático Específico , Neoplasias da Próstata , Masculino , Humanos , Incidência , Finlândia/epidemiologia , Detecção Precoce de Câncer , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/epidemiologia , Fatores de Risco
9.
Prostate ; 83(3): 246-258, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36325820

RESUMO

BACKGROUND: Diabetes has been associated with an increased risk of benign prostatic hyperplasia (BPH). However, the role of antidiabetic drugs as a BPH risk factor is unclear. The objective of our study was to examine the risk of BPH by antidiabetic drug use and glycemic control in a large population-based cohort of Finnish men. METHODS: A total of 74,754 men in the Finnish Randomized Study of Screening for Prostate Cancer (FinRSPC) free of BPH at baseline in 1996-1999 were linked to the national medication reimbursement database for information on physician-prescribed antidiabetic drug purchases. Information on recorded BPH procedures and diagnoses was obtained from the National Care Register for Health Care, and for a subgroup of 17,739 men, information on blood glucose levels (BGLs) from the Fimlab Laboratories database. Cox regression with antidiabetic drug use and BGL as time-dependent variables was used to analyze the risks for starting BPH medication, recorded BPH diagnosis, and undergoing BPH surgery. The analysis was adjusted for age, use of statins, antihypertensive medication, and nonsteroidal anti-inflammatory drugs. RESULTS: Of the subjects, 14,012 men (18.7%) used antidiabetic medication. Of the subgroup with fasting blood glucose data available, 7487 (42.2%) had diabetic level. The risks for BPH diagnosis (HR: 1.08, 95% CI: 1.03-1.13) and surgery (HR: 1.16, 95% CI: 1.09-1.24) were slightly elevated among antidiabetic drug users compared to nonusers. The association was strongest for insulin use. Similarly, risk of BPH surgery was increased in men with diabetic blood glucose compared to normoglycemic men. The risk association was attenuated by use of antidiabetic drugs. CONCLUSIONS: Diabetic BGL and antidiabetic medication use, especially insulin, are associated with an elevated risk of BPH surgery compared to nondiabetic men. These findings support the roles of insulin use and untreated hyperglycemia as possible BPH risk factors.


Assuntos
Diabetes Mellitus , Hiperplasia Prostática , Neoplasias da Próstata , Masculino , Humanos , Hipoglicemiantes/efeitos adversos , Hiperplasia Prostática/tratamento farmacológico , Hiperplasia Prostática/epidemiologia , Hiperplasia Prostática/cirurgia , Glicemia , Controle Glicêmico , Fatores de Risco , Insulina/efeitos adversos
10.
N Engl J Med ; 383(11): 1040-1049, 2020 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-32905676

RESUMO

BACKGROUND: Darolutamide is a structurally distinct androgen-receptor inhibitor that is approved for the treatment of nonmetastatic, castration-resistant prostate cancer. In the planned primary analysis of a phase 3 trial, the median metastasis-free survival was significantly longer with darolutamide (40.4 months) than with placebo (18.4 months). The data for the analysis of overall survival were immature at the time of the primary analysis. METHODS: In this double-blind, placebo-controlled trial, we randomly assigned 1509 men, in a 2:1 ratio, to receive darolutamide (955 patients) or placebo (554 patients) while they continued to receive androgen-deprivation therapy. After the results of the primary end-point analysis were found to be positive, unblinding of the treatment assignments occurred, and patients in the placebo group were permitted to cross over to receive open-label darolutamide treatment. At the time of this prespecified final analysis, which had been planned to be performed after approximately 240 deaths had occurred, overall survival and all other secondary end points were evaluated. RESULTS: The median follow-up time was 29.0 months. At the time of unblinding of the data, all 170 patients who were still receiving placebo crossed over to receive darolutamide; 137 patients who had discontinued placebo before unblinding had occurred received at least one other life-prolonging therapy. Overall survival at 3 years was 83% (95% confidence interval [CI], 80 to 86) in the darolutamide group and 77% (95% CI, 72 to 81) in the placebo group. The risk of death was significantly lower, by 31%, in the darolutamide group than in the placebo group (hazard ratio for death, 0.69; 95% CI, 0.53 to 0.88; P = 0.003). Darolutamide was also associated with a significant benefit with respect to all other secondary end points, including the time to first symptomatic skeletal event and the time to first use of cytotoxic chemotherapy. The incidence of adverse events after the start of treatment was similar in the two groups; no new safety signals were observed. CONCLUSIONS: Among men with nonmetastatic, castration-resistant prostate cancer, the percentage of patients who were alive at 3 years was significantly higher among those who received darolutamide than among those who received placebo. The incidence of adverse events was similar in the two groups. (Funded by Bayer HealthCare and Orion Pharma; ARAMIS ClinicalTrials.gov number, NCT02200614.).


Assuntos
Antagonistas de Receptores de Andrógenos/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Pirazóis/uso terapêutico , Idoso , Antagonistas de Receptores de Andrógenos/efeitos adversos , Estudos Cross-Over , Método Duplo-Cego , Fadiga/induzido quimicamente , Fraturas Ósseas/induzido quimicamente , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Antígeno Prostático Específico/sangue , Neoplasias de Próstata Resistentes à Castração/mortalidade , Neoplasias de Próstata Resistentes à Castração/patologia , Pirazóis/efeitos adversos
11.
Acta Oncol ; 62(12): 1898-1904, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37971326

RESUMO

BACKGROUND: Concerns have been expressed over the safety of testosterone replacement therapy (TRT) in men with late-onset hypogonadism (LOH). Previous studies have shown controversial results regarding the association of TRT with the risk of cardiovascular events or prostate cancer (PCa) incidence, aggressiveness, and mortality. This study explores the overall risk of PCa and risk by tumor grade and stage, as well as mortality from PCa and cardiovascular disease (CVD), among men treated with TRT compared to men without LOH and TRT use. MATERIALS AND METHODS: The study included 78,615 men of age 55-67 years at baseline from the Finnish Randomized Study of Screening for Prostate Cancer (FinRSPC). Follow-up started at randomization and ended at death, emigration, or a common closing date January 1st, 2017. Cox proportional hazards regression model with time-dependent variables and adjustment for age, trial arm, use of other medications, and Charlson comorbidity index was used. Comprehensive information on TRT purchases during 1995-2015 was obtained from the Finnish National Prescription Database. PCa cases were identified from the Finnish Cancer Registry and causes of death obtained from Statistics Finland. RESULTS: Over the course of 18 years of follow-up, 2919 men were on TRT, and 285 PCa cases were diagnosed among them. TRT users did not exhibit a higher incidence or mortality rate of PCa compared to non-users. On the contrary, men using TRT had lower PCa mortality than non-users (HR = 0.52; 95% CI 0.3-0.91). Additionally, TRT users had slightly lower CVD and all-cause mortality compared to non-users (HR = 0.87; 95% CI 0.75-1.01 and HR = 0.93; 95% CI 0.87-1.0, respectively). No time- or dose-dependency of TRT use was evident in any of the analyses. CONCLUSION: Men using TRT were not associated to increased risk for PCa and did not experience increased PCa- or CVD-specific mortality compared to non-users. Further studies considering blood testosterone levels are warranted.


Assuntos
Doenças Cardiovasculares , Hipogonadismo , Neoplasias da Próstata , Idoso , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Cardiovasculares/epidemiologia , Finlândia/epidemiologia , Hipogonadismo/tratamento farmacológico , Hipogonadismo/epidemiologia , Hipogonadismo/induzido quimicamente , Incidência , Testosterona/efeitos adversos
12.
Health Qual Life Outcomes ; 21(1): 89, 2023 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-37580759

RESUMO

BACKGROUND: Researchers and clinicians using common clinical assessments need to attend to the prevalence of missing data to ensure the validity of the information gathered. The Expanded Prostate Cancer Index Short Form (EPIC-26) is a commonly used measurement scale used for assessing patients' quality of life, but the measure lacks comprehensive analysis on missing data. We aimed to explore the quantity of missing answers in EPIC-26 and to characterize patterns and possible explanations of missing data in the survey. METHODS: The survey sample consisted of 625 Finnish prostate cancer patients who participated in a study with a 1-year follow-up with three measurement points (0, 6, and 12 months). Descriptive statistics were used to describe the study population and missingness level. A logistic regression was performed for each EPIC domain to study factors related to missingness during the follow-up. RESULTS: Proportions of missing answers in EPIC-26 were low (3.1-3.9%) between survey rounds. As much as 37% of patients left at least one question unanswered during their follow-up. The hormonal domain produced the most missing answers. Questions about breast tenderness/enlargement (question 13.b.), hot flashes (question 13.a.), frequency of erections (question 10.), and ability to reach orgasm (question 8.b.) were most frequently left unanswered. Higher age, lower education level, no relationship, more severe cancer, lower function scores in some EPIC domains, lower treatment satisfaction or self-rated health were associated with missingness. CONCLUSIONS: Questions 13.b. and 13.a. might be considered female-specific symptoms, thus difficult to comprehend unless patients had already experienced side effects from androgen deprivation therapy. Questions 10. and 8.b. might be difficult to answer if the patient has been sexually inactive. To improve the measure's validity, the questionnaire's hormonal section requires additional explanation that the inquired symptoms are common treatment side effects of anti-androgen therapy; questions 8-10 require a not-applicable category for sexually inactive patients.


Assuntos
Neoplasias da Próstata , Masculino , Humanos , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/diagnóstico , Qualidade de Vida , Antagonistas de Androgênios/uso terapêutico , Prevalência , Inquéritos e Questionários
13.
Acta Anaesthesiol Scand ; 67(3): 347-355, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36547262

RESUMO

BACKGROUND: In open abdominal surgery, continuous epidural analgesia is commonly used method for postoperative analgesia. However, ultrasound (US)-guided fascial plane blocks may be a reasonable alternative. METHODS: In this randomized controlled trial, we compared posterior quadratus lumborum block (QLB) with epidural analgesia for postoperative pain after open radical cystectomy (ORC). Adult patients aged 18-85 with bladder cancer (BC) scheduled for open RC were randomized in two groups. Exclusion criteria were complicated diabetes mellitus type I, lack of cooperation, and persistent pain for reasons other than BC. In one group, a bilateral US-guided single injection posterior QLB was performed with 3.75 mg/ml ropivacaine 20 ml/side. In the other group, continuous epidural analgesia with ropivacaine was used. Basic analgesia was oral paracetamol 1000 mg three times daily, and long-acting opioid twice daily in both groups. All patients had patient-controlled rescue analgesia with oxycodone. Postoperative cumulative rescue opioid consumption was recorded for the day of surgery, and the following 2 postoperative days (POD 0-2). Secondary outcomes were postoperative pain and nausea and vomiting. RESULTS: In total, 20 patients (QLB), and 19 patients (epidural analgesia) groups, were included in the analyses. Cumulative rescue opioid consumption on POD 0, being of duration 9-12 h, was 14 mg (7.6-33.3) in the QLB group versus 6.1 mg (2.0-16.1) in the epidural analgesia group, p = 0.089, and as doses, 8 doses (3.6-15.7) versus 4 doses (1.3-8.5), p = .057. On POD 1 consumption was 25.3 mg (11.0-52.9) versus 18.0 mg (14.4-43.7), p = .749, and as doses 12 (5.5-23.0) versus 10 (8-20), p > .9, respectively. On POD 2 consumption was 19.1 mg (7.9-31.0) versus 18.0 mg (5.4-27.6) p = .749, and as doses 8.5 (5.2-14.7) versus 11 (3.0-18.0) p > .9, respectively. CONCLUSION: Opioid consumption did not differ significantly between posterior QLB and an epidural infusion with ropivacaine for the first 2 postoperative days following RC. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT03328988.


Assuntos
Analgesia Epidural , Neoplasias da Bexiga Urinária , Adulto , Humanos , Ropivacaina , Analgesia Epidural/efeitos adversos , Analgésicos Opioides/uso terapêutico , Cistectomia/efeitos adversos , Dor Pós-Operatória/tratamento farmacológico , Dor Pós-Operatória/etiologia , Neoplasias da Bexiga Urinária/cirurgia , Anestésicos Locais , Ultrassonografia de Intervenção/métodos
14.
Cult Health Sex ; : 1-15, 2023 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-37665659

RESUMO

Narrating illness experiences in a culturally acceptable manner is essential for retaining quality of life after the disruptive event of being diagnosed for prostate cancer. Psychological pressures caused by treatment side-effects such as erectile dysfunction require reinterpretation of the meanings and impacts of these side-effects on masculinity. This helps maintain coherence in men's lives. We studied how men employ culturally available discursive strategies (compensation, redefinition, recontextualisation, and normalisation) in reconstructing masculinity and sexuality. Our data consists of 22 interviews of heterosexual Finnish prostate cancer patients who had undergone surgery. The aim was to analyse the ways in which various life situations and social relations shaped and limited the use of these strategies. Discourse analysis revealed that older age, a supportive spouse, children, supportive male friends, and good health - were key elements men used in reconstructing a coherent new self-image and conception of life following cancer treatment. Men with sexually active male friends, men without families, younger men and men with new intimate relationships struggled to develop a new version of their masculinity. Being able to effectively utilise certain aspects of one's life situation in re-constructing masculinity is important in maintaining quality of life despite troublesome treatment side-effects.

15.
Br J Cancer ; 127(4): 704-711, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35505251

RESUMO

BACKGROUND: Drugs with histone deacetylase inhibitory (HDACi) properties have shown to decrease prostate cancer (PCa) cell growth in vitro. METHODS: A cohort of 9261 PCa cases from the Finnish Randomized Study of Screening for Prostate Cancer (FinRSPC) was used to evaluate prostate cancer-specific mortality in men using anti-epileptic drugs (AEDs). A national subscription database was used to obtain information on medication use. Cox regression with AED use as a time-dependent variable was used to analyse prostate cancer mortality in men using AEDs compared to non-users, and in men using HDACi AEDs compared to users of other AEDs. The analysis was adjusted for age, screening trial arm, PCa risk group, primary treatment of PCa, Charlson co-morbidity score and concomitant use of other drugs. RESULTS: The use of AEDs, in general, was associated with an increased risk of PCa death. The use of HDACi AEDs was not significantly associated with decreased PCa mortality compared to use of other AEDs (HR 0.61, 95% CI 0.31-1.23). CONCLUSIONS: AED usage is associated with elevated PCa mortality compared to non-users, likely reflecting the differences between men with epilepsy and those without. No benefit was observed from HDACi drugs compared to other AEDs.


Assuntos
Detecção Precoce de Câncer , Neoplasias da Próstata , Finlândia/epidemiologia , Humanos , Masculino , Próstata , Antígeno Prostático Específico
16.
N Engl J Med ; 380(13): 1235-1246, 2019 03 28.
Artigo em Inglês | MEDLINE | ID: mdl-30763142

RESUMO

BACKGROUND: Darolutamide is a structurally unique androgen-receptor antagonist that is under development for the treatment of prostate cancer. We evaluated the efficacy of darolutamide for delaying metastasis and death in men with nonmetastatic, castration-resistant prostate cancer. METHODS: We conducted a randomized, double-blind, placebo-controlled, phase 3 trial involving men with nonmetastatic, castration-resistant prostate cancer and a prostate-specific antigen doubling time of 10 months or less. Patients were randomly assigned in a 2:1 ratio to receive darolutamide (600 mg [two 300-mg tablets] twice daily) or placebo while continuing androgen-deprivation therapy. The primary end point was metastasis-free survival, with the presence of metastasis determined by independent central review of radiographic imaging every 16 weeks. RESULTS: In total, 1509 patients underwent randomization (955 to the darolutamide group and 554 to the placebo group). In the planned primary analysis, which was performed after 437 primary end-point events had occurred, the median metastasis-free survival was 40.4 months with darolutamide, as compared with 18.4 months with placebo (hazard ratio for metastasis or death in the darolutamide group, 0.41; 95% confidence interval, 0.34 to 0.50; P<0.001). Darolutamide was also associated with benefits with regard to all secondary end points, including overall survival, time to pain progression, time to cytotoxic chemotherapy, and time to a symptomatic skeletal event. The incidence of adverse events that occurred or worsened during the treatment period and had a frequency of 5% or more or were of grade 3 or higher was similar in the two groups; all such events except fatigue occurred in less than 10% of patients in either group. The percentage of patients who discontinued the assigned regimen because of adverse events was 8.9% in the darolutamide group and 8.7% in the placebo group. Darolutamide was not associated with a higher incidence of seizures, falls, fractures, cognitive disorder, or hypertension than placebo. CONCLUSIONS: Among men with nonmetastatic, castration-resistant prostate cancer, metastasis-free survival was significantly longer with darolutamide than with placebo. The incidence of adverse events was similar for darolutamide and placebo. (Funded by Bayer HealthCare and Orion Pharma; ARAMIS ClinicalTrials.gov number, NCT02200614.).


Assuntos
Antagonistas de Receptores de Andrógenos/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Pirazóis/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Antagonistas de Receptores de Andrógenos/efeitos adversos , Método Duplo-Cego , Fadiga/induzido quimicamente , Humanos , Análise de Intenção de Tratamento , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Antígeno Prostático Específico/sangue , Neoplasias de Próstata Resistentes à Castração/mortalidade , Pirazóis/efeitos adversos , Qualidade de Vida
17.
Cancer Causes Control ; 33(2): 313-320, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34921656

RESUMO

PURPOSE: We explored renal cell cancer (RCC) survival among users of antihypertensive medication as hypertension is proposed to be a risk factor for RCC and ACE-inhibitors and angiotensin receptor blockers (ARBs) have been associated with improved prognosis of RCC. METHODS: Finnish cohort of 13,873 participants with RCC diagnosed between 1995-2012 was formed from three national databases. RCC cases were identified from Finnish Cancer Registry, medication usage from national prescription database and co-morbidities from Care Registry of Healthcare. Logistic regression was used to calculate odds ratios for metastatic tumor extent at the time of diagnosis. Risk of RCC specific death after diagnosis was analyzed using Cox regression adjusted for tumor clinical characteristics. RESULTS: A total of 5,179 participants died of RCC during the follow-up. No risk association was found for metastatic tumor extent for any drug group. ACE-inhibitors, but no other drug group were associated with decreased risk of RCC specific death overall (HR 0.88, 95% CI 0.82-0.95) compared to non-users. In time-dependent analysis high-dose use of ACE-inhibitors (392 Defined Daily Dose (DDD)/year), HR 0.54, 95% CI 0.45-0.66) and ARBs (786.1 DDD/year, HR 0.66, 95% CI 0.50-0.87) associated with improved RCC survival. No information of TNM-classification or tobacco smoking was available. CONCLUSION: ACE-inhibitors and ARBs in high dose associated with improved RCC specific survival. This may reflect overall benefit of treating hypertension with medication targeting renin-angiotensin system (RAS) system among RCC patients. Further studies are needed to explore the role of RAS in RCC.


Assuntos
Neoplasias Renais , Preparações Farmacêuticas , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Humanos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/epidemiologia , Prognóstico , Sistema Renina-Angiotensina
18.
J Urol ; 207(6): 1285-1294, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35470712

RESUMO

PURPOSE: The utility of male lower urinary tract symptoms (LUTS) as mortality risk factors remains unclear. We explored LUTS-associated mortality among Finnish men, evaluating the association of symptom severity and bother with risk of death. MATERIALS AND METHODS: A questionnaire including the Danish Prostatic Symptom Score was mailed to a population-based cohort of 3,143 men aged 50, 60 and 70 years in 1994, with repeat surveys in 1999, 2004, 2009 and 2015. The men were followed until the end of 2018. Mortality associated with LUTS was analyzed using time-dependent Cox regression adjusted for age and comorbidity, updating symptom data every 5 years, including interaction terms between symptoms and associated bother. RESULTS: Of the 1,167 men in the analysis, 591 (50.6%) died during the 24-year followup. In analyses of moderate and severe symptoms disregarding bother, overall voiding and storage LUTS, daytime frequency and urgency incontinence were associated with increased mortality: the multivariable-adjusted hazard ratios were 1.19 (95% CI 1.00-1.40), 1.35 (1.13-1.62), 1.31 (1.09-1.58) and 2.19 (1.42-3.37), respectively. In analyses disregarding symptom severity and bother, voiding LUTS were associated with decreased mortality, while daytime frequency and nocturia were associated with increased mortality: the HRs were 0.82 (95% CI 0.67-1.00), 1.31 (95% CI 1.09-1.58) and 1.52 (95% CI 1.21-1.91), respectively. Excess mortality associated with bothersome daytime frequency and nocturia tended to be slightly higher: the HRs were 1.86 (95% CI 1.41-2.47) and 1.88 (95% CI 1.38-2.58), respectively. No significant interactions were found between symptoms and associated bother, however. CONCLUSIONS: Moderate and severe LUTS are potential risk factors for mortality, independently of their bother.


Assuntos
Sintomas do Trato Urinário Inferior , Noctúria , Incontinência Urinária , Feminino , Finlândia/epidemiologia , Humanos , Sintomas do Trato Urinário Inferior/diagnóstico , Sintomas do Trato Urinário Inferior/epidemiologia , Masculino , Prevalência , Qualidade de Vida , Inquéritos e Questionários
19.
BJU Int ; 130(2): 193-199, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-34958531

RESUMO

OBJECTIVES: To evaluate the feasibility of a population-based screening trial using prostate-specific antigen (PSA), a kallikrein panel and multiparametric magnetic resonance imaging (MRI) aimed at minimizing overdiagnosis, while retaining mortality benefit. PATIENTS AND METHODS: Feasibility of the screening algorithm was evaluated in terms of participation, screening test results and cancer detection. A random sample of 400 men aged 65 years was identified from the population registry and invited for screening with three stepwise tests (PSA, kallikrein panel and MRI). Men with PSA levels ≥3 ng/mL were further tested with the kallikrein panel, and those with positive findings (risk >7.5%) were referred for prostate MRI. Men with positive MRI (Prostate Imaging Reporting and Data System [PI-RADS] score 3-5) had targeted biopsies only. Men with negative MRI, but PSA density ≥0.15 underwent systematic biopsies. RESULTS: Of the 399 men invited, 158 (40%) participated and 27 had PSA levels ≥3 ng/mL (7% of the invited and 17% of the participants). Of these, 22 had a positive kallikrein panel (6% of the invited and 81% of the PSA-positive men). Finally, 10 men (3% of the invited and 45% of 4Kscore [kallikrein panel]-positive) had a suspicious MRI finding (PI-RADS score ≥3) and five were diagnosed with a clinically significant prostate cancer (Gleason Grade Group [GG] ≥2) at fusion biopsy (3% of the participants), with two GG 1 cases (1%). Additional testing (kallikrein panel and MRI) after PSA reduced biopsies by 56%. CONCLUSION: The findings constitute proof of principle for our screening protocol, as we achieved a substantial detection rate for clinically significant cancer with few clinically insignificant cases. Participation, however, was suboptimal.


Assuntos
Antígeno Prostático Específico , Neoplasias da Próstata , Detecção Precoce de Câncer/métodos , Humanos , Biópsia Guiada por Imagem/métodos , Calicreínas , Imageamento por Ressonância Magnética , Masculino , Projetos Piloto , Neoplasias da Próstata/diagnóstico por imagem
20.
Qual Life Res ; 31(3): 855-864, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34291363

RESUMO

INTRODUCTION: This study investigates comments that prostate cancer patients spontaneously write in the margins of the Expanded Prostate Cancer Index Short Form (EPIC-26) questionnaire. We aim to show the possible barriers that patients face while answering the survey, and to consider how these barriers may affect the response data generated. We investigate the kind of information patients' comments on EPIC-26 contain, and patients' motivations to provide this information. We also study why some EPIC domains spark more comments than others. METHOD: We analyzed 28 pages of transcribed comments and four pages of supplementary letters from our survey participants (n = 496). Using inductive content analysis, we generated 10 categories describing the content of participants' comments, and four themes demonstrating their motives for commenting. The comments regarding each EPIC domain were quantified to discover any differences between domains. RESULTS: The sexual domain of EPIC-26 provoked over half of all comments. Patients without recent sexual activity or desire had difficulties answering sexual function questions 8-10. The lack of instructions on whether to take erectile aid use into account when answering erectile function questions led to a diversity of answering strategies. Patients with urinary catheters could not find suitable answer options for questions 1-4. All domains sparked comments containing additional information about experienced symptoms. CONCLUSION: Patients are mainly willing to report their symptoms, but a lack of suitable answer options causes missing data and differing answering strategies in the sexual and urinary domains of EPIC-26, weakening the quality of the response data received.


Assuntos
Neoplasias da Próstata , Qualidade de Vida , Humanos , Masculino , Neoplasias da Próstata/terapia , Qualidade de Vida/psicologia , Comportamento Sexual , Inquéritos e Questionários
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