RESUMO
PURPOSE: Anticoagulants may reduce mortality of cancer patients, though the evidence remains controversial. We studied the association between different anticoagulants and cancer death. METHODS: All anticoagulant use during 1995-2015 was analyzed among 75,336 men in the Finnish Randomized Study of Screening for Prostate Cancer. Men with prevalent cancer were excluded. Multivariable Cox regression was performed to compare risk of death from any cancer and disease-specific death from 9 specific cancer types between (1) anticoagulant users overall and (2) warfarin users compared to anticoagulant non-users and (3) warfarin or (4) low-molecular-weight heparins (LMWH) compared to users of other anticoagulants. Medication use was analyzed as time-dependent variable to minimize immortal time bias. 1-, 2- and 3-year lag-time analyses were performed. RESULTS: During a median follow-up of 17.2 years, a total of 27,233 men died of whom 8033 with cancer as the primary cause of death. In total, 32,628 men (43%) used anticoagulants. Any anticoagulant use was associated with an increased risk of cancer death (HR = 2.50, 95% CI 2.37-2.64) compared to non-users. Risk was similar independent of the amount, duration, or intensity of use. The risk increase was observed both among warfarin and LMWH users, although not as strong in warfarin users. Additionally, cancer-specific risks of death were similar to overall cancer mortality in all anticoagulant categories. CONCLUSION: Our study does not support reduced cancer mortality among anticoagulant users. Future studies on drug use and cancer mortality should be adjusted for anticoagulants as they are associated with significantly higher risk of cancer death.
Assuntos
Anticoagulantes/uso terapêutico , Heparina de Baixo Peso Molecular/uso terapêutico , Neoplasias da Próstata , Varfarina/uso terapêutico , Idoso , Detecção Precoce de Câncer , Finlândia/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/mortalidade , Fatores de RiscoRESUMO
BACKGROUND: The prognostic value of prostate-specific antigen (PSA) kinetics in untreated prostate cancer (PCa) patients is debatable. We investigated the association between PSA doubling time (PSAdt), PSA velocity (PSAvel) and PSAvel risk count (PSAvRC) and PCa mortality in a cohort of patients with localised PCa managed on watchful waiting. PATIENTS AND METHODS: Patients with clinically localised PCa managed observationally, who were randomised to and remained on placebo for minimum 18 months in the SPCG-6 study, were included. All patients survived at least 2 years and had a minimum of three PSA determinations available. The prognostic value of PSA kinetics was analysed and patients were stratified according to their PSA at consent: ≤10, 10.1-25, and >25 ng/ml. Cumulative incidences of PCa-specific mortality were estimated with the Aalen-Johansen method. RESULTS: Two hundred and sixty-three patients were included of which 116, 76 and 71 had a PSA at consent ≤10, 10.1-25, and >25 ng/ml, respectively. Median follow-up was 13.6 years. For patients with PSA at consent between 10.1 and 25 ng/ml, the 13-year risks of PCa mortality were associated with PSA kinetics: PSAdt ≤3 years: 62.0% versus PSAdt >3 years: 16.3% (Gray's test: P < 0.0001), PSAvel ≥2 ng/ml/year: 48.0% versus PSAvel <2 ng/ml/year: 11.0% (Gray's test: P = 0.0008), and PSAvRC 2: 45.0% versus 0-1: 3.8% (Gray's test: P = 0.001). In contrast, none of the PSA kinetics were significantly associated with changes of 13-year risks of PCa mortality in patients with PSA at consent ≤10 or >25 ng/ml. CONCLUSION: We found that magnitude changes in 13-year risks of PCa mortality that can be indicated by PSA kinetics depend on PSA level in patients with localised PCa who were managed observationally. Our results question PSA kinetics as surrogate marker for PCa mortality in patients with low and high PSA values. CLINICAL TRIAL NUMBER: NCT00672282.
Assuntos
Anilidas/uso terapêutico , Nitrilas/uso terapêutico , Antígeno Prostático Específico/sangue , Prostatectomia , Neoplasias da Próstata/sangue , Neoplasias da Próstata/terapia , Compostos de Tosil/uso terapêutico , Idoso , Anilidas/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Nitrilas/efeitos adversos , Placebos/uso terapêutico , Neoplasias da Próstata/mortalidade , Compostos de Tosil/efeitos adversos , Resultado do TratamentoRESUMO
PURPOSE: Long-term usage of the antiarrhythmic drug digoxin has been connected to lowered risk of prostate cancer. A recent study has suggested that beta-blockers might also have similar risk-decreasing effects. We evaluated the association between use of digoxin, beta-blocker sotalol, and other antiarrhythmic drugs and prostate cancer risk in a retrospective cohort study. METHODS: Our study population consisted of men in the Finnish Prostate Cancer Screening Trial during 1996-2012 (n = 78,615). During median follow-up of 12 years, 6,639 prostate cancer cases were diagnosed. The national prescription database was the source of the information of antiarrhythmic drug purchases. Data were analyzed using Cox regression method with medication use as a time-dependent variable. RESULTS: No association was found for overall prostate cancer risk with antiarrhythmic drug use (HR 1.05 95% CI 0.94-1.18). Neither sotalol (HR 0.97 95% CI 0.76-1.24) nor digoxin (HR 1.01 95% CI 0.87-1.16) users had a decreased risk of prostate cancer. Similar results were obtained for high-grade (Gleason 7-10) and metastatic prostate cancer. Nevertheless, the risk estimates for Gleason 7-10 prostate cancer tended to decrease by duration of digoxin use (p for trend = 0.052), suggesting that the drug may reduce the risk in long-term usage (HR 0.71, 95% CI 0.49-1.03). In analysis stratified by screening trial arm, the protective association against Gleason 7-10 disease was observed only in the screening arm (HR 0.31, 95% CI 0.12-0.84 for men who had used digoxin for 5 years or longer). CONCLUSION: Digoxin or other antiarrhythmic drugs are not associated with any clear decrease in prostate cancer risk. However, digoxin might have a benefit in long-term use by reducing risk of high-grade disease. Further research will be needed to evaluate possible effects on prostate cancer survival.
Assuntos
Antagonistas Adrenérgicos beta/uso terapêutico , Antiarrítmicos/uso terapêutico , Digoxina/uso terapêutico , Neoplasias da Próstata/epidemiologia , Sotalol/uso terapêutico , Idoso , Estudos de Coortes , Finlândia/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Antígeno Prostático Específico , Neoplasias da Próstata/patologia , Fatores de Proteção , Estudos RetrospectivosRESUMO
BACKGROUND: The association between nonsteroidal antiinflammatory drugs (NSAIDs) and prostate cancer risk remains controversial. We examined the risk among NSAID users in 78 615 men in the Finnish Prostate Cancer Screening Trial. METHODS: We obtained information on NSAID prescription usage from Finnish nationwide prescription database and on over-the-counter use by a questionnaire. Prostate cancer cases were identified from the Finnish Cancer Registry. RESULTS: Prostate cancer risk was elevated among current NSAID prescription users irrespective of screening (hazard ratio (HR)=1.45, confidence interval (95% CI)=1.33-1.59 and HR=1.71, 95% CI=1.58-1.86 in the screening and control arm, respectively), but not for previous use of NSAIDs. The risk increase was similar among coxib and acetaminophen current users, and stronger for metastatic prostate cancer (HR=2.41, 95% CI=1.59-3.67 and HR=3.44, 95% CI=2.60-4.55 in the screening and control arm, respectively). Previous use of NSAIDs, aspirin use and over-the-counter NSAID usage were not associated with prostate cancer. CONCLUSIONS: Differing association for current and previous use suggests that the risk increase is unlikely to be directly caused by the medication, but may be due to the conditions indicating NSAID prescription usage, such as symptoms of undiagnosed prostate cancer. To reduce inconsistency between the study outcomes, future epidemiological studies on NSAID use and prostate cancer risk should assess the indications for NSAID usage.
Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Neoplasias da Próstata/etiologia , Idoso , Anti-Inflamatórios não Esteroides/uso terapêutico , Detecção Precoce de Câncer , Finlândia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/epidemiologia , Fatores de RiscoRESUMO
OBJECTIVE: To compare outcome of lower urinary tract symptoms (LUTS) between men with medical and surgical treatment. MATERIALS AND METHODS: A questionnaire was mailed to men aged 55, 65 and 75 years living in Tampere region, Finland in 1999 and the survey was repeated in 2004. LUTS were evaluated using DAN-PSS-1 questionnaire. A total of 1679 men (68% of the eligible) responded to both questionnaires. Of them, 114 men reported LUTS at baseline and medical treatment in the repeat survey and 47 men with LUTS had received surgical treatment. Seventy-two men with prostate cancer were excluded. Men with no medical treatment or surgery for LUTS in either questionnaire were included to no-treatment group. RESULTS: The men after surgical treatment showed a reduction in all LUTS symptom groups. However, among the medically treated and untreated men, all the symptoms worsened during the follow up. The proportion of symptomatic men after surgery was lower than among the medically treated men. In men with medical treatment, the prevalence of all 12 LUTS increased. Dysuria and postmicturition dribble were the only symptoms that had slightly better results in medical than in surgical treatment group. CONCLUSIONS: In this population-based study, operative treatment seemed to relieve LUTS, whereas medical treatment only slowed down their progression. These findings suggest that men with surgical treatment experience a more favourable outcome in LUTS than those receiving medical treatment.
Assuntos
Inibidores de 5-alfa Redutase/uso terapêutico , Antagonistas Adrenérgicos/uso terapêutico , Prostatectomia/métodos , Prostatismo/terapia , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
Overexpression of amplified genes is often associated with the acquisition of resistance to cancer therapeutic agents in vitro. We have identified a similar molecular mechanism in vivo for endocrine treatment failure in human prostate cancer which involves amplification of the androgen receptor (AR) gene. Comparative genomic hybridization shows that amplification of the Xq11-q13 region (the location), is common in tumours recurring during androgen deprivation therapy. We found high-level AR amplification in seven of 23 (30%) recurrent tumours, but in none of the specimens taken from the same patients prior to therapy. Our results suggest that AR amplification emerges during androgen deprivation therapy by facilitating tumour cell growth in low androgen concentrations.
Assuntos
Amplificação de Genes , Neoplasias da Próstata/genética , Receptores Androgênicos/genética , Idoso , Resistência a Medicamentos/genética , Humanos , Hibridização in Situ Fluorescente/métodos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/terapia , Cromossomo XRESUMO
Over 200,000 new prostate cancer cases are diagnosed in the United States each year, accounting for more than 35% of all cancer cases affecting men, and resulting in 40,000 deaths annually. Attempts to characterize genes predisposing to prostate cancer have been hampered by a high phenocopy rate, the late age of onset of the disease and, in the absence of distinguishing clinical features, the inability to stratify patients into subgroups relative to suspected genetic locus heterogeneity. We previously performed a genome-wide search for hereditary prostate cancer (HPC) genes, finding evidence of a prostate cancer susceptibility locus on chromosome 1 (termed HPC1; ref. 2). Here we present evidence for the location of a second prostate cancer susceptibility gene, which by heterogeneity estimates accounts for approximately 16% of HPC cases. This HPC locus resides on the X chromosome (Xq27-28), a finding consistent with results of previous population-based studies suggesting an X-linked mode of HPC inheritance. Linkage to Xq27-28 was observed in a combined study population of 360 prostate cancer families collected at four independent sites in North America, Finland and Sweden. A maximum two-point lod score of 4.60 was observed at DXS1113, theta=0.26, in the combined data set. Parametric multipoint and non-parametric analyses provided results consistent with the two-point analysis. Significant evidence for genetic locus heterogeneity was observed, with similar estimates of the proportion of linked families in each separate family collection. Genetic mapping of the locus represents an important initial step in the identification of an X-linked gene implicated in the aetiology of HPC.
Assuntos
Predisposição Genética para Doença/genética , Neoplasias da Próstata/genética , Cromossomo X , Adulto , Idoso , Idoso de 80 Anos ou mais , Mapeamento Cromossômico , Marcadores Genéticos , Genótipo , Humanos , Escore Lod , Masculino , Pessoa de Meia-Idade , Linhagem , Receptores Androgênicos/genéticaRESUMO
To compare the effect of statin use in relation to castration-resistant prostate cancer (CRPC) treatment, we assessed the risk of ADT-treated PCa-patients to initiate CRPC treatment by statin use and the outcomes of CRPC treatment by statin use. Our study cohort consisted of 1169 men who participated in the Finnish Randomized Study of Screening for Prostate Cancer (FinRSPC) and initiated androgen deprivation therapy (ADT) during the follow-up (1996-2017). Statin use was associated with slightly decreased risk of initiating CRPC treatment (HR 0.68; 95% CI 0.47-0.97) with a 5.7 years' median follow-up until CRPC for non-users and 7.5 years for statin users. The risk of discontinuation of first or second line CRPC treatment due to inefficacy was not modified by statin use and the results remained similar in subgroup analysis assessing separately patients treated with taxans or androgen receptor signaling inhibitors. We observed an inverse association between statin use and the risk of initiation of the CRPC treatment. No beneficial risk modification by statin use during CRPC treatment was observed. These results suggest that statins might be beneficial during hormone-sensitive phase but not in the later phases of prostate cancer treatment.
Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases , Neoplasias de Próstata Resistentes à Castração , Neoplasias da Próstata , Masculino , Humanos , Neoplasias da Próstata/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Antagonistas de Androgênios/uso terapêutico , Próstata , FinlândiaRESUMO
BACKGROUND: Silodosin is a new selective therapy with a high pharmacologic selectivity for the a (1A)-adrenoreceptor. OBJECTIVE: Our aim was to test silodosin's superiority to placebo and noninferiority to tamsulosin and discuss the findings in the context of a comprehensive literature review of the new compound silodosin. DESIGN, SETTING, AND PARTICIPANTS: We conducted a multicenter double-blind, placebo-and active-controlled parallel group study. A total of 1228 men > or = 50 yr of age with an International Prostate Symptom Score (IPSS) < or = 13 and a urine maximum flow rate (Q(max))> 4 and < or = 15 ml/s were selected at 72 sites in 11 European countries. The patients were entered into a 2-wk wash-out and a 4-wk placebo run-in period. A total of 955 patients were randomized (2:2:1) to silodosin 8 mg (n = 381), tamsulosin 0.4 mg (n = 384), or placebo (n = 190) once daily for 12 wk. MEASUREMENTS: We calculated the change from baseline in IPSS total score (primary), storage and voiding subscores, quality of life (QoL) due to urinary symptoms, and Q(max). Responders were defined on the basis of IPSS and Q(max) by a decrease of > or = 25% and an increase of > or = 30% from baseline, respectively. RESULTS AND LIMITATIONS: The change from baseline in the IPSS total score with silodosin and tamsulosin was significantly superior to that with placebo (p < 0.001): difference active placebo of -2.3 (95% confidence interval [CI], -3.2, -1.4) with silodosin and -2.0 (95% CI, -2.9, -1.1) with tamsulosin. Responder rates according to total IPSS were significantly higher (p < 0.001) with silodosin (66.8%) and tamsulosin (65.4%) than with placebo (50.8%). Active treatments were also superior to placebo in the IPSS storage and voiding subscore analyses, as well as in QoL due to urinary symptoms. Of note, only silodosin significantly reduced nocturia versus placebo (the change from baseline was -0.9, -0.8, and -0.7 for silodosin, tamsulosin, and placebo, respectively; p = 0.013 for silodosin vs placebo). An increase in Q(max) was observed in all groups. The adjusted mean change from baseline to end point was 3.77 ml/s for silodosin, 3.53 ml/s for tamsulosin, and 2.93 ml/s for placebo, but the change for silodosin and tamsulosin was not statistically significant versus placebo because of a particularly high placebo response (silodosin vs placebo: p = 0.089; tamsulosin vs placebo: p = 0.221). At end point, the percentage of responders by Q(max) was 46.6%, 46.5%, and 40.5% in the silodosin, tamsulosin, and placebo treatment groups, respectively. This difference was not statistically significant (p = 0.155 silodosin vs placebo and p = 0.141 tamsulosin vs placebo). Active treatments were well tolerated, and discontinuation rates due to adverse events were low in all groups (2.1%, 1.0%, and 1.6% with silodosin, tamsulosin, and placebo, respectively). The most frequent adverse event with silodosin was a reduced or absent ejaculation during orgasm (14%), a reversible effect as a consequence of the potent and selective a(1A)-adrenoreceptor antagonism of the drug. The incidence was higher than that observed with tamsulosin (2%); however, only 1.3% of silodosin-treated patients discontinued treatment due to this adverse event. CONCLUSIONS: Silodosin is an effective and well-tolerated treatment for the relief of both voiding and storage symptoms in patients with lower urinary tract symptoms suggestive of bladder outlet obstruction thought to be associated with benign prostatic hyperplasia. Its overall efficacy is not inferior to tamsulosin. Only silodosin showed a significant effect on nocturia over placebo.
Assuntos
Antagonistas de Receptores Adrenérgicos alfa 1/administração & dosagem , Indóis/administração & dosagem , Hiperplasia Prostática/tratamento farmacológico , Antagonistas de Receptores Adrenérgicos alfa 1/efeitos adversos , Adulto , Idoso , Método Duplo-Cego , Ejaculação/efeitos dos fármacos , Europa (Continente) , Humanos , Indóis/efeitos adversos , Masculino , Pessoa de Meia-Idade , Hiperplasia Prostática/fisiopatologia , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Tansulosina , Fatores de Tempo , Bexiga Urinária/fisiopatologia , Micção/efeitos dos fármacosRESUMO
Diabetic men have decreased risk for prostate cancer (PCa) overall and lower PSA compared to non-diabetics. This may affect the outcomes of PSA-based screening. We investigated the effect of PSA-based screening at 4-year intervals on PCa incidence and mortality separately among users and non-users of antidiabetic medication with the hypothesis that screening would detect less low-grade cancer and more high-grade cancer in diabetic men. A cohort of 80,458 men from the Finnish Randomized Study of Screening for Prostate Cancer (FinRSPC) were linked to national prescription database to obtain information on antidiabetic medication purchases. PCa risk and mortality were compared between the FinRSPC screening arm (SA) and the control arm (CA) separately among users and non-users of antidiabetic medication. Among antidiabetic medication users median PSA was lower than in non-users (0.93 and 1.09 ng/ml, respectively, P for difference = 0.001). Screening increased overall PCa incidence compared to CA after the first screen both among medication users and non-users (HR 1.31, 95% CI 1.08-1.60 and HR 1.55, 95% CI 1.44-1.66, respectively). On the second and third screen the difference between SA and CA attenuated only among medication users. Detection of Gleason 6 tumors was lower among medication users, whereas no difference was observed in detection of Gleason 8-10 cancers. Concordantly, screening affected PCa mortality similarly regardless of antidiabetic medication use (HR 0.38, 95% CI 0.14-1.07 and HR 0.19, 95% CI 0.11-0.33 among users and non-users after three screens, respectively. P for difference = 0.18). Median PSA is lower in men using antidiabetic drugs than among non-users. Systematic PSA screening detects less low-risk tumors among medication users, whereas detection of high-risk tumors and mortality effects are similar regardless of medication use. This suggests that antidiabetic medication users may form a suitable target group for PCa screening, with less screening-related overdiagnosis of indolent tumors.
Assuntos
Detecção Precoce de Câncer/estatística & dados numéricos , Hipoglicemiantes/uso terapêutico , Neoplasias da Próstata/diagnóstico , Idoso , Bases de Dados Factuais , Complicações do Diabetes/diagnóstico , Progressão da Doença , Finlândia , Seguimentos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Antígeno Prostático Específico/biossíntese , Neoplasias da Próstata/complicações , Neoplasias da Próstata/epidemiologia , Risco , Resultado do TratamentoRESUMO
PURPOSE: Statins' cholesterol-lowering efficacy is well-known. Recent epidemiological studies have found that inhibition of cholesterol synthesis may have beneficial effects on prostate cancer (PCa) patients, especially patients treated with androgen deprivation therapy (ADT). We evaluated statins' effect on prostate cancer prognosis among patients treated with ADT. MATERIALS AND METHODS: Our study population consisted of 8253 PCa patients detected among the study population of the Finnish randomized study of screening for prostate cancer. These were limited to 4428 men who initiated ADT during the follow-up. Cox proportional regression model adjusted for tumor clinical characteristics and comorbidities was used to estimate hazard ratios for risk of PSA relapse after ADT initiation and prostate cancer death. RESULTS: During the median follow-up of 6.3 years after the ADT initiation, there were 834 PCa deaths and 1565 PSA relapses in a study cohort. Statin use after ADT was associated with a decreased risk of PSA relapse (HR 0.73, 95% CI 0.65-0.82) and prostate cancer death (HR 0.82; 95% CI 0.69-0.96). In contrast, statin use defined with a one-year lag (HR 0.89, 95% CI 0.76-1.04), statin use before ADT initiation (HR 1.12, 95% CI 0.96-1.31), and use in the first year on ADT (HR 1.02, 95% CI 0.85-1.24) were not associated with prostate cancer death, without dose dependency. CONCLUSION: Statin use after initiation of ADT, but not before, was associated with improved prostate cancer prognosis.
Assuntos
Neoplasias da Próstata/tratamento farmacológico , Idoso , Antagonistas de Androgênios , Estudos de Casos e Controles , Progressão da Doença , Quimioterapia Combinada , Finlândia/epidemiologia , Seguimentos , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases , Masculino , Pessoa de Meia-Idade , Prognóstico , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/patologia , Taxa de SobrevidaRESUMO
Prostate cancer is heterogeneous and patients would benefit from methods that stratify those who are likely to respond to systemic therapy. Here, we employ single-cell assays for transposase-accessible chromatin (ATAC) and RNA sequencing in models of early treatment response and resistance to enzalutamide. In doing so, we identify pre-existing and treatment-persistent cell subpopulations that possess regenerative potential when subjected to treatment. We find distinct chromatin landscapes associated with enzalutamide treatment and resistance that are linked to alternative transcriptional programs. Transcriptional profiles characteristic of persistent cells are able to stratify the treatment response of patients. Ultimately, we show that defining changes in chromatin and gene expression in single-cell populations from pre-clinical models can reveal as yet unrecognized molecular predictors of treatment response. This suggests that the application of single-cell methods with high analytical resolution in pre-clinical models may powerfully inform clinical decision-making.
Assuntos
Cromatina/química , DNA de Neoplasias/genética , Resistencia a Medicamentos Antineoplásicos/genética , Proteínas de Neoplasias/genética , Neoplasias da Próstata/genética , Transcriptoma , Antineoplásicos/uso terapêutico , Benzamidas/uso terapêutico , Linhagem Celular Tumoral , Cromatina/metabolismo , DNA de Neoplasias/metabolismo , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Proteínas de Neoplasias/metabolismo , Nitrilas/uso terapêutico , Feniltioidantoína/uso terapêutico , Próstata/metabolismo , Próstata/patologia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/mortalidade , Neoplasias da Próstata/patologia , Análise de Sequência de RNA/métodos , Análise de Célula Única/métodos , Análise de Sobrevida , Sequenciamento do ExomaRESUMO
BACKGROUND: There is evidence that prostate cancer (PC) screening with prostate-specific antigen (PSA) serum test decreases PC mortality, but screening has adverse effects, such as a high false-positive (FP) rate. We investigated the proportion of FPs in a population-based randomised screening trial in Finland. METHODS: Finland is the largest centre in the European Randomized Study of Screening for Prostate Cancer. We have completed three screening rounds with a 4-year screening interval (mean follow-up time 9.2 years) using a PSA cutoff level of 4.0 ng ml(-1); in addition, men with PSA 3.0-3.9 and a positive auxiliary test were referred. An FP result was defined as a positive screening result without cancer in biopsy within 1 year from the screening test. RESULTS: The proportion of FP screening results varied from 3.3 to 12.1% per round. Of the screened men, 12.5% had at least one FP during three rounds. The risk of next-round PC following an FP result was 12.3-19.7 vs 1.4-3.7% following a screen-negative result (depending on the screening round), risk ratio 3.6-9.9. More than half of the men with one FP result had another one at a subsequent screen. Men with an FP result were 1.5 to 2.0 times more likely to not participate in subsequent rounds compared with men with a normal screening result (21.6-29.6 vs 14.0-16.7%). CONCLUSION: An FP result is a common adverse effect of PC screening and affects at least every eighth man screened repeatedly, even when using a relatively high cutoff level. False-positive men constitute a special group that receives unnecessary interventions but may harbour missed cancers. New strategies are needed for risk stratification in PC screening to minimise the proportion of FP men.
Assuntos
Programas de Rastreamento , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/diagnóstico , Idoso , Biópsia , Detecção Precoce de Câncer , Reações Falso-Positivas , Finlândia , Humanos , Masculino , Pessoa de Meia-Idade , Próstata/patologia , Hiperplasia Prostática/tratamento farmacológicoRESUMO
Growing evidence points to a role for inflammation in prostate carcinogenesis. The significance of C-reactive protein (CRP), an inflammatory and innate immunity molecule, has not been evaluated thoroughly in prostate cancer (PC). In this study of 739 Finnish patients with PC and 760 healthy men, we evaluated the associations of CRP genotypes and haplotypes with total PC risk and PC progression, using prostate-specific antigen (PSA) as a marker of metastatic disease. Although the haplotype frequencies were similar in patients and controls, an association between haplotype ACCCA and patients' PSA levels was found. The carriers more often had a high PSA than non-carriers (P=0.0002) and the SNP rs2794521 A-allele and rs1800947 C-allele carriers had a higher PSA than non-carriers (P=0.009 and P=0.0004, respectively). A trend for a younger age at diagnosis was found among the carriers of ACCCA (P=0.07) and the rs1800947 C-allele (P=0.06), as well as a trend for the latter to have more likely metastases (P=0.06), but not after Bonferroni correction (alpha=0.00208). This is the first study to suggest association between PSA and CRP variants in PC and, therefore, further studies are warranted. CRP alleles previously found to protect against increased CRP levels are now suggested to be associated with metastatic PC, indicated by elevated PSA.
Assuntos
Biomarcadores Tumorais/sangue , Neoplasias Ósseas/genética , Proteína C-Reativa/genética , Haplótipos/genética , Polimorfismo de Nucleotídeo Único/genética , Antígeno Prostático Específico/genética , Neoplasias da Próstata/genética , Adolescente , Adulto , Idoso , Neoplasias Ósseas/sangue , Neoplasias Ósseas/secundário , Proteína C-Reativa/metabolismo , Estudos de Casos e Controles , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/sangue , Neoplasias da Próstata/patologia , Fatores de Risco , Taxa de Sobrevida , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: The Prostate Cancer Prevention Trial has shown a protective effect of finasteride on prostate cancer in low-risk men. It is uncertain whether similar results can be expected when finasteride is used to treat benign prostatic hyperplasia. METHODS: We performed an observational cohort study within the Finnish Prostate Cancer Screening Trial. Using a comprehensive prescription database on medication reimbursements during 1995-2004 of men using finasteride or alpha-blockers for benign prostatic hyperplasia, we evaluated prostate cancer incidence among 23 320 men screened during 1996-2004. RESULTS: Compared to medication non-users, overall prostate cancer incidence was not significantly affected in finasteride users (hazard ratio 0.87; 95% CI 0.63-1.19). Incidence of Gleason 2-6 tumours, however, was decreased among finasteride users (HR 0.59; 95% CI 0.38-0.91), whereas incidence of Gleason 7-10 tumours was unchanged (HR 1.33; 95% CI 0.77-2.30). The protective effect concerned mainly screen-detected tumours. Overall prostate cancer risk was not significantly reduced among alpha-blocker users relative to non-users, but decreased incidence of high-grade tumours was observed (0.55; 95% CI 0.31-0.96). CONCLUSIONS: The detection of low-grade, early-stage tumours is decreased among men who use finasteride for symptomatic BPH. The protective effect of finasteride can also be expected in men with benign prostatic hyperplasia.
Assuntos
Antagonistas Adrenérgicos alfa/uso terapêutico , Finasterida/uso terapêutico , Programas de Rastreamento , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/prevenção & controle , Idoso , Estudos de Coortes , Interpretação Estatística de Dados , Finlândia/epidemiologia , Seguimentos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/tratamento farmacológico , Fatores de Risco , Fatores de TempoRESUMO
BACKGROUND: Prostate cancer (PCa) is a leading cause of mortality and genetic factors can influence tumour aggressiveness. Several germline variants have been associated with PCa-specific mortality (PCSM), but further replication evidence is needed. METHODS: Twenty-two previously identified PCSM-associated genetic variants were genotyped in seven PCa cohorts (12,082 patients; 1544 PCa deaths). For each cohort, Cox proportional hazards models were used to calculate hazard ratios and 95% confidence intervals for risk of PCSM associated with each variant. Data were then combined using a meta-analysis approach. RESULTS: Fifteen SNPs were associated with PCSM in at least one of the seven cohorts. In the meta-analysis, after adjustment for clinicopathological factors, variants in the MGMT (rs2308327; HR 0.90; p-value = 3.5 × 10-2) and IL4 (rs2070874; HR 1.22; p-value = 1.1 × 10-3) genes were confirmed to be associated with risk of PCSM. In analyses limited to men diagnosed with local or regional stage disease, a variant in AKT1, rs2494750, was also confirmed to be associated with PCSM risk (HR 0.81; p-value = 3.6 × 10-2). CONCLUSIONS: This meta-analysis confirms the association of three genetic variants with risk of PCSM, providing further evidence that genetic background plays a role in PCa-specific survival. While these variants alone are not sufficient as prognostic biomarkers, these results may provide insights into the biological pathways modulating tumour aggressiveness.
Assuntos
Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Mutação em Linhagem Germinativa , Interleucina-4/genética , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/genética , Neoplasias da Próstata/mortalidade , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Supressoras de Tumor/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Ensaios Clínicos como Assunto , Estudos de Coortes , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Neoplasias da Próstata/patologia , Taxa de SobrevidaRESUMO
It is unclear whether high blood pressure per se or antihypertensive drug use causes erectile dysfunction (ED). The aim of this study was to investigate the effect of cardiovascular diseases and their concomitant medications use on the incidence of ED. The target population consisted of men aged 55, 65 or 75 years old residing in the study area in Finland in 1999. Questionnaires were mailed to 2837 men in 1999 and to 2510 of them 5 years later. The follow-up sample consisted of 1665 men (66% of those eligible) who responded to both baseline and follow-up questionnaires. Men free of moderate or severe ED at baseline (N=1000) were included in the study. ED was assessed by two questions on subject ability to achieve or maintain an erection sufficient for intercourse. Poisson regression model was used in the multivariable analyses. The risk of ED was higher in men suffering from treated hypertension or heart disease than in those with the untreated condition. The risk of ED was higher in men using calcium channel inhibitor (adjusted relative risk (RR)=1.6, 95% confidence interval (CI) 1.0-2.4), angiotensin II antagonist (RR=2.2, 95% CI 1.0-4.7), non-selective beta-blocker (RR=1.7, 95% CI 0.9-3.2) or diuretic (RR=1.3, CI 0.7-2.4) compared with non-users. ED was not associated with using organic nitrates, angiotensin-converting enzyme inhibitors, selective beta-blockers and serum lipid-lowering agents. In summary, calcium channel inhibitors, angiotensin II antagonists, non-selective beta-blockers and diuretics may increase the risk of ED.
Assuntos
Fármacos Cardiovasculares/efeitos adversos , Fármacos Cardiovasculares/uso terapêutico , Disfunção Erétil/epidemiologia , Idoso , Angiotensina II/antagonistas & inibidores , Bloqueadores dos Canais de Cálcio/efeitos adversos , Bloqueadores dos Canais de Cálcio/uso terapêutico , Diuréticos/efeitos adversos , Diuréticos/uso terapêutico , Disfunção Erétil/induzido quimicamente , Finlândia/epidemiologia , Seguimentos , Humanos , Hipertensão/tratamento farmacológico , Incidência , Masculino , Pessoa de Meia-IdadeRESUMO
It is unclear whether lower urinary tract symptoms (LUTS) cause erectile dysfunction (ED) independently or through common underlying pathophysiology and shared risk factors. The aim of this study was to investigate the effect of ED on the incidence of frequency and bother of LUTS. Target population consisted of men aged 50, 60 or 70 years residing in the study area in Finland in 1994. Questionnaires were mailed to 3143 men in 1994 and to 2837 of them 5 years later. The follow-up sample comprised 1683 men who responded to both baseline and follow-up surveys. ED was assessed by two questions on subject's ability to achieve or maintain an erection sufficient for intercourse and LUTS by the Danish Prostatic Symptom Score questionnaire. A dose-response relation was found between the severity of ED at baseline and the incidence of LUTS or bother during follow-up. After adjustment for the confounders, the incidence rate ratio (RR) of LUTS was higher in men with moderate (RR 1.5, 95% confidence interval (CI) 1.0-2.3) or severe ED (RR 2.3, 95% CI 1.4-3.8) than in those free of ED at entry. Compared with men free of ED at baseline, the RRs of urinary bother were 1.6 (95% CI 1.1-2.4), 1.9 (95% CI 1.1-3.2) and 2.2 (95% CI 1.1-4.3) for minimal, moderate or severe ED, respectively. In summary, ED is associated with an increased incidence of LUTS and bother. ED and LUTS may have a common underlying pathophysiology or shared risk factors.
Assuntos
Disfunção Erétil/epidemiologia , Disfunção Erétil/microbiologia , Infecções Urinárias/complicações , Infecções Urinárias/epidemiologia , Idoso , Finlândia/epidemiologia , Seguimentos , Humanos , Incidência , Estudos Longitudinais , Masculino , Pessoa de Meia-IdadeRESUMO
Several linkage and loss of heterozygosity (LOH) analyses suggest that the region 3p21-p26, which is a chromosomal location of MLH1, could harbour a susceptibility gene for prostate cancer (PRCA). Furthermore, in a recent candidate single nucleotide polymorphism (SNP) analysis the I219V variation of the MLH1 gene was associated with PRCA. Microsatellite instability (MSI) and germ-line MLH1 mutations were originally demonstrated in hereditary non-polyposis colorectal cancer (HNPCC) but MSI and loss of MLH1 function have also been detected in PRCA. To assess the contribution of MLH1 germline mutations to the development of PRCA in Finland different approaches were used. First, the samples from 11 PRCA-colon cancer patients were screened for MLH1, MSH2 and MSH6 protein expression by immunohistochemistry (IHC). IHC revealed one patient with a putative MLH1 aberration and sequencing of this sample revealed five sequence variants including two missense variants P434L and I219V. Second, the samples from Finnish hereditary prostate cancer (HPC) families were used for the screening of MLH1 mutations which produced twelve MLH1 sequence variants including two missense mutations, I219V, as in the PRCA-colon cancer patient, and V647M. P434L and V647 were both novel, rare variants. Carrier frequencies of the I219V mutation were compared between hereditary prostate cancer (HPC) patients, unselected PRCA cases, patients with benign prostate hyperplasia and controls, but no differences between the sample groups were found. P434L was not present in this study population and V647M was a very rare variant found only in one HPC family. According to the present results, MLH1 does not have a major role in PRCA causation in Finland.
Assuntos
Proteínas de Transporte/genética , Mutação em Linhagem Germinativa/genética , Mutação de Sentido Incorreto/genética , Proteínas Nucleares/genética , Neoplasias da Próstata/genética , Proteínas Adaptadoras de Transdução de Sinal , Adulto , Idoso , Idoso de 80 Anos ou mais , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Proteína 1 Homóloga a MutL , Linhagem , Sistema de RegistrosRESUMO
Peroxiredoxins (Prxs) 1-6 were assessed in 138 renal cell carcinomas (RCC) using immunohistochemistry and selected samples by Western blotting analysis. Oxidative/nitrosative damage was evaluated using nitrotyrosine immunoreactivity. The expressions of Prxs were correlated with tumor grade and survival and nitrotyrosine reactivity. Non-malignant kidney tubular cells showed positivity with variable intensity for all six Prxs. In RCCs, most cases were positive for Prxs 1 and 2, while only 15-20% of tumors showed expression for Prxs 3 and 4. Prx 2 was associated with tumors of a lower grade (p=0.009) and with a lower frequency of distant metastases (p=0.046). Patients with tumors expressing Prx2 had better prognosis (p=0.027). Instead, nitrotyrosine was significantly associated with high grade tumors (p=0.001). Compared with the non-malignant kidney tubular cells, low Prx expression in the tumor cells can make them more susceptible to oxidative damage. Prx 2 was more abundantly expressed in low grade tumors, suggesting that this protein could play a role in preventing the development of oxidative damage, which in turn can lead to the activation of pathways leading to aggressive tumors.