Standard therapy for metastatic, hormone-sensitive prostate cancer is androgen-deprivation therapy, usually with docetaxel. A large, multinational, phase 3 trial assessed the addition of the ...androgen-receptor blocker darolutamide to standard therapy. At 4 years, survival was higher with darolutamide than with placebo (62.7% vs. 50.4%), with no major differences in the frequency of adverse events.
MicroRNAs (miRNA) are small, endogenously expressed noncoding RNAs that negatively regulate expression of protein-coding genes at the translational level. Accumulating evidence, such as aberrant ...expression of miRNAs, suggests that they are involved in the development of cancer. They have been identified in various tumor types, showing that different sets of miRNAs are usually deregulated in different cancers. To identify the miRNA signature specific for prostate cancer, miRNA expression profiling of 6 prostate cancer cell lines, 9 prostate cancer xenografts samples, 4 benign prostatic hyperplasia (BPH), and 9 prostate carcinoma samples was carried out by using an oligonucleotide array hybridization method. Differential expression of 51 individual miRNAs between benign tumors and carcinoma tumors was detected, 37 of them showing down-regulation and 14 up-regulation in carcinoma samples, thus identifying those miRNAs that could be significant in prostate cancer development and/or growth. There was a significant trend (P=0.029) between the expression of miRNAs and miRNA locus copy number determined by array comparative genomic hybridization, indicating that genetic aberrations may target miRNAs. Hierarchical clustering of the tumor samples by their miRNA expression accurately separated the carcinomas from the BPH samples and also further classified the carcinoma tumors according to their androgen dependence (hormone naive versus hormone refractory), indicating the potential of miRNAs as a novel diagnostic and prognostic tool for prostate cancer.
Men receiving androgen-deprivation therapy for nonmetastatic prostate cancer are at high risk for bone loss and fractures. This placebo-controlled study investigated the effects of denosumab, a fully ...human monoclonal antibody against the receptor activator of nuclear factor-κB ligand, on bone mineral density and fractures in such men. Use of denosumab was associated with increased bone mineral density at all sites and reduction in the incidence of new vertebral fractures.
This study investigated the effects of denosumab on bone mineral density and fractures in men receiving androgen-deprivation therapy for prostate cancer. Use of denosumab was associated with increased bone mineral density at all sites and reduction in the incidence of new vertebral fractures.
Prostate cancer is the most common newly diagnosed cancer in men worldwide.
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In the United States, prostate cancer accounts for approximately 25% of all new cancer diagnoses and 10% of all deaths from cancer.
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Androgen-deprivation therapy, through bilateral orchiectomy or treatment with gonadotropin-releasing hormone (GnRH) agonists, is the standard first-line therapy for metastatic prostate cancer.
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,
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GnRH agonists are also frequently used to treat men with nonmetastatic prostate cancer.
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Androgen-deprivation therapy improves disease-free and overall survival in various clinical settings, such as when used as adjuvant treatment in men with locally advanced prostate cancer who are undergoing radiation therapy
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, . . .
Abstract Background No study has compared the bothersomeness of all lower urinary tract symptoms (LUTS) using a population-based sample of adults. Despite this lack of evidence, investigators have ...often cited their LUTS of interest as the “most bothersome” or “one of the most bothersome.” Objective To compare the population- and individual-level burden of LUTS in men and women. Design, setting, and participants In this population-based cross-sectional study, questionnaires were mailed to 6000 individuals (18–79 yr of age) randomly identified from the Finnish Population Register. Outcome measurements and statistical analysis The validated Danish Prostatic Symptom Score questionnaire was used for assessment of bother of 12 different LUTS. The age-standardized prevalence of at least moderate bother was calculated for each symptom (population-level burden). Among symptomatic individuals, the proportion of affected individuals with at least moderate bother was calculated for each symptom (individual-level bother). Results and limitations A total of 3727 individuals (62.4%) participated (53.7% female). The LUTS with the greatest population-level burden were urgency (7.9% with at least moderate bother), stress urinary incontinence (SUI) (6.5%), nocturia (6.0%), postmicturition dribble (5.8%), and urgency urinary incontinence (UUI) (5.0%). Burden from incontinence symptoms was higher in women than men, and the opposite was true for voiding and postmicturition symptoms. At the individual level, UUI was the most bothersome for both genders. Although the response proportion was high, approximately a third did not participate. Conclusions Both men and women with UUI report moderate or major bother more frequently than individuals with other LUTS. At the population level, the most prevalent bothersome symptoms are urgency, SUI, and nocturia. Patient summary Urinary urgency was the most common troubling symptom in a large population-based study; however, for individuals, urgency incontinence was the most likely to be rated as bothersome.
In this trial, investigators tested the effect of prostate-specific–antigen testing on the death rate from prostate cancer in more than 162,000 men between the ages of 55 and 69 years in seven ...European countries. A significant reduction in prostate-cancer mortality was found after a median follow-up of 9 years. Overdiagnosis and overtreatment were important limitations of the screening program.
Measurement of serum prostate-specific antigen (PSA), a biomarker for prostate cancer,
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is useful for the detection of early prostate cancer.
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Nevertheless, the effect of PSA-based screening on prostate-cancer mortality remains unclear.
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The European Randomized Study of Screening for Prostate Cancer (ERSPC) was initiated in the early 1990s to determine whether a reduction of 25% in prostate-cancer mortality could be achieved by PSA-based screening.
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Preliminary data from this study have been published and can be accessed at www.erspc.org. Another randomized screening trial in the United States, the Prostate, Lung, Colon, and Ovarian (PLCO) Cancer Screening Trial, was initiated around the same . . .
Abstract Background Silodosin is a new selective therapy with a high pharmacologic selectivity for the α1A -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 ≥50 yr of age with an International Prostate Symptom Score (IPSS) ≥13 and a urine maximum flow rate (Qmax ) >4 and ≤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 Qmax . Responders were defined on the basis of IPSS and Qmax by a decrease of ≥25% and an increase of ≥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 Qmax 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 Qmax was 46.6%, 46.5%, and 40.5% in the silodosin, tamsulosin, and placebo treatment groups, respectively. This difference was not statistically significantly ( 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 α1A -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. Trial registration ClinicalTrials.gov Identifier NCT00359905.
Abstract Background Nocturia (ie, waking at night to void) is common and disrupts sleep. Traditionally, one nightly episode has been regarded as clinically meaningless, yet the justification for this ...belief remains weak. Objective To evaluate the association among frequency of nocturia and bother and health-related quality of life (HRQoL). Design, setting, and participants In 2003–2004, a survey was mailed to a random sample of 6000 subjects aged 18–79 yr who were identified from the Finnish Population Register Centre (response proportion was 62.4%; 53.7% were females). Measurements HRQoL and bother from nocturia were examined in relation to self-reported nocturia frequency (using the American Urological Association Symptom Index and the Danish Prostatic Symptom Score). Bother from nocturia was assessed on a four-point scale (none, small, moderate, major). HRQoL was measured with the generic 15D instrument on a 0–1 scale with a minimum clinically important difference of 0.03. Results and limitations Degree of bother increased with nocturia frequency ( p < 0.01). The most commonly cited degree of bother for those with one, two, and three nightly voids was no bother, small bother, and moderate bother, respectively. The mean age-adjusted 15D score for men (and women) without nocturia was 0.953 (0.950) and 0.925 (0.927) with one void per night, 0.898 (0.890) with two voids per night, and 0.833 (0.840) with three or more voids per night. Statistically significant decreases were found in 15D score and in all 15D dimensions except eating. Although the response rate was high, approximately one third of those contacted did not participate in the study. Conclusions At least two voids per night is associated with impaired HRQoL. The majority of people report having bother when the number of nocturia episodes is two and moderate or major bother when the number is three or more. One void per night does not identify subjects with interference from nocturia and, thus, is not a suitable criterion for clinically relevant nocturia.
Abstract Context Despite widespread screening for prostate cancer (PCa) and major advances in the treatment of metastatic disease, PCa remains the second most common cause of cancer death for men in ...the Western world. In addition, the use of prostate-specific antigen testing has led to the diagnosis of many potentially indolent cancers, and aggressive treatment of these cancers has caused significant morbidity without clinical benefit in many cases. The recent discoveries of inherited and acquired genetic markers associated with PCa initiation and progression provide an opportunity to apply these findings to guide clinical decision making. Objective In this review, we discuss the potential use of genetic markers to better define groups of men at high risk of developing PCa, to improve screening techniques, to discriminate indolent versus aggressive disease, and to improve therapeutic strategies in patients with advanced disease. Evidence acquisition PubMed-based literature searches and abstracts through January 2012 provided the basis for this literature review. We also examined secondary sources from reference lists of retrieved articles and data presented at recent congresses. Cited review articles are only from the years 2007–2012, favoring more recent discussions because of the rapidly changing field. Original research articles were curated based on favoring large sample sizes, independent validation, frequent citations, and basic science directly related to potentially clinically relevant prognostic or predictive markers. In addition, all authors on the manuscript evaluated and interpreted the data acquired. Evidence synthesis We address the use of inherited genetic variants to assess risk of PCa development, risk of advanced disease, and duration of response to hormonal therapies. The potential for using urine measurements such as prostate cancer antigen 3 ( PCA3 ) RNA and the transmembrane protease, serine 2 v-ets erythroblastosis virus E26 oncogene homolog (avian) ( TMPRSS2-ERG ) gene fusion to aid screening is discussed. Multiple groups have developed gene expression signatures from primary prostate tumors correlating with poor prognosis, and attempts to improve and standardize these signatures as diagnostic tests are presented. Massive sequencing efforts are underway to define important somatic genetic alterations (amplifications, deletions, point mutations, translocations) in PCa, and these alterations hold great promise as prognostic markers and for predicting response to therapy. We provide a rationale for assessing genetic markers in metastatic disease for guiding choice of therapy and for stratifying patients in clinical trials, and discuss challenges in clinical trial design incorporating the use of these markers. Conclusions The use of genetic markers has the potential to aid disease screening, improve prognostic discrimination, and prediction of response to treatment. However, most markers have not been prospectively validated for providing useful prognostic or predictive information or improvement upon clinicopathologic parameters already in use. Significant efforts are underway to develop these research findings into clinically useful diagnostic tests in order to improve clinical decision making.
Androgen deprivation therapy is the cornerstone treatment of advanced prostate cancer. Eventually prostate cancer cells overcome androgen deprivation therapy, giving rise to castration resistant ...prostate cancer (CRPC) characterized by increased androgen receptor (AR) activity. Understanding the cellular mechanisms leading to CRPC is needed for development of novel treatments. We used long-term cell cultures to model CRPC; a testosterone-dependent cell line (VCaP-T) and cell line adapted to grow in low testosterone (VCaP-CT). These were used to uncover persistent and adaptive responses to testosterone level. RNA was sequenced to study AR-regulated genes. Expression level changed due to testosterone depletion in 418 genes in VCaP-T (AR-associated genes). To evaluate significance for CRPC growth, we compared which of them were adaptive i.e., restored expression level in VCaP-CT. Adaptive genes were enriched to steroid metabolism, immune response and lipid metabolism. The Cancer Genome Atlas Prostate Adenocarcinoma data were used to assess the association with cancer aggressiveness and progression-free survival. Expressions of 47 AR-associated or association gaining genes were statistically significant markers for progression-free survival. These included genes related to immune response, adhesion and transport. Taken together, we identified and clinically validated multiple genes being linked with progression of prostate cancer and propose several novel risk genes. Possible use as biomarkers or therapeutic targets should be studied further.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract Background The European Randomized Study of Screening for Prostate Cancer (ERSPC) has shown a 21% reduction in prostate cancer (PCa) mortality and a 1.6-fold increase in PCa incidence with ...prostate-specific antigen (PSA)-based screening (at 13 yr of follow-up). We evaluated PCa incidence by risk category at diagnosis across the study arms to assess the potential impact on PCa mortality. Design, setting, and participants Information on arm, centre, T and M stage, Gleason score, serum PSA at diagnosis, age at randomisation, follow-up time, and vital status were extracted from the ERSPC database. Four risk categories at diagnosis were defined: 1, low; 2, intermediate; 3, high; 4, metastatic disease. PSA (≤100 or >100 ng/ml) was used as the indicator of metastasis. Outcome measurements and statistical analysis Incidence rate ratios (IRRs) for screening versus control arm by risk category at diagnosis and follow-up time were calculated using Poisson regression analysis for seven centres. Follow-up was truncated at 13 yr. Missing data were imputed using chained equations. The analyses were carried out on an intention-to-treat basis. Results and limitations In the screening arm, 7408 PCa cases were diagnosed and 6107 in the control arm. The proportion of missing stage, Gleason score, or PSA value was comparable in the two arms (8% vs 10%), but differed among centres. The IRRs were elevated in the screening arm for the low-risk (IRR: 2.14; 95% CI, 2.03–2.25) and intermediate-risk (IRR: 1.24; 95% CI, 1.16–1.34) categories at diagnosis, equal to unity for the high-risk category at diagnosis (IRR: 1.00; 95% CI, 0.89–1.13), and reduced for metastatic disease at diagnosis (IRR: 0.60; 95% CI, 0.52–0.70). The IRR of metastatic disease had temporal pattern similar to mortality, shifted forwards an average of almost 3 yr, although the mortality reduction was smaller. Conclusions The results confirm a reduction in metastatic disease at diagnosis in the screening arm, preceding mortality reduction by almost 3 yr. Patient summary The findings of this study indicate that the decrease in metastatic disease at diagnosis is the major determinant of the prostate cancer mortality reduction in the European Randomized study of Screening for Prostate Cancer.
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