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Introduction: Active surveillance (AS) strategies were established to avoid overtreatment of low-risk prostate cancer (PCa) patients. Low tumor volume represents one indication criteria; however, applying this criterion after MRI-targeted prostate biopsies may lead to overestimation of tumor volume; wherefore, patients suitable for AS would be exposed to the risk of overtreatment. Methods: This retrospective analysis included 318 patients in which PCa was detected by MRI-TRUS fusion prostate biopsy. Classic and extended indication for AS included Gleason 6 and Gleason 3 + 4 cancer, respectively. We assessed the effect of targeted biopsies and temporary rating strategies on eligibility for AS and developed new “composite” algorithms to more accurately assess eligibility for AS. Results: Forty-four (13.8%) and 60 (18.9%) of the 318 patients qualified for AS according to “classic” and “extended” criteria, respectively. Application of the “composite 1” definition led to AS eligibility of 52 of 248 patients (20.97%) in the classic and of 77 of 248 patients (31.05%) in the “extended” group. Conclusions: We could demonstrate that classic algorithms led to ineligibility of patients for AS. We propose a new rating algorithm to improve tumor assessment for a more accurate indication for AS.

Background Differential treatment between trial arms has been suggested to bias prostate cancer (PC) mortality in the European Randomized Study of Screening for Prostate Cancer (ERSPC). Objective To quantify the contribution of treatment differences to the observed PC mortality reduction between the screening arm (SA) and the control arm (CA). Design, setting, and participants A total of 14 136 men with PC (SA: 7310; CA: 6826) in the core age group (55–69 yr) at 16 yr of follow-up. Outcome measurements and statistical analysis The outcomes measurements were observed and estimated numbers of PC deaths by treatment allocation in the SA and CA, respectively. Primary treatment allocation was modeled using multinomial logistic regression adjusting for center, age, year, prostate-specific antigen, grade group, and tumor-node-metastasis stage. For each treatment, logistic regression models were fitted for risk of PC death, separately for the SA and CA, and using the same covariates as for the treatment allocation model. Treatment probabilities were multiplied by estimated PC death risks for each treatment based on one arm, and then summed and compared with the observed number of deaths. Results and limitations The difference between the observed and estimated treatment distributions (hormonal therapy, radical prostatectomy, radiotherapy, and active surveillance/watchful waiting) in the two arms ranged from −3.3% to 3.3%. These figures, which represent the part of the treatment differences between arms that cannot be explained by clinicopathological differences, are small compared with the observed differences between arms that ranged between 7.2% and 10.1%. The difference between the observed and estimated numbers of PC deaths among men with PC was 0.05% (95% confidence interval [CI] −0.1%, 0.2%) when applying the CA model to the SA, had the two groups received identical primary treatment, given their clinical characteristics. When instead applying the SA model to the CA, the difference was, as expected, very similar—0.01% (95% CI −0.3%, 0.2%). Consistency of the results of the models demonstrates the robustness of the modeling approach. As the observed difference between trial arms was 4.2%, our findings suggest that differential treatment explains only a trivial proportion of the main findings of ERSPC. A limitation of the study is that only data on primary treatment were available. Conclusions Use of prostate-specific antigen remains the predominant explanation for the reduction in PC mortality seen in the ERSPC trial and is not attributable to differential treatment between trial arms. Patient summary This study shows that prostate cancer deaths in the European screening trial (European Randomized Study of Screening for Prostate Cancer) were prevented because men were diagnosed and treated earlier through prostate-specific antigen screening, and not because of different, or better, treatment in the screening arm compared with the control arm.

Background: The European Randomized study of Screening for Prostate Cancer (ERSPC) has previously demonstrated that prostate-specific antigen (PSA) screening decreases prostate cancer (PCa) mortality. Objective: To determine whether PSA screening decreases PCa mortality for up to 16 yr and to assess results following adjustment for nonparticipation and the number of screening rounds attended. Design, setting, and participants: This multicentre population-based randomised screening trial was conducted in eight European countries. Report includes 182 160 men, followed up until 2014 (maximum of 16 yr), with a predefined core age group of 162 389 men (55-69 yr), selected from population registry. Outcome measurements and statistical analysis: The outcome was PCa mortality, also assessed with adjustment for nonparticipation and the number of screening rounds attended. Results and limitations: The rate ratio of PCa mortality was 0.80 (95% confidence interval [CI] 0.72-0.89, p 20 ng/ml (9.9% compared with 4.1% in the second round, p

The European Randomised Study of Screening for Prostate Cancer (ERSPC) showed that Prostate-Specific Antigen (PSA) based screening results in a significant prostate cancer mortality reduction. Although there are concerns on overdiagnosis and overtreatment, it has been shown that the benefits can outweigh the harms if screening is stopped in older ages to prevent overdiagnosis. A limited screening program (for example screening at ages 55–59 years), including active surveillance for men with low-risk tumors, can even be cost-saving, compared with testing in an opportunistic setting in the wrong ages, as currently in Europe. Further improvements are expected in the use of active surveillance and in discrimination between indolent and significant disease due to new biomarkers and magnetic resonance imaging. However, these future developments are no reason to postpone feasibility studies of high-quality PSA screening and reduce opportunistic testing at old ages.

INTRODUCTION AND OBJECTIVES:Chemoprevention of prostate cancer (PCa) has been extensively investigated in the last decades. So far only 5-alpha-reductase-inhibitors (5-ARI) are supported by clinica...

Objective To assess the value of a positive family history (FH) as a risk factor for prostate cancer incidence and grade among men undergoing organised prostate-specific antigen (PSA) screening in a population-based study. Subjects and Methods The study cohort comprised all attendees of the Swiss arm of the European Randomised Study of Screening for Prostate Cancer (ERSPC) with systematic PSA level tests every 4 years. Men reporting first-degree relative(s) diagnosed with prostate cancer were considered to have a positive FH. Biopsy was exclusively PSA triggered at a PSA level threshold of 3 ng/mL. The primary endpoint was prostate cancer diagnosis. Kaplan–Meier and Cox regression analyses were used. Results Of 4 932 attendees with a median (interquartile range, IQR) age of 60.9 (57.6–65.1) years, 334 (6.8%) reported a positive FH. The median (IQR) follow-up duration was 11.6 (10.3–13.3) years. Cumulative prostate cancer incidence was 60/334 (18%, positive FH) and 550/4 598 (12%, negative FH) [odds ratio 1.6, 95% confidence interval (CI) 1.2–2.2, P = 0.001). In both groups, most prostate cancer diagnosed was low grade. There were no significant differences in PSA level at diagnosis, biopsy Gleason score or Gleason score on pathological specimen among men who underwent radical prostatectomy between both groups. On multivariable analysis, age (hazard ratio [HR] 1.04, 95% CI 1.02–1.06), baseline PSA level (HR 1.13, 95% CI 1.12–1.14), and FH (HR 1.6, 95% CI 1.24–2.14) were independent predictors for overall prostate cancer incidence (all P < 0.001). Only baseline PSA level (HR 1.14, 95% CI 1.12–1.16, P < 0.001) was an independent predictor of Gleason score ≥7 prostate cancer on prostate biopsy. The proportion of interval prostate cancer diagnosed in-between the screening rounds was not significantly different. Conclusion Irrespective of the FH status, the current PSA-based screening setting detects the majority of aggressive prostate cancers and missed only a minority of interval cancers with a 4-year screening algorithm. Our results suggest that men with a positive FH are at increased risk of low-grade but not aggressive prostate cancer.

In daily routine business, various prostate-specific antigen (PSA) retest strategies are being promoted.To investigate rescreening intervals according to baseline PSA3 ng/ml stratified by any and aggressive prostate cancer (PCa).From 1998 to 2012, data from 4350 men aged 55-70 yr were analyzed from a population-based prospective screening study (median follow-up: 11.6 yr).The primary end point was detection of aggressive PCa (Gleason score 7-10). Cox regression analysis was used to examine the relationship between covariates.Baseline PSA of1.0 ng/ml, 1-1.9 ng/ml, and 2-2.9 ng/ml was present in 2416 men (55.5%: group 1), 1371 men (31.6%: group 2), and 563 men (12.9%: group 3), respectively. Stratified according to these PSA groups, aggressive PCa was detected in 25 patients (1.0%), 80 patients (5.8%), and 34 patients (6.0%), respectively. During 4 yr, these numbers were 0.0%, 0.29%, and 1.8%, whereas during 8 yr, the numbers were 0.2%, 1.4%, and 2.5%, respectively. In multivariable Cox regression analysis, the only independent risk factor for aggressive PCa was baseline PSA (hazard ratio [HR]: 6.06; 95% confidence interval [CI], 3.82-9.61; p0.0001, group 2 vs group 1; and HR: 7.33; 95% CI, 4.29-12.52; p0.0001, group 3 vs group 1).Baseline PSA was the only predictor regarding aggressive PCa. According to the low rate of potentially missed PCa in these groups, rescreening intervals can be safely adapted to baseline PSA values corresponding to a "PSA pyramid": 6-8 yr if baseline PSA is1.0 ng/ml, 3-4 yr if baseline PSA is 1-1.99 ng/ml, and yearly if baseline PSA is 2-2.99 ng/ml.We observed men with a prostate-specific antigen (PSA) value ≤3 ng/ml during 12 yr and found that men can be retested according to their initial PSA value ("PSA pyramid"): PSA1 (base), retest interval every 8 yr; PSA 1-2 (center), retest interval every 4 yr; and PSA 2-3 (top), retest yearly after risk stratification.

Recent studies indicate frequent early PSA retesting unrelated of men's baseline PSA, which increases the harms of early detection especially among men with low PSA. The current study investigates the PCa incidence among men with baseline PSA

Introduction: Very low-risk prostate cancer (PCa) is being increasingly managed by active surveillance (AS). Our aim was to assess the influence of the origin of diagnosis on PCa characteristics and treatment rates among men with very low-risk PCa in our prospective AS cohort. Methods: Overall, 191 men with very low-risk PCa fulfilling Epstein-criteria underwent protocol-based AS. These men originated either from the prospective population-based screening program (P-AS) or were diagnosed by opportunistic screening (O-AS). Results: Overall, n = 86 (45.0%) originated from the P-AS group, whereas n = 105 (55.0%) from the O-AS group. On univariate Cox regression analysis, age (HR 0.96, 95% CI 0.92-1.00; p = 0.05), origin of diagnosis (HR 0.72, 95% CI 0.41-1.28; p = 0.001), number of positive cores (HR 2.15, 95% CI 1.18-3.90; p = 0.01) and maximum core involvement (HR 1.03, 95% CI 0.99-1.05; p = 0.05) were predictors for treatment necessity. On multivariate analysis, age (HR 0.95, 95% CI 0.89-0.99; p = 0.05), number of positive cores (HR 2.07, 95% CI 1.10-3.88; p = 0.02), maximum core involvement (HR 1.03, 95% CI 1.00-1.06; p = 0.04) but not origin of diagnosis were independent predictors for treatment necessity. Four men developed biochemical recurrence (all from O-AS group [p = 0.05]). Conclusion: The origin of PCa diagnosis in men undergoing AS had no influence on disease progression and treatment necessity.

The European Randomised Study of Screening for Prostate Cancer (ERSPC) showed that Prostate-Specific Antigen (PSA) based screening results in a significant prostate cancer mortality reduction. Although there are concerns on overdiagnosis and overtreatment, it has been shown that the benefits can outweigh the harms if screening is stopped in older ages to prevent overdiagnosis. A limited screening program (for example screening at ages 55-59 years), including active surveillance for men with low-risk tumors, can even be cost-saving, compared with testing in an opportunistic setting in the wrong ages, as currently in Europe. Further improvements are expected in the use of active surveillance and in discrimination between indolent and significant disease due to new biomarkers and magnetic resonance imaging. However, these future developments are no reason to postpone feasibility studies of high-quality PSA screening and reduce opportunistic testing at old ages.

To analyze the effect of the oral antidiabetic drug metformin on PSA level, free-to-total PSA ratio (f/t-ratio), PCa incidence and grade as well as mortality in men participating in a population-based screening trial. Data from 4,314 men aged 55–70 years from a population-based PSA-screening trial (ERSPC Aarau) were analyzed. Information on metformin exposure was obtained by a self-administered questionnaire. Serum PSA threshold at ≥3 ng/ml triggered prostate biopsy. Data on PCa incidence and mortality were obtained through registry linkages. Median follow-up time was 7.6 years. Mean age at baseline was 65.5 years (±SD 4.4). In all, n = 150 (3.5 %) men used metformin [metf+]. Mean baseline PSA levels were comparable between both groups ([metf+] 1.6 ng/ml ± 2.4 vs. [metf−] 1.8ug/l ± 2.2, p = 0.4) while f/t-ratio was slightly higher in metformin users ([metf+] 30.7 % ± 10.9 vs. [metf−] 27.3 % ± 10.9, p = 0.01). Overall, n = 372 (8.6 %) PCa cases were detected. Neither cumulative PCa incidence (n = 11; 7.3 % [metf+] vs. n = 361 8.7 % [metf−]; p = 0.5) nor d`Amico risk groups were significantly different between both groups. One man in each group (metf+ 0.7 % and metf− 0.02 %) died from PCa (p

To date, evidence on active surveillance (AS) is restricted to protocol-based studies. Conversely, practice patterns outside of such protocols are unknown. The aim of this study was to capture the current AS treatment patterns for localized prostate cancer in patients managed by office-based urologists compared to patients treated at a tertiary care center.Two prospective cohorts were investigated: 361 AS arm patients of the German Hormonal treatment, Active surveillance, Radiation therapy, OP, Watchful waiting (HAROW) study, an observational health service study and 387 protocol-based AS patients treated at the Department of Urology of the Kantonsspital Aarau, Switzerland were included. Observational non-protocol HAROW versus on-protocol Kantonsspital Aarau (KSA) was compared, and active-treatment-free survival represented the primary outcome.Study population of the observational HAROW versus tertiary care protocol-based KSA cohorts differed statistically significantly regarding age (p0.001) and proportion of patients meeting the Chism criteria (p0.001). In stratified analyses, AFTS at 1 and 2 years was, respectively, 87.7 % (95 % CI 84.0-91.7) and 75.0 % (95 % CI 69.7-80.8) in HAROW patients compared to 90.8 % (95 % CI 87.8-93.9) and 75.3 % (95 % CI 70.7-80.1) for patients in the KSA cohort (p = 0.97).We demonstrate significant differences in terms of AS inclusion, surveillance and discontinuation criteria between patients managed by office-based urologists compared to their tertiary care counterparts. Interestingly, the risk of deferred active therapy was equally moderate for both groups in the short-term follow-up.

To analyze the influence of aspirin (ASA) intake on PSA values and prostate cancer (PCa) development in a prospective screening study cohort. 4314 men from the Swiss section of the European Randomized Study of Screening for Prostate Cancer (ERSPC) were included. A transrectal prostate biopsy was performed in men with a PSA level ≥ 3 ng/ml. Mortality data were obtained through registry linkages. PCa incidence and grade, total PSA, free-to-total PSA and overall survival were compared between ASA users and non-users. Median follow-up time was 9.6 years. In 789 men (18.3%) using aspirin [ASA +], the overall PCa incidence was significantly lower (6.8% vs. 9.6%, p = 0.015), but the multivariate Cox regression analysis showed no significant decrease in risk of PCa diagnosis (HR 0.84, p = 0.297). Total PSA values were significantly lower in ASA users for both baseline (1.6 vs. 1.8 ng/ml, p = 0.007) and follow-up visits (1.75 vs. 2.1 ng/ml, p

Background Metastatic disease is a major morbidity of prostate cancer (PCa). Its prevention is an important goal. Objective To assess the effect of screening for PCa on the incidence of metastatic disease in a randomized trial. Design, setting, and participants Data were available for 76 813 men aged 55–69 yr coming from four centers of the European Randomized Study of Screening for Prostate Cancer (ERSPC). The presence of metastatic disease was evaluated by imaging or by prostate-specific antigen (PSA) values >100 ng/ml at diagnosis and during follow-up. Intervention Regular screening based on serum PSA measurements was offered to 36270 men randomized to the screening arm, while no screening was provided to the 40543 men in the control arm. Outcome measurements and statistical analysis The Nelson-Aalen technique and Poisson regression were used to calculate cumulative incidence and rate ratios of M+ disease. Results and limitations After a median follow-up of 12 yr, 666 men with M+ PCa were detected, 256 in the screening arm and 410 in the control arm, resulting in cumulative incidence of 0.67% and 0.86% per 1000 men, respectively ( p p =0.001) in the intention-to-screen analysis and a 42% ( p =0.0001) reduction for men who were actually screened. An absolute risk reduction of metastatic disease of 3.1 per 1000 men randomized (0.31%) was found. A large discrepancy was seen when comparing the rates of M+ detected at diagnosis and all M+ cases that emerged during the total follow-up period, a 50% reduction (HR: 0.50; 95% CI, 0.41–0.62) versus the 30% reduction. The main limitation is incomplete explanation of the lack of an effect of screening during follow-up. Conclusions PSA screening significantly reduces the risk of developing metastatic PCa. However, despite earlier diagnosis with screening, certain men still progress and develop metastases. The ERSPC trial is registered under number ISRCTN49127736.

DNA methylation plays an important role in carcinogenesis and is being recognized as a promising diagnostic and prognostic biomarker for a variety of malignancies including Prostate cancer (PCa). The human kallikrein-related peptidases (KLKs) have emerged as an important family of cancer biomarkers, with KLK3, encoding for Prostate Specific Antigen, being most recognized. However, few studies have examined the epigenetic regulation of KLKs and its implications to PCa. To assess the biological effect of DNA methylation on KLK6 and KLK10 expression, we treated PC3 and 22RV1 PCa cells with a demethylating drug, 5-aza-2′deoxycytidine, and observed increased expression of both KLKs, establishing that DNA methylation plays a role in regulating gene expression. Subsequently, we have quantified KLK6 and KLK10 DNA methylation levels in two independent cohorts of PCa patients operated by radical prostatectomy between 2007–2011 (Cohort I, n = 150) and 1998–2001 (Cohort II, n = 124). In Cohort I, DNA methylation levels of both KLKs were significantly higher in cancerous tissue vs. normal. Further, we evaluated the relationship between DNA methylation and clinicopathological parameters. KLK6 DNA methylation was significantly associated with pathological stage only in Cohort I while KLK10 DNA methylation was significantly associated with pathological stage in both cohorts. In Cohort II, low KLK10 DNA methylation was associated with biochemical recurrence in univariate and multivariate analyses. A similar trend for KLK6 DNA methylation was observed. The results suggest that KLK6 and KLK10 DNA methylation distinguishes organ confined from locally invasive PCa and may have prognostic value.

UNLABELLED Study Type - Therapy (case series). Level of Evidence 4. What's known on the subject? and What does the study add? Low-risk prostate cancer is frequently diagnosed in the context of PSA screening or during a routine check-up. For those patients, to avoid possible overtreatment AS is an increasingly chosen treatment option. However, the concept of AS could possibly misclassify potentially dangerous PCa as a low-risk disease resulting in inferior cancer control outcomes. In the present study, we could demonstrate that the histopathological results of patients treated by RP in course of AS are significantly better if the selection criteria for AS are entirely fulfilled. Our findings underline the importance of a strict and precise admittance procedure for patients with early prostate cancer who are willing to undergo an AS programme. OBJECTIVE • To compare the histopathological outcomes of patients treated with radical prostatectomy (RP) after an initial active surveillance (AS) for localized, low-risk prostate cancers (PCa) among men who fulfilled the Epstein criteria at diagnosis with those who did not. PATIENTS AND METHODS • In all, 283 patients with localized PCa were initially managed at our institution with AS. • In all, ≈ 50% originated from the European Randomized Study of Screening for Prostate Cancer (ERSPC) participants from Switzerland: 75 (26.5%) patients underwent treatment during follow-up and 61 were treated with RP (21.6%). • These patients were stratified into those who did (n= 39) vs those who did not (n= 22) entirely fulfil AS inclusion criteria according to Epstein et al. at PCa diagnosis. RESULTS • Patients who did completely fulfil the AS inclusion criteria had significantly lower prostate-specific antigen (PSA)-values (4.9 vs 7.8 ng/mL; P= 0.02), a significantly lower PSA density at diagnosis (0.09 vs 0.2 ng/mL/ccm; P= 0.007) and at RP, a higher proportion of organ-confined cancers (89.7% vs 59.1%, P= 0.02) and fewer positive surgical margins (25.6% vs 40.9%). • However, the rate of favourable histopathological outcome, defined as organ-confined disease with negative surgical margins, was statistically significantly higher in the group fulfilling AS criteria (69.2% vs 40.9%; P= 0.03). CONCLUSIONS • In our AS series, 26.5% of the patients underwent definitive therapy. • Most patients treated with RP had organ-confined disease in the majority of cases, especially when the Epstein criteria were rigorously fulfilled at PCa diagnosis. • This underlines the importance of a strict and precise per protocol AS for patients with early PCa, otherwise there is a risk of missing more significant disease.

Tumormarker werden unter anderem in der Karzinom Früherkennung, Prognose, Behandlung und Beobachtung des Krankheitsverlaufes eingesetzt. Viele klinische Studien sind heutzutage ohne Einsatz der Tumormarker kaum denkbar. Da die Tumormarker in der klinischen Anwendung eine beschränkte Aussagekraft haben (beschränkte Sensitivität und/oder Spezifität), soll deren Einsatz gezielt erfolgen, d.h. in der klinischen Situation, wo der Nutzen am größten ist. Der am häufigsten benutzte Tumormarker ist das Prostata spezifische Antigen (PSA). Sein Einsatz reicht von der Vorsorge des Prostatakarzinoms bis hin zur Therapiekontrolle des hormonrefraktären Karzinoms. Bevor eine «PSA-Kaskade» im Rahmen der Prostatakrebsvorsorge ausgelöst wird, muss der Patient nicht nur über das Risiko Prostatakrebs, sondern auch über die evtl. Therapieschritte inklusive Nebenwirkungen informiert werden. Stimmt er einer Vorsorge zu, so ist die weitere bioptische Abklärung direkt ab einem PSA von 4.0 ng/ml oder auffälliger digital rektaler Untersuchung indiziert. Die früher beschriebene PSA-«Grauzone» 4–10 ng/ml mit abwartender Haltung ist nicht mehr gerechtfertigt. Ein erhöhter Anteil des freien PSA oberhalb des Cut-off 4.0 ng/ml darf nicht zu einer Protrahierung der Biopsie Indikation führen. Bei PSA zwischen 3.0 und 3.9 ng/ml und gleichzeitig einem Anteil des freien PSA unterhalb des Cut-off 12% ist eine Prostatabiopsie ebenfalls angezeigt. Die PSA-Verlaufskontrollen sind bei einer geschätzten Lebenserwartung über 10 Jahre sinnvoll und vom Ausgangs PSA Wert abhängig: bei PSA zwischen 2 und 3.9 ng/ml jährlich, zwischen 1.0 und 1.9 ng/ml 2-jährlich und unterhalb von 1.0 ng/ml 3-jährlich. Etwa 3–25% der initial entdeckten Karzinome in der Biopsie sind klinisch irrelevant und lassen sich durch Vorhersagemodelle mittels PSA, Gleason Score und Tumorbefall der Biopsien prätherapeutisch bestimmen. Zusammenfassend: «Nicht jedes früh erkannte Prostatakarzinom muss behandelt werden, aber das Behandlungsbedürftige muss früh erkannt werden!». Rund ein Drittel der primär mittels kompletter Prostatektomie oder Radiotherapie behandelten organbegrenzten Karzinome werden ein Rezidiv entwickeln. Lediglich ein Drittel dieser Männer wird jedoch eine klinische Symptomatik zeigen respektive tumorbedingt sterben. Hier ist die Verlaufskontrolle des PSA, insbesondere seine Verdopplungszeit, ein zukünftiger Parameter, die Patienten mit hohem Risiko einer klinischen Manifestation des Rezidivs zu isolieren.

Das Prostatakarzinom stellt als zweithaufigste Todesursache maligner Genese beim Mann ein zunehmendes gesundheitspolitisches Problem dar, das durch die demographische Entwicklung noch verstarkt wird. „Nicht jedes fruh erkannte Prostatakarzinom muss behandelt werden, aber das Behandlungsbedurftige muss fruh erkannt werden!“ lautet die Kernaussage der individuellen Vorsorge. Dies bedeutet, dass die Masnahmen zur individuellen Fruherkennung mit den Patienten besprochen werden mussen, um sie einerseits uber ihr Erkrankungsrisiko und die Notwendigkeit einer fruhzeitigen Therapie in kurativer Intention einschlieslich der moglichen Nebenwirkungen aufzuklaren. Andererseits muss eine mogliche Ubertherapie verhindert werden. Studienergebnisse zum generellen aktiven Massen-Screening auf Evidenzlevel A stehen aus und sind etwa 2010 zu erwarten. Zwischenauswertungen mit den Metastasierungsraten als primare Endpunkte zeigen einen Benefit in den Screening-Armen im Vergleich zu den Kontrollgruppen. Dies darf zum jetzigen Zeitpunkt jedoch nicht auf die Mortalitat projiziert werden. Ergebnisse von Studien mit Evidenzlevel B sprechen fur den Nutzen der individuellen Vorsorge. Die sich aus der Vorsorge ergebende „Uberdiagnostik“ latenter Karzinome (2–20%) sollte vermehrt durch prazisere Modelle zur „active surveillance“ angegangen werden. Studien, die sich gegen eine Vorsorge aussprechen, sind bei genauer Betrachtung als insuffizient anzusehen, da sie an einem zu alten Patientenkollektiv mit zu kurzer Nachbeobachtungszeit und falschen Endpunkten durchgefuhrt wurden.

Ces 10 dernieres annees, les differents collectifs de patients surveilles ont permis de progresser dans la precision de la sous-population de cancers prostatiques les plus susceptibles de beneficier de cette attitude conservatrice, en s’attachant au maximum a ne pas prendre de risque significatif par rapport a la survie specifique au cancer.

In den letzten zehn Jahren konnten anhand verschiedener uberwachter Patien­tenkollektive Subpopulationen genauer eingegrenzt werden, deren Prostatakarzinom fur ein konservatives Vorgehen in Form von aktiver Uberwachung (active surveillance) geeignet ist, wobei vor allem darauf ­geachtet wird, dass in Bezug auf das prostatakrebsspezfische Uberleben kein Risiko besteht.

INTRODUCTION AND OBJECTIVES: There is conflicting data regarding the effect of the oral antidiabetic drug metformin on prostate cancer (PCa) incidence and mortality. We aimed to assess the effect of metformin on PCa incidence and mortality in men participating in a prospective, population-based screening trial. METHODS: Data of men who underwent PSA-screening in our population-based screening trial (ERSPC Aarau) were analysed. Information on metformin exposure before biopsy was obtained by a selfadministered questionnaire. Cox regression analysis was used to examine the relationship between covariates and PCa incidence. RESULTS: Overall, 4,314 men were observed during a mean follow-up time of 7.3 ( SD2.3) years. Mean age at baseline was 65.5 years (65.5 SD 4.4). Overall, n1⁄4150 (3.5%) men used metformin [metfþ] at baseline. Of those, 80% (88 of 110) who were actively screened during follow-up visit were still on metformin after 4 years whereas 105 men had new [metfþ] exposure. Mean baseline PSAlevels were comparable between both groups ([metfþ] 1.6ng/ml 2.4 vs. [metf-] 1.8ug/l 2.2, p1⁄40.4) while f/t-ratio was slightly higher in metformin users ([metfþ] 30.7% 10.9 vs. [metf-] 27.3% 10.9, p1⁄40.01). Overall, n1⁄4372 (8.6%) PCa cases were detected. Neither cumulative PCa incidence (n1⁄411; 7.3% [metfþ] vs. n1⁄4361 8.7% [metf-]; p1⁄40.5) nor d’Amico risk groups were significantly different between both groups. On multivariate analysis, only increasing baseline PSA (HR 1.11, 95%CI 1.09-1.13; p

La validite du dosage du PSA a surtout ete remise en cause par le biais du Prostate Cancer Prevention Trial. D’autres donnees montrent cependant que la hauteur du taux de PSA initial pourrait etre un parametre pronostique optimal de l’evolution au long cours d’un carcinome cliniquement pertinent et soulignent ainsi le role du PSA comme outil de stratification de risque a long terme.

Die Validitat des PSA-Screenings wurde insbesondere durch den Prostate Cancer Prevention Trial angezweifelt. Andere Daten dokumentieren jedoch die Hohe des initialen PSA-Wertes als idealen Parameter fur die Langzeitentwicklung eines klinisch relevanten Karzinoms und unterstreichen damit die Rolle des PSA als Risiko­stratifizierer.

The determination of complexed prostate specific antigen (cPSA) has been suggested to be promising for prostate cancer (PCa) diagnosis. In a multicenter trial we evaluate the diagnostic use of PSA forms in the low total PSA (tPSA) range.A total of 283 white men with and 417 without PCa and tPSA concentrations between 0 and 6 ng/ml were retrospectively analyzed. All 700 untreated subjects underwent a multisector needle biopsy of the prostate. The Elecsys analyser 1010 (Roche Diagnostics, Mannheim, Germany) was used for determination of tPSA and free PSA. Determination of cPSA and tPSA was performed using immunoassays of the Bayer Immuno 1 system (Bayer Diagnostics, Tarrytown, New York).Receiver operating characteristics analyses for discrimination between cases with and without PCa were performed. The areas under the curves (AUC) for cPSA, tPSA and free-to-total PSA (f/tPSA) showed no significant differences in the tPSA ranges of 0 to 6 (700 cases), 0 to 4 (510) and 0.5 to 2.5 ng/ml (253). Within the tPSA range of 2.5 to 4 ng/ml (230 cases) the AUC for cPSA (0.61) was significantly larger than that for tPSA (Roche 0.51, Bayer 0.54) but did not differ from the AUC of f/tPSA (Roche). On the basis of the cutoffs for 95% specificity or sensitivity, no significant increase in corresponding sensitivity or specificity was found between tPSA with cPSA.In the tPSA range of less than 4 ng/ml no improvement in diagnostic accuracy was shown between cPSA with tPSA or the ratio of f/tPSA. The search for a useful marker in the low PSA range must continue.

Recent studies indicate frequent early PSA retesting unrelated of men's baseline PSA, which increases the harms of early detection especially among men with low PSA. The current study investigates the PCa incidence among men with baseline PSA1.0 ng ml(-1) in order to adjust retest intervals for more targeted early detection. Between 1998 and 2012, 2,416 men with baseline PSA1.0 ng ml(-1) were prospectively observed. Primary endpoint was PCa diagnosis. Negative predictive value (NPV) and number needed to screen (NNS) to detect one PCa were calculated. During a median follow-up time of 12.1 years, 54 (2.2%) PCa were diagnosed with n = 26 (48.1%) among men with baseline PSA of 0.75 ≤ 1.0 ng ml(-1) (upper baseline PSA quartile). The 10-year probability of being diagnosed with PCa increased significantly from 0.19% (baseline PSA 0.40 ng ml(-1) ) to 2.0% (baseline PSA 0.40 ≤ 0.56 ng ml(-1) ), 2.5% (baseline PSA 0.56 ≤ 0.75 ng ml(-1) ) over 4.4% (baseline PSA 0.75 ≤ 1.0 ng ml(-1) ) (all p values0.0001), respectively. The frequency of Gleason ≥7 PCa increased from 1 (0.17%) to 8 (1.4%), 5 (0.8) over 11 (1.8%) in these groups. The 8-year NPV for Gleason ≥ 7 PCa were 99.8 (baseline PSA 0.40 ng ml(-1) ), 99.8 (baseline PSA 0.40 ≤ 0.56 ng ml(-1) ), 100 (baseline PSA 0.56 ≤ 0.75 ng ml(-1) ) and 99.5 (baseline PSA 0.75 ≤ 1.0 ng ml(-1) ), respectively. During 12 years, the numbers were 99.8, 98.6, 99.2, and 98.2, respectively. Therefore, due to the very low rate of Gleason ≥ 7 PCa, further screening might be omitted in men with baseline PSA 0.4 ng ml(-1) . Between 0.4 and 1.0 ng ml(-1) , an 8-year interval can be discussed.

In der gesundheitspolitischen Diskussion zu Vorsorgemasnahmen stellt die Kontroverse des PSA-Screenings eine Vorreiterrolle dar (verglichen z. B. mit dem eher auser Frage gestellten Mamma- oder Kolonscreening). Dies hat erfreulicherweise zu einer vertieften kritischeren Analyse der Datenlage gefuhrt. Auf der einen Seite zeigt sich durch PSA-Screening ein Uberlebensbenefit, der mit langerer Nachbeobachtungszeit zunimmt. Das quantitative Ausmas des Benefits kann in der Studiendurchfuhrung z. B. durch Prascreening, pravalentes Screening, fehlende Compliance, Kontamination und einen „healthy screen bias“ falschlich reduziert sein. Trotzdem hatte z. B. die „European randomized Screening Study of Prostate Cancer-“ (ERSPC-)Studie aufgrund der hohen Teilnehmerzahl eine genugende statistische Power, um die Frage Screeningbenefit nach 9 bzw. 11 Jahren mit Ja zu beantworten (Evidenzlevel A). Andererseits findet sich auch beim Prostatakarzinom das der Vorsorgemedizin innewohnende Problem der Uberdiagnostik/-therapie, u. a. abhangig vom Alter der Screeningpopulation sowie der Screeningfrequenz (28–52 %). Unnotig erlittene Lebensqualitatseinbusen dieser Patienten reduzieren den Uberlebensbenefit. Durch ein „PSA-Finetuning“ und eine Risikostratifikation liesen sich ca. ein Drittel der Diagnosen/Therapien vermeiden. Die kontrollierte Beobachtung nicht behandlungswurdiger Tumore „Active Surveillance“ sollte zusammen mit einer vermehrten Qualitatsverbesserung der Therapien einen groseren Stellenwert einnehmen.

Little is known about the incidence rate and clinical relevance of prostate cancer in a low prostate specific antigen (PSA) level. In a prospective PSA based screening study we investigated the incidence and clinicopathological features of prostate cancer that occurred within PSA range 1 to 3 ng./ml. when the free-to-total ratio was 0.20 or less.Men participating in the Aarau, Switzerland, section of the European Randomized Study of Screening for Prostate Cancer between October 1998 and July 2000 were included in the study. As a side study, all men with PSA between 1 and 3 ng./ml. and free-to-total ratio 0.20 or less were invited to undergo further evaluation with ultrasound guided sextant prostate biopsy.Overall, 168 (7.8%) participants fulfilled inclusion criteria. A total of 158 (94%) patients underwent prostate biopsy, and prostate cancer was detected in 17 (10.8%). There were no statistically significant differences between prostate cancer and benign prostatic hyperplasia in regard to patient age (60.7 versus 59.8 years), prostate volume (23.9 versus 23.0 cc), PSA (1.98 versus 1.86 ng./ml.), free-to-total ratio (0.161 versus 0.160), PSA density (0.089 versus 0.076 ng./ml.) or PSA transition zone density (0.33 versus 0.24 ng./ml., respectively). Median Gleason score was 5 on prostate biopsy versus 6 on retropubic prostatectomy specimen. Of the 14 patients who underwent surgery there were positive lymph nodes in 1, stage pT3b Gleason 7 disease in 1, and pathologically organ confined Gleason 5 in 2, Gleason 6 in 5 and Gleason 7 in 5. Mean tumor volume was 1.01 cc (range 0.02 to 5.17). There were 2 (14.3%) insignificant (less than 0.2 cc, Gleason grade 3 or less), 1 (7.1%) minimal (less than 0.5cc, Gleason grade 3 or less) and 11 (78.6%) clinically relevant and potentially harmful cancers.There is a significant number of prostate cancer cases diagnosed at PSA as low as 1 to 3 ng./ml. A majority of these tumors are clinically significant. This free-to-total ratio range may be helpful for identifying prostate cancer. The "window of opportunity" for detection of curable cancer may change in populations with higher life expectancy towards lower PSA. Lack of specificity and characterization of tumor aggressiveness remains an unsolved issue for PSA.

Objectives. Human glandular kallikrein (hK2) possesses 80% structure identity with prostate-specific antigen (PSA) and is secreted by identical prostate epithelial cells. Although increasing with pathologic stage, PSA is not clinically sufficient to predict histologic grade and pathologic stage of prostate cancer (PCa) in individual cases. To address this issue, serum hK2 in various PCa grades was investigated. Methods. Sera from 122 consecutive patients with PCa, graded as well-differentiated (G1, n = 35); moderately differentiated (G2, n = 61), and poorly differentiated (G3, n = 26) PCa, was studied. In patients who underwent radical prostatectomy (n = 42), 24 had organ-confined (pT2a-b) and 18 extracapsular (pT3a or greater) disease. hK2 was measured by an indirect immunofluorometric assay with a functional sensitivity of 0.03 ng/mL. Total PSA (tPSA), free PSA (fPSA), and PSA bound to alpha1-antichymotrypsin (PSA-ACT) were also measured. Multivariate logistic regression analysis was used for evaluation of the best combinations of tumor markers. Results. Median hK2 and tPSA increased twofold from G1 to G2 tumors (hK2 0.07 versus 0.14 ng/mL, P

Human glandular kallikrein (hK2) possesses approximately 80% structure identity with prostate-specific antigen (PSA). Moreover, messenger ribonucleic acid for hK2 and for PSA is expressed in both benign and malignant prostatic tissue. We investigated whether the hK2 serum measurement may improve the detection of prostate cancer (PCa) in patients with total PSA of 4 to 10 ng/mL (diagnostic "gray zone").Blood samples were obtained from 90 consecutive male patients with lower urinary tract symptoms and total PSA values of 4 to 10 ng/mL. Eighty-one patients underwent transurethral resection of the prostate and 6 radical prostatectomy. The patients were divided into two groups: I, patients with PCa (n = 20) and II, patients with benign prostatic hyperplasia (BPH) (n = 70). An "in-house" immunofluorometric assay with analytical sensitivity of 0.01 ng/mL and the functional sensitivity of 0.05 ng/mL (at this level the mean coefficient of variation, calculated from the precision profile based on the assays of serum samples, was less than 20%) was used to determine serum hK2 concentrations. Total PSA, free PSA (ProStatus), and PSA complexed to alpha1-antichymotrypsin (PSA-ACT) were also measured. Free/total PSA, hK2/total PSA, and hK2/free PSA ratios were calculated.The serum hK2 could be detected in all samples and in 76 (84.4%) of 90 samples (PCa, n = 18; BPH, n = 58) at given functional sensitivity level. For these cases the median concentration of hK2 was 0.135 ng/mL in PCa and 0.09 ng/mL in BPH (P0.1). The median hK2/total PSA ratio was 2% for PCa and 1.6% for BPH (P0.2). The median free/total PSA ratio was 0.122 for PCa and 0.215 for BPH (P0.0008) and the hK2/free PSA ratio was 0.139 for PCa and 0.075 for BPH (P0.000003). At a 7.2% cutoff, the specificity of hK2/free PSA ratio was 48.2% at 100% sensitivity and increased to 60.3% at 94.4% sensitivity level (the area under the receiver operating characteristic curve was 0.86). In comparison, the free/total PSA ratio at a 25.2% cutoff had a sensitivity of 94.4% and a specificity of 27.6% (area under the curve = 0.76).hK2 was detected in all sera with total PSA values of 4 to 10 ng/mL. Of particular clinical interest is the finding that the hK2/free PSA ratio had a better specificity without loss of sensitivity for PCa than total PSA or the PSA free/total ratio within the range of 4 to 10 ng/mL total PSA. hK2 in combination with free PSA may offer a new diagnostic means for PCa detection.

Objective: To determine whether the serum levels of total prostate-specific antigen (t-PSA), free PSA (f-PSA) and PSA complexed to α1-antichymotrypsin (PSA-ACT) result fr

Background Various reasons exist for so-called bacillus Calmette-Guerin (BCG) failure in patients with non–muscle-invasive urothelial bladder carcinoma (NMIBC). Objective To explore whether urothelial carcinoma of the upper urinary tract (UUT) and/or prostatic urethra may be a cause for BCG failure. Design, setting, and participants Retrospective analysis of 110 patients with high-risk NMIBC repeatedly treated with intravesical BCG, diagnosed with disease recurrence, and followed for a median time of 9.1 yr. Intervention Two or more intravesical BCG induction courses without maintenance. Outcome measurements and statistical analysis Primary outcome was pattern of disease recurrence (BCG failure) within the urinary tract categorised into UUT and/or urethral carcinoma (with or without intravesical recurrence), and intravesical recurrence alone. Secondary outcome was survival. Predictors of UUT and/or urethral carcinoma and the effect of pattern of disease recurrence on cancer-specific survival were assessed with multivariable Cox regression analysis adjusting for multiple clinical and tumour characteristics. Results and limitations Of the 110 patients, 57 (52%) had UUT and/or urethral carcinoma (with or without intravesical recurrence), and 53 (48%) had intravesical recurrence alone. In patients with UUT and/or urethral carcinoma, bladder carcinoma in situ (Tis) before the first and second BCG course was present in 42 of 57 (74%) and 47 of 57 (82%) patients, respectively. On multivariable analysis, bladder Tis before the first and/or second BCG course was the only independent predictor of UUT and/or urethral carcinoma. Of the 110 patients, 69 (63%) were alive at last follow-up visit, 18 (16%) had died due to metastatic urothelial carcinoma, and 23 (21%) had died of other causes. Pattern of disease recurrence within the urinary tract was not an independent predictor of cancer-specific survival. Main study limitations were retrospective design and limited power for survival analysis. Conclusions In our patients with high-risk NMIBC failing after two or more courses of intravesical BCG, UUT and/or urethral carcinoma was detected in >50% of the cases during follow-up. The vast majority of these patients had bladder Tis before the first and/or second BCG course. In patients experiencing the so-called BCG failure, a diagnostic work-up of UUT and prostatic urethra should always be performed to exclude urothelial carcinoma before additional intravesical therapy or even a radical cystectomy is considered.

INTRODUCTION AND OBJECTIVES: The ERSPC indicates prostate biopsy at the PSA cut-off value 3.0 ng/ml. All men with a PSA below 3ng/ml at baseline are reinvited 4 years later. Whether this somewhat arbitrary interval adequately reflects the natural history of PCa is under scientific scrutiny at the moment. The current study describes the outcome of men who had an initial PSA 3.0 ng/ml in the Swiss section of the ERSPC cohort. METHODS: Our study cohort consisted of n 4332 men (55-70 years of age). Re-screening took place every 4 years. In case of PSA-values 3ng/ml, prostate biopsies were recommended. PCa cases were identified at rescreens every 4 years (screen detected PCa) or as interval cancers (through opportunistic PSA testing), which were detected through linkage with the pathology cancer registry. RESULTS: The PSA-distribution at baseline was as follows: n 587 (13.6%) ranged between 2 to 2.99ng/ml, n 1437 (33.2%)from 1 to 1.99ng/ml and n 2308 (53.3%) from 0 to 0.99ng/ml, respectively. Overall, n 342 PCa cases were identified in the study cohort (median follow-up 10.2 years). In the 8-year period after the initial screening (comprising three screening rounds), the PCa rate including interval cancers of the very low PSA-group (0-0.99ng/ml) was 1.6% (n 36). If only PCa with a Gleason Score (GS) higher than 3 3 6 were counted, the rate was 0.69% (n 16 for GS 3 4) and 0.30% (n 7 for GS 4 3), respectively. In the 1–1.99 group, during 4 years (comprising two screening rounds), 59 PCa were diagnosed including interval cancers (4.1%). Of those, only n 12 (0.83%) had a GS of 3 4 and n 5 (0.34%) had a GS of 4 3. Men with an initial PSA between 2.0-2.99ng/ml were found to have a clearly higher PCa rate during 4 years of n 89 (15.1%) of which 19 (3.2%) had a GS of 3 4 and 7 (1.2%) with a GS of 4 3. With increasing PSA ranges, only 2 (0.09%), 4 (0.28%) and 2 (0.17%) men, respectively, died from PCa. CONCLUSIONS: The incidence of clinically relevant PCa (defined by GS) and PCa specific mortality was very low during the follow-up of 10.2 years. We therefore suggest a “PSApyramid” with re-test intervals of 6-8 years at pyramid basis (0-0.99ng/ml). At center part (1.0-1.99ng/ml), a re-test should be done after 3-4 years. Men at the top level (2–2.99 ng/ml) are considered to undergo PSA testing 1–2 years. PSA-pyramid could serve as an efficient gate-keeper reassuring most of men for long time period and allowing to decrease substantially the number of PSA tests.