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Sökning: WFRF:(Vickers Andrew J.)

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1.
  • 2021
  • swepub:Mat__t
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2.
  • 2019
  • Tidskriftsartikel (refereegranskat)
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3.
  • Arndt, D. S., et al. (författare)
  • STATE OF THE CLIMATE IN 2017
  • 2018
  • Ingår i: Bulletin of The American Meteorological Society - (BAMS). - : American Meteorological Society. - 0003-0007 .- 1520-0477. ; 99:8, s. S1-S310
  • Forskningsöversikt (refereegranskat)
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5.
  • Vickers, Andrew J, et al. (författare)
  • The relationship between prostate-specific antigen and prostate cancer risk: the Prostate Biopsy Collaborative Group.
  • 2010
  • Ingår i: Clinical cancer research : an official journal of the American Association for Cancer Research. - 1078-0432. ; 16:17, s. 4374-81
  • Tidskriftsartikel (refereegranskat)abstract
    • The relationship between prostate-specific antigen (PSA) level and prostate cancer risk remains subject to fundamental disagreements. We hypothesized that the risk of prostate cancer on biopsy for a given PSA level is affected by identifiable characteristics of the cohort under study.
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6.
  • Chu, Jacqueline J., et al. (författare)
  • Remote Symptom Monitoring with Clinical Alerts Following Mastectomy: Do Early Symptoms Predict 30-Day Surgical Complications
  • 2024
  • Ingår i: ANNALS OF SURGICAL ONCOLOGY. - 1068-9265 .- 1534-4681.
  • Tidskriftsartikel (refereegranskat)abstract
    • Background. Electronic patient-reported outcome measures (ePROMs) for real-time remote symptom monitoring facilitate early recognition of postoperative complications. We sought to determine whether remote, electronic, patient-reported symptom-monitoring with Recovery Tracker predicts 30-day readmission or reoperation in outpatient mastectomy patients. Methods. We conducted a retrospective review of breast cancer patients who underwent outpatient (< 24-h stay) mastectomy with or without reconstruction from April 2017 to January 2022 and who received the Recovery Tracker on Days 1-10 postoperatively. Of 5,130 patients, 3,888 met the inclusion criteria (2,880 mastectomy with immediate reconstruction and 1,008 mastectomy only). We focused on symptoms concerning for surgical complications and assessed if symptoms reaching prespecified alert levels-prompting a nursing call-predicted risk of 30-day readmission or reoperation. Results. Daily Recovery Tracker response rates ranged from 45% to 70%. Overall, 1,461 of 3,888 patients (38%) triggered at least one alert. Most red (urgent) alerts were triggered by pain and fever; most yellow (less urgent) alerts were triggered by wound redness and pain severity. The 30-day readmission and reoperation rates were low at 3.8% and 2.4%, respectively. There was no statistically significant association between symptom alerts and 30-day reoperation or readmission, and a clinically relevant increase in risk can be excluded (odds ratio 1.08; 95% confidence interval 0.8-1.46; p = 0.6). Conclusions. Breast cancer patients undergoing mastectomy with or without reconstruction in the ambulatory setting have a low burden of concerning symptoms, even in the first few days after surgery. Patients can be reassured that symptoms that do present resolve quickly thereafter.
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7.
  • Carlsson, Sigrid V., et al. (författare)
  • Estimating the harms and benefits of prostate cancer screening as used in common practice versus recommended good practice : A microsimulation screening analysis
  • 2016
  • Ingår i: Cancer. - : Wiley. - 0008-543X .- 1097-0142. ; 122:21, s. 3386-3393
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Prostate-specific antigen (PSA) screening and concomitant treatment can be implemented in several ways. The authors investigated how the net benefit of PSA screening varies between common practice versus “good practice.”. METHODS: Microsimulation screening analysis (MISCAN) was used to evaluate the effect on quality-adjusted life-years (QALYs) if 4 recommendations were followed: limited screening in older men, selective biopsy in men with elevated PSA, active surveillance for low-risk tumors, and treatment preferentially delivered at high-volume centers. Outcomes were compared with a base model in which annual screening started at ages 55 to 69 years and were simulated using data from the European Randomized Study of Screening for Prostate Cancer. RESULTS: In terms of QALYs gained compared with no screening, for 1000 screened men who were followed over their lifetime, recommended good practice led to 73 life-years (LYs) and 74 QALYs gained compared with 73 LYs and 56 QALYs for the base model. In contrast, common practice led to 78 LYs gained but only 19 QALYs gained, for a greater than 75% relative reduction in QALYs gained from unadjusted LYs gained. The poor outcomes for common practice were influenced predominantly by the use of aggressive treatment for men with low-risk disease, and PSA testing in older men also strongly reduced potential QALY gains. CONCLUSIONS: Commonly used PSA screening and treatment practices are associated with little net benefit. Following a few straightforward clinical recommendations, particularly greater use of active surveillance for low-risk disease and reducing screening in older men, would lead to an almost 4-fold increase in the net benefit of prostate cancer screening. Cancer 2016;122:3386–3393.
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9.
  • Gallagher, David J., et al. (författare)
  • Susceptibility Loci Associated with Prostate Cancer Progression and Mortality
  • 2010
  • Ingår i: Clinical Cancer Research. - 1078-0432. ; 16:10, s. 2819-2832
  • Tidskriftsartikel (refereegranskat)abstract
    • Purpose: Prostate cancer is a heterogenous disease with a variable natural history that is not accurately predicted by currently used prognostic tools. Experimental Design: We genotyped 798 prostate cancer cases of Ashkenazi Jewish ancestry treated for localized prostate cancer between June 1988 and December 2007. Blood samples were prospectively collected and de-identified before being genotyped and matched to clinical data. The survival analysis was adjusted for Gleason score and prostate-specific antigen. We investigated associations between 29 single nucleotide polymorphisms (SNP) and biochemical recurrence, castration-resistant metastasis, and prostate cancer-specific survival. Subsequently, we did an independent analysis using a high-resolution panel of 13 SNPs. Results: On univariate analysis, two SNPs were associated (P < 0.05) with biochemical recurrence, three SNPs were associated with clinical metastases, and one SNP was associated with prostate cancer specific mortality. Applying a Bonferroni correction (P < 0.0017), one association with biochemical recurrence (P = 0.0007) was significant. Three SNPs showed associations on multivariable analysis, although not after correcting for multiple testing. The secondary analysis identified an additional association with prostate cancer-specific mortality in KLK3 (P < 0.0005 by both univariate and multivariable analysis). Conclusions: We identified associations between prostate cancer susceptibility SNPs and clinical end points. The rs61752561 in KLK3 and rs2735839 in the KLK2-KLK3 intergenic region were strongly associated with prostate cancer-specific survival, and rs10486567 in the 7JAZF1 gene were associated with biochemical recurrence. A larger study will be required to independently validate these findings and determine the role of these SNPs in prognostic models. Clin Cancer Res; 16(10); 2819-32. (C) 2010 AACR.
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10.
  • Klein, Robert J., et al. (författare)
  • Evaluation of Multiple Risk-Associated Single Nucleotide Polymorphisms Versus Prostate-Specific Antigen at Baseline to Predict Prostate Cancer in Unscreened Men
  • 2012
  • Ingår i: European Urology. - : Elsevier BV. - 1873-7560 .- 0302-2838. ; 61:3, s. 471-477
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Although case-control studies have identified numerous single nucleotide polymorphisms (SNPs) associated with prostate cancer, the clinical role of these SNPs remains unclear. Objective: Evaluate previously identified SNPs for association with prostate cancer and accuracy in predicting prostate cancer in a large prospective population-based cohort of unscreened men. Design, setting, and participants: This study used a nested case-control design based on the Malmo Diet and Cancer cohort with 943 men diagnosed with prostate cancer and 2829 matched controls. Blood samples were collected between 1991 and 1996, and follow-up lasted through 2005. Measurements: We genotyped 50 SNPs, analyzed prostate-specific antigen (PSA) in blood from baseline, and tested for association with prostate cancer using the Cochran-Mantel-Haenszel test. We further developed a predictive model using SNPs nominally significant in univariate analysis and determined its accuracy to predict prostate cancer. Results and limitations: Eighteen SNPs at 10 independent loci were associated with prostate cancer. Four independent SNPs at four independent loci remained significant after multiple test correction (p < 0.001). Seven SNPs at five independent loci were associated with advanced prostate cancer defined as clinical stage >= T3 or evidence of metastasis at diagnosis. Four independent SNPs were associated with advanced or aggressive cancer defined as stage >= T3, metastasis, Gleason score >= 8, or World Health Organization grade 3 at diagnosis. Prostate cancer risk prediction with SNPs alone was less accurate than with PSA at baseline (area under the curve of 0.57 vs 0.79), with no benefit from combining SNPs with PSA. This study is limited by our reliance on clinical diagnosis of prostate cancer; there are likely undiagnosed cases among our control group. Conclusions: Only a few previously reported SNPs were associated with prostate cancer risk in the large prospective Diet and Cancer cohort in Malmo, Sweden. SNPs were less useful in predicting prostate cancer risk than PSA at baseline. (C) 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved.
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11.
  • Secin, Fernando P., et al. (författare)
  • The Learning Curve for Laparoscopic Radical Prostatectomy: An International Multicenter Study
  • 2010
  • Ingår i: Journal of Urology. - : Ovid Technologies (Wolters Kluwer Health). - 1527-3792 .- 0022-5347. ; 184:6, s. 2291-2296
  • Tidskriftsartikel (refereegranskat)abstract
    • Purpose: It is not yet possible to estimate the number of cases required for a beginner to become expert in laparoscopic radical prostatectomy. We estimated the learning curve of laparoscopic radical prostatectomy for positive surgical margins compared to a published learning curve for open radical prostatectomy. Materials and Methods: We reviewed records from 8,544 consecutive patients with prostate cancer treated laparoscopically by 51 surgeons at 14 academic institutions in Europe and the United States. The probability of a positive surgical margin was calculated as a function of surgeon experience with adjustment for pathological stage, Gleason score and prostate specific antigen. A second model incorporated prior experience with open radical prostatectomy and surgeon generation. Results: Positive surgical margins occurred in 1,862 patients (22%). There was an apparent improvement in surgical margin rates up to a plateau at 200 to 250 surgeries. Changes in margin rates once this plateau was reached were relatively minimal relative to the CIs. The absolute risk difference for 10 vs 250 prior surgeries was 4.8% (95% CI 1.5, 8.5). Neither surgeon generation nor prior open radical prostatectomy experience was statistically significant when added to the model. The rate of decrease in positive surgical margins was more rapid in the open vs laparoscopic learning curve. Conclusions: The learning curve for surgical margins after laparoscopic radical prostatectomy plateaus at approximately 200 to 250 cases. Prior open experience and surgeon generation do not improve the margin rate, suggesting that the rate is primarily a function of specifically laparoscopic training and experience.
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13.
  • Vickers, Andrew J., et al. (författare)
  • A Four-Kallikrein Panel Predicts Prostate Cancer in Men with Recent Screening: Data from the European Randomized Study of Screening for Prostate Cancer, Rotterdam
  • 2010
  • Ingår i: Clinical Cancer Research. - 1078-0432. ; 16:12, s. 3232-3239
  • Tidskriftsartikel (refereegranskat)abstract
    • Purpose: We have developed a statistical prediction model for prostate cancer based on four kallikrein markers in blood: total, free, and intact prostate-specific antigen ( PSA), and kallikrein-related peptidase 2 ( hK2). Although this model accurately predicts the result of biopsy in unscreened men, its properties for men with a history of PSA screening have not been fully characterized. Experimental Design: A total of 1,501 previously screened men with elevated PSA underwent initial biopsy during rounds 2 and 3 of the European Randomized Study of Screening for Prostate Cancer, Rotterdam, with 388 cancers diagnosed. Biomarker levels were measured in serum samples taken before biopsy. The prediction model developed on the unscreened cohort was then applied and predictions compared with biopsy outcome. Results: The previously developed four-kallikrein prediction model had much higher predictive accuracy than PSA and age alone ( area under the curve of 0.711 versus 0.585, and 0.713 versus 0.557 with and without digital rectal exam, respectively; both P < 0.001). Similar statistically significant enhancements were seen for high-grade cancer. Applying the model with a cutoff of 20% cancer risk as the criterion for biopsy would reduce the biopsy rate by 362 for every 1,000 men with elevated PSA. Although diagnosis would be delayed for 47 cancers, these would be predominately low-stage and low-grade ( 83% Gleason 6 T-1c). Conclusions: A panel of four kallikreins can help predict the result of initial biopsy in previously screened men with elevated PSA. Use of a statistical model based on the panel would substantially decrease rates of unnecessary biopsy. Clin Cancer Res; 16( 12); 3232-9. (C)2010 AACR.
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14.
  • Vickers, Andrew J, et al. (författare)
  • Prostate specific antigen velocity does not aid prostate cancer detection in men with prior negative biopsy.
  • 2010
  • Ingår i: The Journal of urology. - : Ovid Technologies (Wolters Kluwer Health). - 1527-3792 .- 0022-5347. ; 184:3, s. 907-12
  • Tidskriftsartikel (refereegranskat)abstract
    • Prostate specific antigen velocity has been proposed as a marker to aid in prostate cancer detection. We determined whether prostate specific antigen velocity could predict repeat biopsy results in men with persistently increased prostate specific antigen after initial negative biopsy.
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15.
  • Vickers, Andrew J., et al. (författare)
  • Prostate-Specific Antigen Velocity for Early Detection of Prostate Cancer: Result from a Large, Representative, Population-based Cohort
  • 2009
  • Ingår i: European Urology. - : Elsevier BV. - 1873-7560 .- 0302-2838. ; 56:5, s. 753-760
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: It has been suggested that changes in prostate-specific antigen (PSA) over time (ie, PSA velocity [PSAV]) aid prostate cancer detection. Some guidelines do incorporate PSAV cut points as an indication for biopsy. Objective: To evaluate whether PSAV enhances prediction of biopsy outcome in a large, representative, population-based cohort. Design, setting, and participants: There were 2742 screening-arm participants with PSA < 3 ng/ml at initial screening in the European Randomized Study of Screening for Prostate Cancer in Rotterdam, Netherlands, or Goteborg, Sweden, and who were subsequently biopsied during rounds 2-6 due to elevated PSA. Measurements: Total, free, and intact PSA and human kallikrein 2 were measured for 16 screening rounds at intervals of 2 or 4 yr. We created logistic regression models to predict prostate cancer based on age and PSA, with or without free-to-total PSA ratio (%fPSA). PSAV was added to each model and any enhancement in predictive accuracy assessed by area under the curve (AUC). Results and limitations: PSAV led to small enhancements in predictive accuracy (AUC of 0.569 vs 0.531; 0.626 vs 0.609 if %fPSA was included), although not for high-grade disease. The enhancement depended on modeling a nonlinear relationship between PSAV and cancer. There was no benefit if we excluded men with higher velocities, which were associated with lower risk. These results apply to men in a screening program with elevated PSA; men with prior negative biopsy were not evaluated in this study. Conclusions: In men with PSA of about >= 3 ng/ml, we found little justification for formal calculation of PSAV or for use of PSAV cut points to determine biopsy. Informal assessment of PSAV will likely aid clinical judgment, such as a sudden rise in PSA suggesting prostatitis, which could be further evaluated before biopsy. (C) 2009 European Association of Urology. Published by Elsevier B. V. All rights reserved.
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16.
  • Assel, Melissa J., et al. (författare)
  • Kallikrein markers performance in pretreatment blood to predict early prostate cancer recurrence and metastasis after radical prostatectomy among very high-risk men
  • 2019
  • Ingår i: Prostate. - : Wiley. - 0270-4137.
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: To assess whether a prespecified statistical model based on the four kallikrein markers measured in blood—total, free, and intact prostate-specific antigen (PSA), together with human kallikrein-related peptidase 2 (hK2)—or any individual marker measured in pretreatment serum were associated with biochemical recurrence-free (BCR) or metastasis-free survival after radical prostatectomy (RP) in a subgroup of men with very high-risk disease. Methods: We identified 106 men treated at Mayo Clinic from 2004 to 2008 with pathological Gleason grade group 4 to 5 or seminal vesicle invasion at RP. Univariable and multivariable Cox models were used to test the association between standard predictors (Kattan nomogram and GPSM [Gleason, PSA, seminal vesicle and margin status] score), kallikrein panel, and individual kallikrein markers with the outcomes. Results: BCR and metastasis occurred in 67 and 30 patients, respectively. The median follow-up for patients who did not develop a BCR was 10.3 years (interquartile range = 8.2-11.8). In this high-risk group, neither Kattan risk, GPSM score, or the kallikrein panel model was associated with either outcome. However, after adjusting for Kattan risk and GPSM score, separately, preoperative intact PSA was associated with both outcomes while hK2 was associated with metastasis-free survival. Conclusions: Conventional risk prediction tools were poor discriminators for risk of adverse outcomes after RP (Kattan risk and GPSM risk) in patients with very high-risk disease. Further studies are needed to define the role of individual kallikrein marker forms in the blood to predict adverse prostate cancer outcomes after RP in this high-risk setting.
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18.
  • Carlsson, Sigrid V., et al. (författare)
  • Can one blood draw replace transrectal ultrasonography-estimated prostate volume to predict prostate cancer risk?
  • 2013
  • Ingår i: BJU International. - 1464-4096 .- 1464-410X. ; 112:5, s. 602-609
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective To explore whether a panel of kallikrein markers in blood: total, free and intact prostate-specific antigen (PSA) and kallikrein-related peptidase 2, could be used as a non-invasive alternative for predicting prostate cancer on biopsy in a screening setting. Subjects and Methods The study cohort comprised previously unscreened men who underwent sextant biopsy owing to elevated PSA (3 ng/mL) in two different centres of the European Randomized Study of Screening for Prostate Cancer, Rotterdam (n = 2914) and Gteborg (n = 740). A statistical model, based on kallikrein markers, was compared with one based on established clinical factors for the prediction of biopsy outcome. Results The clinical tests were found to be no better than blood markers, with an area under the curve in favour of the blood measurements of 0.766 vs. 0.763 in Rotterdam and 0.809 vs. 0.774 in Gteborg. Adding digital rectal examination (DRE) or DRE plus transrectal ultrasonography (TRUS) volume to the markers improved discrimination, although the increases were small. Results were similar for predicting high-grade cancer. There was a strong correlation between the blood measurements and TRUS-estimated prostate volume (Spearman's correlation 0.60 in Rotterdam and 0.57 in Gteborg). Conclusions In previously unscreened men, each with indication for biopsy, a statistical model based on kallikrein levels was similar to a clinical model in predicting prostate cancer in a screening setting, outside the day-to-day clinical practice. Whether a clinical approach can be replaced by laboratory analyses or used in combination with decision models (nomograms) is a clinical judgment that may vary from clinician to clinician depending on how they weigh the different advantages and disadvantages (harms, costs, time, invasiveness) of both approaches.
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19.
  • Christensson, Anders, et al. (författare)
  • Intra-individual short-term variability of prostate-specific antigen and other kallikrein markers in a serial collection of blood from men under evaluation for prostate cancer.
  • 2011
  • Ingår i: BJU International. - 1464-4096. ; 107, s. 1769-1774
  • Tidskriftsartikel (refereegranskat)abstract
    • Study Type - Diagnostic (exploratory cohort) Level of Evidence 2b OBJECTIVES: To assess variation of total prostate-specific antigen (tPSA), free PSA (fPSA), percent fPSA, human glandular kallikrein 2 (hK2) and intact PSA measured three times within 2 weeks. Knowledge of the variation in an individual's PSA level is important for clinical decision-making. PATIENTS AND METHODS: Study participants were 149 patients referred for prostate biopsy, of which 97 had benign disease and 52 had prostate cancer. Three blood samples were drawn with a median of 4 h between first and second samples and 12 days between first and third samples. Variability was described by absolute differences, ratios and intra-individual coefficients of variation. Total PSA, fPSA, hK2 and intact PSA were measured in anticoagulated blood plasma. RESULTS: At baseline, the median tPSA was 6.8 (interquartile range, 4.5-9.6) ng/mL. The intra-individual variation was low for all biomarkers, and lowest for tPSA. For 80% of participants, the ratio between first and second time points for tPSA was in the range 0.91-1.09 and the ratio for percent fPSA was in the range 0.89-1.15. Total coefficients of variation between time 1 and 2 for tPSA, fPSA, percent fPSA, hK2 and intact PSA were 4.0%, 6.6%, 6.0%, 9.2% and 9.5%, respectively. The measurements taken several days apart varied more than those taken on the same day, although the variation between both time points was not large. CONCLUSIONS: The intra-individual variation for all the kallikrein-like markers studied was relatively small, especially for samples drawn the same day. Few cases are reclassified between the time points. This indicates the high short-term biological and technical reproducibility of the tests in clinical use.
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20.
  • Fearon, Nkechi J., et al. (författare)
  • Reducing opioid prescribing after ambulatory breast reconstruction surgery
  • 2023
  • Ingår i: JOURNAL OF SURGICAL ONCOLOGY. - 0022-4790 .- 1096-9098. ; 128:8, s. 1235-1242
  • Tidskriftsartikel (refereegranskat)abstract
    • BackgroundThe lack of evidence-based guidelines for postoperative opioid prescriptions following breast reconstruction contributes to a wide variation in prescribing practices and increases potential for misuse and abuse.MethodsBetween August and December 2019, women who underwent outpatient breast reconstruction were surveyed 7-10 days before (n = 97) and after (n = 101) implementing a standardized opioid prescription reduction initiative. We compared postoperative opioid use, pain control, and refills in both groups. Patient reported outcomes were compared using the BREAST-Q physical wellbeing of the chest domain and a novel symptom Recovery Tracker.ResultsBefore changes in prescriptions, patients were prescribed a median of 30 pills and consumed three pills (interquartile range [IQR: 1,9]). After standardization, patients were prescribed eight pills and consumed three pills (IQR: 1,6). There was no evidence of a difference in the proportion of patients experiencing moderate to very severe pain on the Recovery Tracker or in the early BREAST-Q physical wellbeing of the chest scores (p = 0.8 and 0.3, respectively).ConclusionStandardizing and reducing opioid prescriptions for patients undergoing reconstructive breast surgery is feasible and can significantly decrease the number of excess pills prescribed. The was no adverse impact on early physical wellbeing, although larger studies are needed to obtain further data.
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22.
  • Klein, Robert J, et al. (författare)
  • Blood biomarker levels to aid discovery of cancer-related single-nucleotide polymorphisms : kallikreins and prostate cancer
  • 2010
  • Ingår i: Cancer Prevention Research. - : American Association for Cancer Research. - 1940-6207 .- 1940-6215. ; 3:5, s. 611-619
  • Tidskriftsartikel (refereegranskat)abstract
    • Polymorphisms associated with prostate cancer include those in three genes encoding major secretory products of the prostate: KLK2 (encoding kallikrein-related peptidase 2; hK2), KLK3 (encoding prostate-specific antigen; PSA), and MSMB (encoding beta-microseminoprotein). PSA and hK2, members of the kallikrein family, are elevated in sera of men with prostate cancer. In a comprehensive analysis that included sequencing of all coding, flanking, and 2 kb of putative promoter regions of all 15 kallikrein (KLK) genes spanning approximately 280 kb on chromosome 19q, we identified novel single-nucleotide polymorphisms (SNP) and genotyped 104 SNPs in 1,419 cancer cases and 736 controls in Cancer Prostate in Sweden 1, with independent replication in 1,267 cases and 901 controls in Cancer Prostate in Sweden 2. This verified prior associations of SNPs in KLK2 and in MSMB (but not in KLK3) with prostate cancer. Twelve SNPs in KLK2 and KLK3 were associated with levels of PSA forms or hK2 in plasma of control subjects. Based on our comprehensive approach, this is likely to represent all common KLK variants associated with these phenotypes. A T allele at rs198977 in KLK2 was associated with increased cancer risk and a striking decrease of hK2 levels in blood. We also found a strong interaction between rs198977 genotype and hK2 levels in blood in predicting cancer risk. Based on this strong association, we developed a model for predicting prostate cancer risk from standard biomarkers, rs198977 genotype, and rs198977 x hK2 interaction; this model had greater accuracy than did biomarkers alone (area under the receiver operating characteristic curve, 0.874 versus 0.866), providing proof in principle to clinical application for our findings.
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23.
  • Martin, Neil E, et al. (författare)
  • Defining a Standard Set of Patient-centered Outcomes for Men with Localized Prostate Cancer
  • 2015
  • Ingår i: European Urology. - : Elsevier BV. - 0302-2838 .- 1873-7560. ; 67:3, s. 460-467
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Value-based health care has been proposed as a unifying force to drive improved outcomes and cost containment.OBJECTIVE: To develop a standard set of multidimensional patient-centered health outcomes for tracking, comparing, and improving localized prostate cancer (PCa) treatment value.DESIGN, SETTING, AND PARTICIPANTS: We convened an international working group of patients, registry experts, urologists, and radiation oncologists to review existing data and practices.OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The group defined a recommended standard set representing who should be tracked, what should be measured and at what time points, and what data are necessary to make meaningful comparisons. Using a modified Delphi method over a series of teleconferences, the group reached consensus for the Standard Set.RESULTS AND LIMITATIONS: We recommend that the Standard Set apply to men with newly diagnosed localized PCa treated with active surveillance, surgery, radiation, or other methods. The Standard Set includes acute toxicities occurring within 6 mo of treatment as well as patient-reported outcomes tracked regularly out to 10 yr. Patient-reported domains of urinary incontinence and irritation, bowel symptoms, sexual symptoms, and hormonal symptoms are included, and the recommended measurement tool is the Expanded Prostate Cancer Index Composite Short Form. Disease control outcomes include overall, cause-specific, metastasis-free, and biochemical relapse-free survival. Baseline clinical, pathologic, and comorbidity information is included to improve the interpretability of comparisons.CONCLUSIONS: We have defined a simple, easily implemented set of outcomes that we believe should be measured in all men with localized PCa as a crucial first step in improving the value of care.PATIENT SUMMARY: Measuring, reporting, and comparing identical outcomes across treatments and treatment centers will provide patients and providers with information to make informed treatment decisions. We defined a set of outcomes that we recommend being tracked for every man being treated for localized prostate cancer.
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24.
  • Savage, Caroline J, et al. (författare)
  • Empirical Estimates of the Lead Time Distribution for Prostate Cancer Based on Two Independent Representative Cohorts of Men Not Subject to Prostate-Specific Antigen Screening.
  • 2010
  • Ingår i: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. - 1538-7755. ; May 4, s. 1201-1207
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Lead time, the estimated time by which screening advances the date of diagnosis, is used to calculate the risk of overdiagnosis. We sought to describe empirically the distribution of lead times between an elevated prostate-specific antigen (PSA) and subsequent prostate cancer diagnosis. METHODS: We linked the Swedish cancer registry to two independent cohorts: 60-year-olds sampled in 1981-1982 and 51- to 56-year-olds sampled in 1982-1985. We used univariate kernel density estimation to characterize the lead time distribution. Linear regression was used to model the lead time as a function of baseline PSA and logistic regression was used to test for an association between lead time and either stage or grade at diagnosis. RESULTS: Of 1,167 older men, 132 were diagnosed with prostate cancer, of which 57 had PSA >/=3 ng/mL at baseline; 495 of 4,260 younger men were diagnosed with prostate cancer, of which 116 had PSA >/=3 ng/mL at baseline. The median lead time was slightly longer in the younger men (12.8 versus 11.8 years). In both cohorts, wide variation in lead times followed an approximately normal distribution. Longer lead times were significantly associated with a lower risk of high-grade disease in older and younger men [odds ratio, 0.82 (P = 0.023) and 0.77 (P < 0.001)]. CONCLUSION: Our findings suggest that early changes in the natural history of the disease are associated with high-grade cancer at diagnosis. Impact: The distinct differences between the observed distribution of lead times and those used in modeling studies illustrate the need to model overdiagnosis rates using empirical data. Cancer Epidemiol Biomarkers Prev; 19(5); OF1-7. (c)2010 AACR.
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25.
  • Trinh, Quoc-Dien, et al. (författare)
  • A Systematic Review of the Volume-Outcome Relationship for Radical Prostatectomy
  • 2013
  • Ingår i: European Urology. - : Elsevier BV. - 1873-7560 .- 0302-2838. ; 64:5, s. 786-798
  • Forskningsöversikt (refereegranskat)abstract
    • Context: Due to the complexity and challenging nature of radical prostatectomy (RP), it is likely that both short-and long-term outcomes strongly depend on the cumulative number of cases performed by the surgeon as well as by the hospital. Objective: To review systematically the association between hospital and surgeon volume and perioperative, oncologic, and functional outcomes after RP. Evidence acquisition: A systematic review of the literature was performed, searching PubMed, Embase, and Scopus databases for original and review articles between January 1, 1995, and December 31, 2011. Inclusion and exclusion criteria comprised RP, hospital and/or surgeon volume reported as a predictor variable, a measurable end point, and a description of multiple hospitals or surgeons. Evidence synthesis: Overall 45 publications fulfilled the inclusion criteria, where most data originated from retrospective institutional or population-based cohorts. Studies generally focused on hospital or surgeon volume separately. Although most of these analyses corroborated the impact of increasing volume with better outcomes, some failed to find any significant effect. Studies also differed with respect to the proposed volume cut-off for improved outcomes, as well as the statistical means of evaluating the volume-outcome relationship. Five studies simultaneously compared hospital and surgeon volume, where results suggest that the importance of either hospital or surgeon volume largely depends on the end point of interest. Conclusions: Undeniable evidence suggests that increasing volume improves outcomes. Although it would seem reasonable to refer RP patients to high-volume centers, such regionalization may not be entirely practical. As such, the implications of such a shift in practice have yet to be fully determined and warrant further exploration. (C) 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved.
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26.
  • Vickers, Andrew J., et al. (författare)
  • A Panel of Kallikrein Marker Predicts Prostate Cancer in a Large, Population-Based Cohort Followed for 15 Years without Screening
  • 2011
  • Ingår i: Cancer Epidemiology Biomarkers & Prevention. - 1538-7755. ; 20:2, s. 255-261
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Prostate-specific antigen (PSA) has modest specificity for prostate cancer. A panel of four kallikrein markers (total PSA, free PSA, intact PSA, and kallikrein-related peptidase 2) is a highly accurate predictor of biopsy outcome. The clinical significance of biopsy-detectable cancers in men classified as low-risk by this panel remains unclear. Methods: The Malmo Diet and Cancer study is a population-based cohort of 11,063 Swedish men aged 45 to 73 providing a blood sample at baseline during 1991-1996. The Swedish Cancer Registry was used to identify 943 men diagnosed with prostate cancer by December 31, 2006. PSA testing was low. We assessed the predictive accuracy of our published statistical model to predict subsequent prostate cancer diagnosis in men with a total PSA level of 3.0 ng/mL or more at baseline. Results: Compared with total PSA and age, the full kallikrein panel enhanced the predictive accuracy for clinically diagnosed prostate cancer (concordance index 0.65 vs. 0.75; P < 0.001). For every 1,000 men with a total PSA level of 3 ng/mL or more at baseline, the model would classify as high-risk 131 of 152 (86%) of the cancer cases diagnosed clinically within 5 years; 421 men would be classified as low-risk by the panel and recommended against biopsy. Of these, only 2 would be diagnosed with advanced prostate cancer (clinical T3-T4 or metastases) within 5 years. Conclusions: Men with a PSA level of 3 ng/mL or more but defined as low-risk by the panel of four kallikrein markers are unlikely to develop incurable prostate cancer. Impact: Use of the panel to determine referral to biopsy could substantially reduce the number of unnecessary prostate biopsies. Cancer Epidemiol Biomarkers Prev; 20(2); 255-61. (C)2010 AACR.
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27.
  • Vickers, Andrew J., et al. (författare)
  • Empirical estimates of prostate cancer overdiagnosis by age and prostate-specific antigen
  • 2014
  • Ingår i: BMC Medicine. - : Springer Science and Business Media LLC. - 1741-7015. ; 12
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Prostate cancer screening depends on a careful balance of benefits, in terms of reduced prostate cancer mortality, and harms, in terms of overdiagnosis and overtreatment. We aimed to estimate the effect on overdiagnosis of restricting prostate specific antigen (PSA) testing by age and baseline PSA. Methods: Estimates of the effects of age on overdiagnosis were based on population based incidence data from the US Surveillance, Epidemiology and End Results database. To investigate the relationship between PSA and overdiagnosis, we used two separate cohorts subject to PSA testing in clinical trials (n = 1,577 and n = 1,197) and a population-based cohort of Swedish men not subject to PSA-screening followed for 25 years (n = 1,162). Results: If PSA testing had been restricted to younger men, the number of excess cases associated with the introduction of PSA in the US would have been reduced by 85%, 68% and 42% for age cut-offs of 60, 65 and 70, respectively. The risk that a man with screen-detected cancer at age 60 would not subsequently lead to prostate cancer morbidity or mortality decreased exponentially as PSA approached conventional biopsy thresholds. For PSAs below 1 ng/ml, the risk of a positive biopsy is 65 (95% CI 18.2, 72.9) times greater than subsequent prostate cancer mortality. Conclusions: Prostate cancer overdiagnosis has a strong relationship to age and PSA level. Restricting screening in men over 60 to those with PSA above median (>1 ng/ml) and screening men over 70 only in selected circumstances would importantly reduce overdiagnosis and change the ratio of benefits to harms of PSA-screening.
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28.
  • Vickers, Andrew J., et al. (författare)
  • Screening for Prostate Cancer: Early Detection or Overdetection?
  • 2012
  • Ingår i: Annual Review of Medicine. - : Annual Reviews. - 0066-4219 .- 1545-326X. ; 63, s. 161-170
  • Forskningsöversikt (refereegranskat)abstract
    • A sophisticated reading of the randomized trial evidence suggests that, although screening for prostate cancer with prostate-specific antigen (PSA) can reduce cancer-specific mortality, it does so at considerable cost in terms of the number of men who need to be screened, biopsied, and treated to prevent one death. The challenge is to design screening programs that maximize benefits (reducing prostate cancer mortality) and minimize costs (overtreatment). Recent research has suggested that this can be achieved by risk-stratifying screening and biopsy; increasing reliance on active surveillance for low-risk cancer; restricting radical prostatectomy to high-volume surgeons; and using appropriately high-dose radiotherapy. In current U. S. practice, however, many men who are screened are unlikely to benefit, most men found to have low-risk cancers are referred for unnecessary curative treatment, and much treatment is given at low-volume centers.
  •  
29.
  • Vickers, Andrew J., et al. (författare)
  • Strategy for detection of prostate cancer based on relation between prostate specific antigen at age 40-55 and long term risk of metastasis: case-control study
  • 2013
  • Ingår i: BMJ: British Medical Journal. - : BMJ. - 1756-1833. ; 346, s. 2023-2023
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective To determine the association between concentration of prostate specific antigen (PSA) at age 40-55 and subsequent risk of prostate cancer metastasis and mortality in an unscreened population to evaluate when to start screening for prostate cancer and whether rescreening could be risk stratified. Design Case-control study with 1: 3 matching nested within a highly representative population based cohort study. Setting Malmo Preventive Project, Sweden. Participants 21 277 Swedish men aged 27-52 (74% of the eligible population) who provided blood at baseline in 1974-84, and 4922 men invited to provide a second sample six years later. Rates of PSA testing remained extremely low during median follow-up of 27 years. Main outcome measures Metastasis or death from prostate cancer ascertained by review of case notes. Results Risk of death from prostate cancer was associated with baseline PSA: 44% (95% confidence interval 34% to 53%) of deaths occurred in men with a PSA concentration in the highest 10th of the distribution of concentrations at age 45-49 (>= 1.6 mu g/L), with a similar proportion for the highest 10th at age 51-55 (>= 2.4 mu g/L: 44%, 32% to 56%). Although a 25-30 year risk of prostate cancer metastasis could not be ruled out by concentrations below the median at age 45-49 (0.68 mu g/L) or 51-55 (0.85 mu g/L), the 15 year risk remained low at 0.09% (0.03% to 0.23%) at age 45-49 and 0.28% (0.11% to 0.66%) at age 51-55, suggesting that longer intervals between screening would be appropriate in this group. Conclusion Measurement of PSA concentration in early midlife can identify a small group of men at increased risk of prostate cancer metastasis several decades later. Careful surveillance is warranted in these men. Given existing data on the risk of death by PSA concentration at age 60, these results suggest that three lifetime PSA tests (mid to late 40s, early 50s, and 60) are probably sufficient for at least half of men.
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30.
  • Assel, Melissa, et al. (författare)
  • A Four-kallikrein Panel and β-Microseminoprotein in Predicting High-grade Prostate Cancer on Biopsy : An Independent Replication from the Finnish Section of the European Randomized Study of Screening for Prostate Cancer
  • 2019
  • Ingår i: European Urology Focus. - : Elsevier BV. - 2405-4569. ; 5:4, s. 561-567
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: A panel of four kallikrein markers (total, free, and intact prostate-specific antigen [PSA] and human kallikrein-related peptidase 2 [hK2]) improves predictive accuracy for Gleason score ≥7 (high-grade) prostate cancer among men biopsied for elevated PSA. A four-kallikrein panel model was originally developed and validated by the Dutch center of the European Randomized Study of Screening for Prostate Cancer (ERSPC). The kallikrein panel is now commercially available as 4Kscore™. Objective: To assess whether these findings could be replicated among participants in the Finnish section of ERSPC (FinRSPC) and whether β-microseminoprotein (MSP), a candidate prostate cancer biomarker, adds predictive value. Design, setting, and participants: Among 4861 biopsied screening-positive participants in the first three screening rounds of FinRSPC, a case-control subset was selected that included 1632 biopsy-positive cases matched by age at biopsy to biopsy-negative controls. Outcome measurements and statistical analysis: The predictive accuracy of prespecified prediction models was compared with biopsy outcomes. Results and limitations: Among men with PSA of 4.0-25. ng/ml, 1111 had prostate cancer, 318 of whom had high-grade disease. Total PSA and age predicted high-grade cancer with an area under the curve of 0.648 (95% confidence interval [CI] 0.614-0.681) and the four-kallikrein panel increased discrimination to 0.746 (95% CI 0.717-0.774). Adding MSP to the four-kallikrein panel led to a significant (Wald test; p = 0.015) but small increase (0.003) in discrimination. Limitations include a risk of verification bias among men with PSA of 3.0-3.99. ng/ml and the absence of digital rectal examination results. Conclusions: These findings provide additional evidence that kallikrein markers can be used to inform biopsy decision-making. Further studies are needed to define the role of MSP. Patient summary: Four kallikrein markers and β-microseminoprotein in blood improve discrimination of high-grade prostate cancer at biopsy in men with elevated prostate-specific antigen. Four kallikrein markers and β-microseminoprotein (MSP) in blood improve discrimination of high-grade cancer at biopsy in men with elevated prostate-specific antigen. These kallikrein markers can be used to inform biopsy decision-making. Further studies are needed to define the role of MSP.
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31.
  • Assel, Melissa, et al. (författare)
  • Association Between Lead Time and Prostate Cancer Grade : Evidence of Grade Progression from Long-term Follow-up of Large Population-based Cohorts Not Subject to Prostate-specific Antigen Screening
  • 2018
  • Ingår i: European Urology. - : Elsevier BV. - 0302-2838 .- 1873-7560. ; 73:6, s. 961-967
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Lead time (LT) is of key importance in early detection of cancer, but cannot be directly measured. We have previously provided LT estimates for prostate cancer (PCa) using archived blood samples from cohorts followed for many years without screening. Objective: To determine the association between LT and PCa grade at diagnosis to provide an insight into whether grade progresses or is stable over time. Design, setting, and participants: The setting was three long-term epidemiologic studies in Sweden including men not subject to prostate-specific antigen (PSA) screening. The cohort included 1041 men with PSA of 3–10 ng/ml at blood draw and subsequently diagnosed with PCa with grade data available. Outcome measurements and statistical analysis: Multivariable logistic regression was used to predict high-grade (Gleason grade group ≥2 or World Health Organization grade 3) versus low-grade PCa at diagnosis in terms of LT, defined as the time between the date of elevated PSA and the date of PCa diagnosis with adjustment for cohort and age. Results and limitations: The probability that PCa would be high grade at diagnosis increased with LT. Among all men combined, the risk of high-grade disease increased with LT (odds ratio 1.13, 95% confidence interval [CI] 1.10–1.16; p < 0.0001), with no evidence of differences in effect by age group or cohort. Higher PSA predicted shorter LT by 0.46 yr (95% CI 0.28–0.64; p < 0.0001) per 1 ng/ml increase in PSA. However, there was no interaction between PSA and grade, suggesting that the longer LT for high-grade tumors is not simply related to age. Limitations include the assumption that men with elevated PSA and subsequently diagnosed with PCa would have had biopsy-detectable PCa at the time of PSA elevation. Conclusions: Our data support grade progression, whereby following a prostate over time would reveal transitions from benign to low-grade and then high-grade PCa. Patient summary: Men with a longer lead time between elevated prostate-specific antigen and subsequent prostate cancer diagnosis were more likely to have high-grade cancers at diagnosis. The probability that a cancer will be of high grade at diagnosis increases with the lead time. Our findings provide evidence of grade progression, whereby a prostate followed over time would exhibit transitions from benign to low-grade to high-grade prostate cancer.
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32.
  • Bjartell, Anders, et al. (författare)
  • Association of cysteine-rich secretory protein 3 and beta-microseminoprotein with outcome after radical prostatectomy
  • 2007
  • Ingår i: Clinical Cancer Research. - 1078-0432. ; 13:14, s. 4130-4138
  • Tidskriftsartikel (refereegranskat)abstract
    • Purpose: It has been suggested that cysteine-rich secretory protein 3 (CRISP-3) and p-microseminoprotein (MSP) are associated with outcome in prostate cancer. We investigated whether these markers are related to biochemical recurrence and whether addition of the markers improves prediction of recurring disease. Experimental Design: Tissue microarrays of radical prostatectomy specimens were analyzed for CRISP-3 and MSP by immunohistochemistry. Associations between marker positivity and postprostatectomy biochemical recurrence [prostate-specific antigen (PSA) > 0.2 ng/mL with a confirmatory level] were evaluated by univariate and multivariable Cox proportional hazards regression. Multivariable analyses controlled for preoperative PSA and pathologic stage and grade. Results: Among 945 patients, 224 had recurrence. Median follow-up for survivors was 6.0 years. Patients positive for CRISP-3 had smaller recurrence-free probabilities, whereas MSP-positive patients had larger recurrence-free probabilities. On univariate analysis, the hazard ratio for patients positive versus negative for CRISP-3 was 1.53 (P =0.010) and for MSP was 0.63 (P = 0.004). On multivariable analysis, both CRISP-3 (P = 0.007) and MSP (P = 0.002) were associated with recurrence. The hazard ratio among CRISP-3-positive/MSP-negative patients compared with CRISP-3-negative/MSP-positive patients was 2.38. Adding CRISP-3 to a base model that included PSA and pathologic stage and grade did not enhance the prediction of recurrence, but adding MSP increased the concordance index minimally from 0.778 to 0.781. Conclusion: We report evidence that CRISP-3 and MSP are independent predictors of recurrence after radical prostatectomy for localized prostate cancer. However, addition of the markers does not importantly improve the performance of existing predictive models. Further research should aim to elucidate the functions of CRISP-3 and MSP in prostate cancer cells.
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33.
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34.
  • Carlsson, Sigrid, 1982, et al. (författare)
  • A Provider-Facing Decision Support Tool for Prostate Cancer Screening in Primary Care: A Pilot Study
  • 2024
  • Ingår i: APPLIED CLINICAL INFORMATICS. - 1869-0327. ; 15:02, s. 274-281
  • Tidskriftsartikel (refereegranskat)abstract
    • Objectives Our objective was to pilot test an electronic health record-embedded decision support tool to facilitate prostate-specific antigen (PSA) screening discussions in the primary care setting. Methods We pilot-tested a novel decision support tool that was used by 10 primary care physicians (PCPs) for 6 months, followed by a survey. The tool comprised (1) a risk-stratified algorithm, (2) a tool for facilitating shared decision-making (Simple Schema), (3) three best practice advisories (BPAs: <45, 45-75, and >75 years), and (4) a health maintenance module for scheduling automated reminders about PSA rescreening. Results All PCPs found the tool feasible, acceptable, and clear to use. Eight out of ten PCPs reported that the tool made PSA screening conversations somewhat or much easier. Before using the tool, 70% of PCPs felt confident in their ability to discuss PSA screening with their patient, and this improved to 100% after the tool was used by PCPs for 6 months. PCPs found the BPAs for eligible (45-75 years) and older men (>75 years) more useful than the BPA for younger men (<45 years). Among the 10 PCPs, 60% found the Simple Schema to be very useful, and 50% found the health maintenance module to be extremely or very useful. Most PCPs reported the components of the tool to be at least somewhat useful, with 10% finding them to be very burdensome. Conclusion We demonstrated the feasibility and acceptability of the tool, which is notable given the marked low acceptance of existing tools. All PCPs reported that they would consider continuing to use the tool in their clinic and were likely or very likely to recommend the tool to a colleague.
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35.
  • Carlsson, Sigrid, et al. (författare)
  • Predictive Value of Four Kallikrein Markers for Pathologically Insignificant Compared With Aggressive Prostate Cancer in Radical Prostatectomy Specimens: Results From the European Randomized Study of Screening for Prostate Cancer Section Rotterdam
  • 2013
  • Ingår i: European Urology. - : Elsevier BV. - 1873-7560 .- 0302-2838. ; 64:5, s. 693-699
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Treatment decisions can be difficult in men with low-risk prostate cancer (PCa). Objective: To evaluate the ability of a panel of four kallikrein markers in blood-total prostate-specific antigen (PSA), free PSA, intact PSA, and kallikrein-related peptidase 2-to distinguish between pathologically insignificant and aggressive disease on pathologic examination of radical prostatectomy (RP) specimens as well as to calculate the number of avoidable surgeries. Design, setting, and participants: The cohort comprised 392 screened men participating in rounds 1 and 2 of the Rotterdam arm of the European Randomized Study of Screening for Prostate Cancer. Patients were diagnosed with PCa because of an elevated PSA >= 3.0 ng/ml and were treated with RP between 1994 and 2004. Outcome measurements and statistical analysis: We calculated the accuracy (area under the curve [AUC]) of statistical models to predict pathologically aggressive PCa (pT3-T4, extracapsular extension, tumor volume >0.5 cm(3), or any Gleason grade >= 4) based on clinical predictors (age, stage, PSA, biopsy findings) with and without levels of four kallikrein markers in blood. Results and limitations: A total of 261 patients (67%) had significant disease on pathologic evaluation of the RP specimen. While the clinical model had good accuracy in predicting aggressive disease, reflected in a corrected AUC of 0.81, the four kallikrein markers enhanced the base model, with an AUC of 0.84 (p < 0.0005). The model retained its ability in patients with low-risk and very-low-risk disease and in comparison with the Steyerberg nomogram, a published prediction model. Clinical application of the model incorporating the kallikrein markers would reduce rates of surgery by 135 of 1000 patients overall and 110 of 334 patients with pathologically insignificant disease. A limitation of the present study is that clinicians may be hesitant to make recommendations against active treatment on the basis of a statistical model. Conclusions: Our study provided proof of principle that predictions based on levels of four kallikrein markers in blood distinguish between pathologically insignificant and aggressive disease after RP with good accuracy. In the future, clinical use of the model could potentially reduce rates of immediate unnecessary active treatment. (c) 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved.
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36.
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37.
  • Chen, Rui, et al. (författare)
  • Prostate Specific Antigen and Prostate Cancer in Chinese Men Undergoing Initial Prostate Biopsies Compared with Western Cohorts
  • 2017
  • Ingår i: Journal of Urology. - : Ovid Technologies (Wolters Kluwer Health). - 0022-5347 .- 1527-3792. ; 197:1, s. 90-96
  • Tidskriftsartikel (refereegranskat)abstract
    • Purpose We determined the characteristics of Chinese men undergoing initial prostate biopsy and evaluated the relationship between prostate specific antigen levels and prostate cancer/high grade prostate cancer detection in a large Chinese multicenter cohort. Materials and Methods This retrospective study included 13,904 urology outpatients who had undergone biopsy for the indications of prostate specific antigen greater than 4.0 ng/ml or prostate specific antigen less than 4.0 ng/ml but with abnormal digital rectal examination results. The prostate specific antigen measurements were performed in accordance with the standard procedures at the respective institutions. The type of assay used was documented and recalibrated to the WHO standard. Results The incidence of prostate cancer and high grade prostate cancer was lower in the Chinese cohort than the Western cohorts at any given prostate specific antigen level. Around 25% of patients with a prostate specific antigen of 4.0 to 10.0 ng/ml were found to have prostate cancer compared to approximately 40% in U.S. clinical practice. Moreover, the risk curves were generally flatter than those of the Western cohorts, that is risk did not increase as rapidly with higher prostate specific antigen. Conclusions The relationship between prostate specific antigen and prostate cancer risk differs importantly between Chinese and Western populations, with an overall lower risk in the Chinese cohort. Further research should explore whether environmental or genetic differences explain these findings or whether they result from unmeasured differences in screening or benign prostate disease. Caution is required for the implementation of prostate cancer clinical decision rules or prediction models for men in China or other Asian countries with similar genetic and environmental backgrounds.
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38.
  • Christensson, Anders, et al. (författare)
  • Association of cancer with moderately impaired renal function at baseline in a large, representative, population-based cohort followed for up to 30 years.
  • 2013
  • Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136. ; 133:6, s. 1452-1458
  • Tidskriftsartikel (refereegranskat)abstract
    • Patients with chronic renal failure show a greater incidence of malignancies. We evaluated whether moderately impaired renal function at baseline influenced risk of all cancers during long-term follow in young persons. Our cohort included 33,346 subjects, aged 26-61 years at baseline, in a representative, population-based study enrolling subjects from 1974 to 1992. Median follow-up time was 28 years. Plasma creatinine was analysed as a single measure at baseline. Incident cases of cancer were identified from the Swedish Cancer Registry. We studied 24,552 subjects from the cohort. To account for the unique sampling design, participants were divided by sex and age at baseline into 1,132 older men (age 60), 14,254 younger men (age 40-52), 7,498 older women (age 47-57) and 1,688 younger women (age 35-43). Glomerular filtration rate (GFR) was estimated using the CKD-EPI formula. Patients were classified as having either normal to mildly impaired kidney function (eGFR≥60 mL/min/1.73m(2) ), or moderate kidney dysfunction (eGFR<60 mL/min/1.73m(2) ). We calculated the risk of all cancers using competing risks regression. Overall, 6,595 participants were diagnosed with cancer, and 854 subjects (3.5%) had moderately impaired renal dysfunction at baseline. There was a significant association between moderately decreased GFR and subsequent risk of kidney cancer in younger men (hazard ratio, 3.38; 95% CI, 1.48 to 7.71; P=0.004). However, we found no association with overall long-term cancer risk. Our confirmation of an association between moderately impaired renal function and risk of kidney cancer in younger men requires further exploration of high-risk groups and biological mechanisms. © 2013 Wiley Periodicals, Inc.
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39.
  • Darst, Burcu F., et al. (författare)
  • The Four-Kallikrein Panel Is Effective in Identifying Aggressive Prostate Cancer in a Multiethnic Population
  • 2020
  • Ingår i: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. - 1538-7755. ; 29:7, s. 1381-1388
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: The four-kallikrein (4K) panel has been demonstrated to improve prediction of aggressive prostate cancer compared with prostate-specific antigen (PSA) among men with moderately elevated PSA levels. However, the development and testing of the 4K panel has been conducted primarily in White men, with limited data in African Americans and no studies in other racial and ethnic groups. METHODS: We evaluated the 4K panel in a nested case-control study among African American, Latino, Japanese, Native Hawaiian, and White men in the Multiethnic Cohort. Prediagnostic blood levels of free, intact, and total PSA and human kallikrein-related peptidase 2 were measured among 1,667 incident prostate cancer cases and 691 controls with PSA ≥2 ng/mL. We evaluated the discriminative ability of the 4K panel within and across all racial/ethnic groups. RESULTS: The 4K panel enhanced discrimination of overall prostate cancer compared with free plus total PSA and total PSA alone (AUC 0.748 vs. 0.711 and 0.669, respectively). Discrimination was further enhanced for Gleason 8+ prostate cancer, aggressive prostate cancer, and death due to prostate cancer, and to a lesser degree for nonaggressive prostate cancer. Improvement of the 4K panel over PSA was observed in each population. Adding a prostate cancer polygenic risk score slightly improved upon the discriminative ability of the 4K panel. CONCLUSIONS: The superior discriminative ability of the 4K panel over PSA for overall and aggressive prostate cancer across multiethnic populations indicates the broad clinical applicability of the 4K panel. IMPACT: Our multiethnic investigation suggests potential for the 4K panel to improve current prostate cancer screening practices.
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40.
  • Fredsøe, Jacob, et al. (författare)
  • Predicting Grade group 2 or higher cancer at prostate biopsy by 4Kscore in blood and uCaP microRNA model in urine
  • 2022
  • Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 12:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Elevated prostate-specific antigen (PSA) levels often lead to unnecessary and possibly harmful transrectal ultrasound guided biopsy, e.g. when the biopsy is negative or contains only low-grade insignificant cancer, unlikely to become symptomatic in the man’s normal lifespan. A model based on four-kallikrein markers in blood (commercialized as 4Kscore) predicts risk of Grade group 2 or higher prostate cancer at biopsy, reducing unnecessary biopsies. We assessed whether these results extend to a single institution prostate biopsy cohort of Danish men and are enhanced by three microRNAs from urine (referred to as uCaP). The 4Kscore measured in cryopreserved blood from 234 men referred for 10+ core biopsy to Aarhus University Hospital, 29 with PSA > 25 ng/ml. We explored uCaP in urine from 157 of these men. Combined with age and DRE findings, both 4Kscore and uCaP could accurately predict Grade group 2 or higher prostate cancer (all patients: AUC = 0.802 and 0.797; PSA ≤ 25: AUC = 0.763 and 0.759). There was no additive effect when combining the 4Kscore and uCaP. Limitations include a study cohort with higher risk than commonly reported for biopsy cohorts. Our findings further support the clinical use of the 4Kscore to predict Grade group 2 or higher cancers in men being considered for biopsy.
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41.
  • Gaffney, Christopher D., et al. (författare)
  • A brief mind-body intervention to reduce pain and anxiety during prostate needle biopsy: a clinically integrated randomized controlled trial with 2-staged consent
  • 2023
  • Ingår i: Urologic Oncology: Seminars and Original Investigations. - 1078-1439 .- 1873-2496. ; 41:12
  • Tidskriftsartikel (refereegranskat)abstract
    • Objectives: Many patients experience pain, anxiety, and discomfort with prostate biopsy, which may discourage enrollment in active surveillance programs or follow-up biopsy. Guided meditation can significantly reduce pain and anxiety during percutaneous biopsy. We sought to evaluate the effectiveness of a brief mind-body intervention on patient-reported outcomes after prostate biopsy. Methods and materials: We performed a clinically-integrated randomized controlled trial of a brief mind-body intervention during biopsy compared to usual care at a single tertiary care center from 2018 to 2022. All patients offered transrectal ultrasound-guided prostate biopsy in the clinic with local anesthesia were eligible for enrollment. This clinically integrated trial was conducted simultaneously with a randomized controlled trial of 1-stage and 2-stage consent. The primary outcome was patient-reported pain, anxiety, discomfort, and tolerability on a visual-analog scale (0–10). A 15% improvement was prespecified as clinically relevant. We compared the proportion of men in each arm reporting a severe score (7–10) on any of the 4 scales using Fisher's exact test and then compared means for each scale separately using ANCOVA with randomization stratum (first vs. prior biopsy) as a covariate. Results: Of 263 eligible patients, 238 enrolled (119 per arm). One hundred seventy-two (72%) enrolled with 2-stage consent. A total of 37/94 (39%) and 38/102 (37%) patients randomized to usual care and intervention, respectively, reported severe scores in any of the 4 domains, a difference of 2.1% (95% confidence interval [CI] -13, 17%, P = 0.8). There was no evidence of a difference in mean postbiopsy anxiety (P = 0.3), discomfort (P = 0.09), pain (P = 0.4) or tolerability scores (P = 0.2). Conclusions: A clinically meaningful benefit for this brief mind-body intervention during prostate biopsy is unlikely. Robust patient enrollment is feasible using 2-stage consent.
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42.
  • Haas, Gabriel P, et al. (författare)
  • Needle biopsies on autopsy prostates: sensitivity of cancer detection based on true prevalence
  • 2007
  • Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 1460-2105 .- 0027-8874. ; 99:19, s. 1484-1489
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: It is difficult to estimate the diagnostic accuracy of biopsy for prostate cancer because men with negative biopsy do not undergo radical prostatectomy and thus have no confirmation of biopsy findings. METHODS: We performed 18-core needle biopsies on autopsy prostates from 164 men who had no history of prostate cancer. Six-core biopsies were taken from each of the mid peripheral zone (MPZ), the lateral peripheral zone (LPZ), and the central zone (CZ). We tested associations between age and tumor characteristics and analyzed the sensitivity of biopsies at each site. All statistical tests were two-sided. RESULTS: Prostate cancer was present in 47 (29%) prostates. Of the 47 cancers detected, 20 were clinically significant according to histologic criteria. Tumor volume was associated with tumor grade (P = .012) and with age (P<.001). The biopsies from the CZ did not detect any cancer that was not present in biopsies of either the MPZ or LPZ. The sensitivity of the biopsies taken from the MPZ and LPZ together (53%, 95% confidence interval [CI] = 38% to 68%) was therefore the same as that of 18-core biopsies and was superior to that of biopsies of the MPZ alone (30%, 95% CI = 17% to 45%) (P = .003). The sensitivities of biopsies from the MPZ for clinically significant and insignificant cancer were 55% (95% CI = 32% to 77%) and 11% (95% CI = 2% to 29%), respectively, compared with 80% (95% CI = 56% to 94%) and 33% (95% CI = 17% to 54%) for those from the MPZ and LPZ combined. CONCLUSIONS: The ability to detect prostate cancer was more related to the biopsy site than to the number of biopsy cores taken. The 12-core biopsies, six cores each from the MPZ and LPZ, were most likely to detect the majority of clinically significant cancers but also detected many insignificant cancers. When the six-core biopsies from the CZ were added, no increase in sensitivity was observed.
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43.
  • Haiman, Christopher A, et al. (författare)
  • Levels of Beta-Microseminoprotein in Blood and Risk of Prostate Cancer in Multiple Populations.
  • 2012
  • Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 1460-2105 .- 0027-8874.
  • Tidskriftsartikel (refereegranskat)abstract
    • BackgroundA common genetic variant (rs10993994) in the 5' region of the gene encoding β-microseminoprotein (MSP) is associated with circulating levels of MSP and prostate cancer risk. Whether MSP levels are predictive of prostate cancer risk has not been evaluated.MethodsWe investigated the prospective relationship between circulating plasma levels of MSP and prostate cancer risk in a nested case-control study of 1503 case subjects and 1503 control subjects among black, Latino, Japanese, Native Hawaiian, and white men from the Multiethnic Cohort study. We also examined the ability of MSP to serve as a biomarker for discriminating prostate cancer case subjects from control subjects. All statistical tests are two-sided.ResultsIn all racial and ethnic groups, men with lower MSP levels were at greater risk of developing prostate cancer (odds ratio = 1.02 per one unit decrease in MSP, P < .001 in the prostate-specific antigen [PSA]-adjusted analysis). Compared with men in the highest decile of MSP, the multivariable PSA-adjusted odds ratio was 3.64 (95% confidence interval = 2.41 to 5.49) for men in the lowest decile. The positive association with lower MSP levels was observed consistently across racial and ethnic populations, by disease stage and Gleason score, for men with both high and low levels of PSA and across all genotype classes of rs10993994. However, we did not detect strong evidence of MSP levels in improving prostate cancer prediction beyond that of PSA.ConclusionsRegardless of race and ethnicity or rs10993994 genotype, men with low blood levels of MSP have increased risk of prostate cancer.
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44.
  • Kim, Eric H., et al. (författare)
  • Detection of High Grade Prostate Cancer among PLCO Participants Using a Prespecified 4-Kallikrein Marker Panel
  • 2016
  • Ingår i: Journal of Urology. - : Ovid Technologies (Wolters Kluwer Health). - 0022-5347 .- 1527-3792.
  • Tidskriftsartikel (refereegranskat)abstract
    • Purpose: We assessed the performance of a 4-kallikrein panel with and without microseminoprotein-β to predict high grade (Gleason 7+/Gleason Grade Group 2+) prostate cancer on biopsy in a multiethnic cohort from PLCO (Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial). Materials and Methods: Levels of free, intact, total prostate specific antigen, human kallikrein-2 and microseminoprotein-β were measured while blinded to outcomes in cryopreserved serum from men in the intervention arm of PLCO. Marker levels of 946 men, of whom 100 were African American, were incorporated into a prespecified statistical model to predict high grade prostate cancer on biopsy. Results: The detection of high grade prostate cancer in 94 men (10%) was enhanced by the 4-kallikrein panel with an AUC of 0.79 compared to 0.73 for PCPTRC (Prostate Cancer Prevention Trial Risk Calculator), representing a 0.060 increase (95% CI 0.032-0.088, p <0.01). Additionally, the AUC increased from 0.79 to 0.81 when microseminoprotein-β was added to the 4-kallikrein panel. In African American men, the 4-kallikrein panel model also enhanced high grade prostate cancer detection over that of prostate specific antigen (AUC 0.80 vs 0.67). As an illustration of clinical implications, using 1 cutoff point for biopsy (6% risk of high grade prostate cancer) with the 4-kallikrein panel model would have eliminated unnecessary biopsies in 420 per 1,000 men (42%) while detecting high grade prostate cancer in 83 of 93 (88%). Conclusions: In a multiethnic United States population, the 4-kallikrein panel demonstrated improved risk discrimination for high grade prostate cancer over conventional clinical variables (age, prostate specific antigen and digital rectal examination) as well as PCPTRC.
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45.
  • Klein, Robert J., et al. (författare)
  • Prostate cancer polygenic risk score and prediction of lethal prostate cancer
  • 2022
  • Ingår i: npj Precision Oncology. - : Nature Publishing Group. - 2397-768X. ; 6:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Polygenic risk scores (PRS) for prostate cancer incidence have been proposed to optimize prostate cancer screening. Prediction of lethal prostate cancer is key to any stratified screening program to avoid excessive overdiagnosis. Herein, PRS for incident prostate cancer was evaluated in two population-based cohorts of unscreened middle-aged men linked to cancer and death registries: the Västerbotten Intervention Project (VIP) and the Malmö Diet and Cancer study (MDC). SNP genotypes were measured by genome-wide SNP genotyping by array followed by imputation or genotyping of selected SNPs using mass spectrometry. The ability of PRS to predict lethal prostate cancer was compared to PSA and a commercialized pre-specified model based on four kallikrein markers. The PRS was associated with incident prostate cancer, replicating previously reported relative risks, and was also associated with prostate cancer death. However, unlike PSA, the PRS did not show stronger association with lethal disease: the hazard ratio for prostate cancer incidence vs. prostate cancer metastasis and death was 1.69 vs. 1.65 in VIP and 1.25 vs. 1.25 in MDC. PSA was a much stronger predictor of prostate cancer metastasis or death with an area-under-the-curve of 0.78 versus 0.63 for the PRS. Importantly, addition of PRS to PSA did not contribute additional risk stratification for lethal prostate cancer. We have shown that a PRS that predicts prostate cancer incidence does not have utility above and beyond that of PSA measured at baseline when applied to the clinically relevant endpoint of prostate cancer death. These findings have implications for public health policies for delivery of prostate cancer screening. Focusing polygenic risk scores on clinically significant endpoints such as prostate cancer metastasis or death would likely improve clinical utility.
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46.
  • Lilja, Hans, et al. (författare)
  • Long-term prediction of prostate cancer up to 25 years before diagnosis of prostate cancer using prostate kallikreins measured at age 44 to 50 years.
  • 2007
  • Ingår i: Journal of Clinical Oncology. - 1527-7755. ; 25:4, s. 431-436
  • Tidskriftsartikel (refereegranskat)abstract
    • Purpose We examined whether prostate-specific antigen (PSA) forms and human kallikrein 2 (hK2) measured at age 44 to 50 years predict long-term risk of incident prostate cancer. Methods From 1974 to 1986, 21,277 men age <= 50 years in Malmo, Sweden, enrolled onto a cardiovascular study (74% participation). The rate of PSA screening in this population is low. According to the Swedish Cancer Registry, 498 were later diagnosed with prostate cancer. We measured hK2, free PSA, and total PSA (tPSA) in archived blood plasma from 462 participants later diagnosed with prostate cancer and from 1,222 matched controls. Conditional logistic regression was used to test for association of prostate cancer with hK2 and PSA forms measured at baseline. Results Median delay between venipuncture and prostate cancer diagnosis was 18 years. hK2 and all PSA forms were strongly associated with prostate cancer (all P < .0005). None of the 90 anthropometric, lifestyle, biochemical, and medical history variables measured at baseline was importantly predictive. A tPSA increase of 1 ng/mL was associated with an increase in odds of cancer of 3.69 (95% CI, 2.99 to 4.56); addition of other PSA forms or hK2 did not add to the predictive value of tPSA. tPSA remained predictive for men diagnosed >= 20 years after venipuncture, and the predictive value remained unchanged in an analysis restricted to palpable disease. Conclusion A single PSA test at age 44 to 50 years predicts subsequent clinically diagnosed prostate cancer. This raises the possibility of risk stratification for prostate cancer screening programs.
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47.
  • Lilja, Hans, et al. (författare)
  • Prediction of Significant Prostate Cancer Diagnosed 20 to 30 Years Later With a Single Measure of Prostate-Specific Antigen at or Before Age 50
  • 2011
  • Ingår i: Cancer. - : Wiley. - 1097-0142 .- 0008-543X. ; 117:6, s. 1210-1219
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: We previously reported that a single prostate-specific antigen (PSA) measured at ages 44-50 was highly predictive of subsequent prostate cancer diagnosis in an unscreened population. Here we report an additional 7 years of follow-up. This provides replication using an independent data set and allows estimates of the association between early PSA and subsequent advanced cancer (clinical stage >= T3 or metastases at diagnosis). METHODS: Blood was collected from 21,277 men in a Swedish city (74% participation rate) during 1974-1986 at ages 33-50. Through 2006, prostate cancer was diagnosed in 1408 participants; we measured PSA in archived plasma for 1312 of these cases (93%) and for 3728 controls. RESULTS: At a median follow-up of 23 years, baseline PSA was strongly associated with subsequent prostate cancer (area under the curve, 0.72; 95% Cl, 0.70-0.74; for advanced cancer, 0.75; 95% Cl, 0.72-0.78). Associations between PSA and prostate cancer were virtually identical for the initial and replication data sets, with 81% of advanced cases (95% Cl, 77%-86%) found in men with PSA above the median (0.63 ng/mL at ages 44-50). CONCLUSIONS: A single PSA at or before age 50 predicts advanced prostate cancer diagnosed up to 30 years later. Use of early PSA to stratify risk would allow a large group of low-risk men to be screened less often but increase frequency of testing on a more limited number of high-risk men. This is likely to improve the ratio of benefit to harm for screening. Cancer 2011;117:1210-9. (C) 2010 American Cancer Society
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48.
  • Lilja, Hans, et al. (författare)
  • Prostate-specific antigen and prostate cancer: prediction, detection and monitoring
  • 2008
  • Ingår i: Nature Reviews. Cancer. - : Springer Science and Business Media LLC. - 1474-1768 .- 1474-175X. ; 8:4, s. 268-278
  • Forskningsöversikt (refereegranskat)abstract
    • Testing for prostate-specific antigen ( PSA) has profoundly affected the diagnosis and treatment of prostate cancer. PSA testing has enabled physicians to detect prostate tumours while they are still small, low-grade and localized. This very ability has, however, created controversy over whether we are now diagnosing and treating insignificant cancers. PSA testing has also transformed the monitoring of treatment response and detection of disease recurrence. Much current research is directed at establishing the most appropriate uses of PSA testing and at developing methods to improve on the conventional PSA test.
  •  
49.
  • Lonergan, Peter E., et al. (författare)
  • Prospective validation of microseminoprotein-β added to the 4Kscore in predicting high-grade prostate cancer in an international multicentre cohort
  • 2021
  • Ingår i: BJU International. - : Wiley. - 1464-4096 .- 1464-410X. ; 128:2, s. 218-224
  • Tidskriftsartikel (refereegranskat)abstract
    • Objectives: To prospectively evaluate the performance of a pre-specified statistical model based on four kallikrein markers in blood (total prostate-specific antigen [PSA], free PSA, intact PSA, and human kallikrein-related peptidase 2), commercially available as the 4Kscore, in predicting Gleason Grade Group (GG) ≥2 prostate cancer at biopsy in an international multicentre study at three academic medical centres, and whether microseminoprotein-β (MSP) adds predictive value. Patients and Methods: A total of 984 men were prospectively enrolled at three academic centres. The primary outcome was GG ≥2 on prostate biopsy. Three pre-specified statistical models were used: a base model including PSA, age, digital rectal examination and prior negative biopsy; a model that added free PSA to the base model; and the 4Kscore. Results: A total of 947 men were included in the final analysis and 273 (29%) had GG ≥2 on prostate biopsy. The base model area under the receiver operating characteristic curve of 0.775 increased to 0.802 with the addition of free PSA, and to 0.824 for the 4Kscore. Adding MSP to the 4Kscore model yielded an increase (0.014–0.019) in discrimination. In decision-curve analysis of clinical utility, the 4Kscore showed a benefit starting at a 7.5% threshold. Conclusion: A prospective multicentre evaluation of a pre-specified model based on four kallikrein markers (4Kscore) with the addition of MSP improves the predictive discrimination for GG ≥2 prostate cancer on biopsy and could be used to inform biopsy decision-making.
  •  
50.
  • Nazarian, Arpi, et al. (författare)
  • Inhibition of Circulating Dipeptidyl Peptidase 4 Activity in Patients with Metastatic Prostate Cancer
  • 2014
  • Ingår i: Molecular & Cellular Proteomics. - 1535-9484. ; 13:11, s. 3082-3096
  • Tidskriftsartikel (refereegranskat)abstract
    • Cancer is responsible for many deaths and is a major source of healthcare expenditures. The identification of new, non-invasive biomarkers might allow improvement of the direct diagnostic or prognostic ability of already available tools. Here, we took the innovative approach of interrogating the activity of exopeptidases in the serum of cancer patients with the aim of establishing a distinction based on enzymatic function, instead of simple protein levels, as a means to biomarker discovery. We first analyzed two well-characterized mouse models of prostate cancer, each with a distinct genetic lesion, and established that broad exopeptidase and targeted aminopeptidase activity tests reveal proteolytic changes associated with tumor development. We also describe new peptide-based freeze-frame reagents uniquely suited to probe the altered balance of selected aminopeptidases, as opposed to the full array of exopeptidases, and/or their modulators in patient serum or plasma. One particular proteolytic activity was impaired in animals with aggressive disease relative to cancer-free littermates. We identified the protease in question as dipeptidyl peptidase 4 (DPP4) by analyzing selected knockout mice and evaluating the effect of specific inhibitors. DPP4 activity was also reduced in the sera of patients with metastatic prostate cancer relative to patients with localized disease or healthy controls. However, no significant differences in DPP4 serum levels were observed, which established the loss of activity as the result of impaired enzymatic function. Biochemical analysis indicated that reduced activity was the result not of post-translational modifications or allosteric changes, but instead of a low-molecular-weight inhibitor. After we adjusted for age and total prostate-specific antigen, reduced DPP4 activity remained a significant predictor of cancer status. The results of this proof-of-principle study suggest that DPP4 activity might be a potential blood-based indicator of the presence of metastatic cancer of prostatic origin, either by itself or, more likely, as a means to improve the sensitivity and specificity of existing markers.
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