| 41. |
- Haas, Gabriel P, et al.
(författare)
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Needle biopsies on autopsy prostates: sensitivity of cancer detection based on true prevalence
- 2007
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 1460-2105 .- 0027-8874. ; 99:19, s. 1484-1489
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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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| 42. |
- Haiman, Christopher A, et al.
(författare)
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Levels of Beta-Microseminoprotein in Blood and Risk of Prostate Cancer in Multiple Populations.
- 2012
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 1460-2105 .- 0027-8874.
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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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| 43. |
- Kim, Eric H., et al.
(författare)
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Detection of High Grade Prostate Cancer among PLCO Participants Using a Prespecified 4-Kallikrein Marker Panel
- 2016
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Ingår i: Journal of Urology. - : Ovid Technologies (Wolters Kluwer Health). - 0022-5347 .- 1527-3792.
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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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| 44. |
- Klein, Robert J., et al.
(författare)
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Prostate cancer polygenic risk score and prediction of lethal prostate cancer
- 2022
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Ingår i: npj Precision Oncology. - : Nature Publishing Group. - 2397-768X. ; 6:1
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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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| 45. |
- Lilja, Hans, et al.
(författare)
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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
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Ingår i: Journal of Clinical Oncology. - 1527-7755. ; 25:4, s. 431-436
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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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| 46. |
- Lilja, Hans, et al.
(författare)
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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
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Ingår i: Cancer. - : Wiley. - 1097-0142 .- 0008-543X. ; 117:6, s. 1210-1219
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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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| 47. |
- Lilja, Hans, et al.
(författare)
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Prostate-specific antigen and prostate cancer: prediction, detection and monitoring
- 2008
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Ingår i: Nature Reviews. Cancer. - : Springer Science and Business Media LLC. - 1474-1768 .- 1474-175X. ; 8:4, s. 268-278
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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.
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| 48. |
- Lonergan, Peter E., et al.
(författare)
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Prospective validation of microseminoprotein-β added to the 4Kscore in predicting high-grade prostate cancer in an international multicentre cohort
- 2021
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Ingår i: BJU International. - : Wiley. - 1464-4096 .- 1464-410X. ; 128:2, s. 218-224
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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.
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| 49. |
- Nazarian, Arpi, et al.
(författare)
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Inhibition of Circulating Dipeptidyl Peptidase 4 Activity in Patients with Metastatic Prostate Cancer
- 2014
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Ingår i: Molecular & Cellular Proteomics. - 1535-9484. ; 13:11, s. 3082-3096
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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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| 50. |
- Pellegrino, Francesco, et al.
(författare)
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Predictive value of kallikrein forms and β-microseminoprotein in blood from patients with evidence of detectable levels of PSA after radical prostatectomy
- 2023
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Ingår i: World Journal of Urology. - 1433-8726. ; 41, s. 1489-1495
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: To determine whether β-microseminoprotein or any of the kallikrein forms in blood-free, total or intact PSA or total hK2-predict metastasis in patients with evidence of detectable levels of PSA in blood after radical prostatectomy.METHOD: We determined marker concentrations in blood from 173 men treated with radical prostatectomy and evidence of detectable levels of PSA in the blood (PSA ≥ 0.05) after surgery between 2014 and 2015 and at least 1 year after any adjuvant therapy. We used Cox regression to determine whether any marker was associated with metastasis using both univariate and multivariable models that included standard clinical predictors.RESULTS: Overall, 42 patients had metastasis, with a median follow-up of 67 months among patients without an event. The levels of intact and free PSA and free-to-total PSA ratio were significantly associated with metastasis. Discrimination was highest for free PSA (c-index: 0.645) and free-to-total PSA ratio (0.625). Only free-to-total PSA ratio remained associated with overall metastasis (either regional or distant) after including standard clinical predictors (p = 0.025) and increased discrimination from 0.686 to 0.697. Similar results were found using distant metastasis as an outcome (p = 0.011; c-index increased from 0.658 to 0.723).CONCLUSION: Our results provide evidence that free-to-total PSA ratio can risk stratifying patients with evidence of detectable levels of PSA in blood after RP. Further research is warranted on the biology of prostate cancer markers in patients with evidence of detectable levels of PSA in blood after radical prostatectomy. Our findings on the free-to-total ratio for predicting adverse oncologic outcomes need to be validated in other cohorts.
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