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1.  Serum total prostate-specific antigen values in men with symptomatic prostate enlargement in Nigeria: role in clinical decision-making 
Background
Prostatic enlargement is a common cause of bladder outlet obstruction in men in Nigeria. Malignant enlargements must be differentiated from benign enlargements for adequate treatment of each patient. High serum total prostate-specific antigen (tPSA) levels suggest malignancy, but some of the biopsies done due to a serum tPSA value >4 ng/mL would be negative for malignancy because of the low specificity of tPSA for prostate cancer. This study aims to compare the histologic findings of all prostate specimens obtained from core needle biopsy, open simple prostatectomy, and transurethral resection of the prostate with the respective serum tPSA values in an attempt to decipher the role of serum tPSA in the management of these patients.
Methods
The case notes of patients attended to from April 2009 to March 2012 were analyzed. Essentially, the age of the patient, findings on digital rectal examination, abdominopelvic ultrasonography report on the prostate, serum tPSA, and histology reports from biopsy or prostatectomy specimens as indicated were extracted for analysis.
Results
The relationship between age, findings on digital rectal examination, serum tPSA, abdominopelvic ultrasonography report, and histology are compared. A statistically significant relationship existed between a malignant histology and age 65 years and older, suspicious findings on digital rectal examination, suspicious ultrasonography findings, and serum tPSA >10 ng/mL, but not tPSA >4 ng/mL.
Conclusion
In Nigerian patients with symptomatic prostate enlargement, serum tPSA should be seen as a continuum with increasing risk of prostate malignancy.
doi:10.2147/CIA.S73814
PMCID: PMC4284028  PMID: 25565791
serum total prostate-specific antigen; symptomatic prostate enlargement; prostate histology
2.  Cancer Screening: A Mathematical Model Relating Secreted Blood Biomarker Levels to Tumor Sizes  
PLoS Medicine  2008;5(8):e170.
Background
Increasing efforts and financial resources are being invested in early cancer detection research. Blood assays detecting tumor biomarkers promise noninvasive and financially reasonable screening for early cancer with high potential of positive impact on patients' survival and quality of life. For novel tumor biomarkers, the actual tumor detection limits are usually unknown and there have been no studies exploring the tumor burden detection limits of blood tumor biomarkers using mathematical models. Therefore, the purpose of this study was to develop a mathematical model relating blood biomarker levels to tumor burden.
Methods and Findings
Using a linear one-compartment model, the steady state between tumor biomarker secretion into and removal out of the intravascular space was calculated. Two conditions were assumed: (1) the compartment (plasma) is well-mixed and kinetically homogenous; (2) the tumor biomarker consists of a protein that is secreted by tumor cells into the extracellular fluid compartment, and a certain percentage of the secreted protein enters the intravascular space at a continuous rate. The model was applied to two pathophysiologic conditions: tumor biomarker is secreted (1) exclusively by the tumor cells or (2) by both tumor cells and healthy normal cells. To test the model, a sensitivity analysis was performed assuming variable conditions of the model parameters. The model parameters were primed on the basis of literature data for two established and well-studied tumor biomarkers (CA125 and prostate-specific antigen [PSA]). Assuming biomarker secretion by tumor cells only and 10% of the secreted tumor biomarker reaching the plasma, the calculated minimally detectable tumor sizes ranged between 0.11 mm3 and 3,610.14 mm3 for CA125 and between 0.21 mm3 and 131.51 mm3 for PSA. When biomarker secretion by healthy cells and tumor cells was assumed, the calculated tumor sizes leading to positive test results ranged between 116.7 mm3 and 1.52 × 106 mm3 for CA125 and between 27 mm3 and 3.45 × 105 mm3 for PSA. One of the limitations of the study is the absence of quantitative data available in the literature on the secreted tumor biomarker amount per cancer cell in intact whole body animal tumor models or in cancer patients. Additionally, the fraction of secreted tumor biomarkers actually reaching the plasma is unknown. Therefore, we used data from published cell culture experiments to estimate tumor cell biomarker secretion rates and assumed a wide range of secretion rates to account for their potential changes due to field effects of the tumor environment.
Conclusions
This study introduced a linear one-compartment mathematical model that allows estimation of minimal detectable tumor sizes based on blood tumor biomarker assays. Assuming physiological data on CA125 and PSA from the literature, the model predicted detection limits of tumors that were in qualitative agreement with the actual clinical performance of both biomarkers. The model may be helpful in future estimation of minimal detectable tumor sizes for novel proteomic biomarker assays if sufficient physiologic data for the biomarker are available. The model may address the potential and limitations of tumor biomarkers, help prioritize biomarkers, and guide investments into early cancer detection research efforts.
Sanjiv Gambhir and colleagues describe a linear one-compartment mathematical model that allows estimation of minimal detectable tumor sizes based on blood tumor biomarker assays.
Editors' Summary
Background.
Cancers—disorganized masses of cells that can occur in any tissue—develop when cells acquire genetic changes that allow them to grow uncontrollably and to spread around the body (metastasize). If a cancer (tumor) is detected when it is small, surgery can often provide a cure. Unfortunately, many cancers (particularly those deep inside the body) are not detected until they are large enough to cause pain or other symptoms by pressing against surrounding tissue. By this time, it may be impossible to remove the original tumor surgically and there may be metastases scattered around the body. In such cases, radiotherapy and chemotherapy can sometimes help, but the outlook for patients whose cancers are detected late is often poor. Consequently, researchers are trying to develop early detection tests for different types of cancer. Many tumors release specific proteins—“cancer biomarkers”—into the blood and the hope is that it might be possible to find sets of blood biomarkers that detect cancers when they are still small and thus save many lives.
Why Was This Study Done?
For most biomarkers, it is not known how the amount of protein detected in the blood relates to tumor size or how sensitive the assays for biomarkers must be to improve patient survival. In this study, the researchers develop a “linear one-compartment” mathematical model to predict how large tumors need to be before blood biomarkers can be used to detect them and test this model using published data on two established cancer biomarkers—CA125 and prostate-specific antigen (PSA). CA125 is used to monitor the progress of patients with ovarian cancer after treatment; ovarian cancer is rarely diagnosed in its early stages and only one-fourth of women with advanced disease survive for 5 y after diagnosis. PSA is used to screen for prostate cancer and has increased the detection of this cancer in its early stages when it is curable.
What Did the Researchers Do and Find?
To develop a model that relates secreted blood biomarker levels to tumor sizes, the researchers assumed that biomarkers mix evenly throughout the patient's blood, that cancer cells secrete biomarkers into the fluid that surrounds them, that 0.1%–20% of these secreted proteins enter the blood at a continuous rate, and that biomarkers are continuously removed from the blood. The researchers then used their model to calculate the smallest tumor sizes that might be detectable with these biomarkers by feeding in existing data on CA125 and on PSA, including assay detection limits and the biomarker secretion rates of cancer cells growing in dishes. When only tumor cells secreted the biomarker and 10% of the secreted biomarker reach the blood, the model predicted that ovarian tumors between 0.11 mm3 (smaller than a grain of salt) and nearly 4,000 mm3 (about the size of a cherry) would be detectable by measuring CA125 blood levels (the range was determined by varying the amount of biomarker secreted by the tumor cells and the assay sensitivity); for prostate cancer, the detectable tumor sizes ranged from similar lower size to about 130 mm3 (pea-sized). However, healthy cells often also secrete small quantities of cancer biomarkers. With this condition incorporated into the model, the estimated detectable tumor sizes (or total tumor burden including metastases) ranged between grape-sized and melon-sized for ovarian cancers and between pea-sized to about grapefruit-sized for prostate cancers.
What Do These Findings Mean?
The accuracy of the calculated tumor sizes provided by the researchers' mathematical model is limited by the lack of data on how tumors behave in the human body and by the many assumptions incorporated into the model. Nevertheless, the model predicts detection limits for ovarian and prostate cancer that broadly mirror the clinical performance of both biomarkers. Somewhat worryingly, the model also indicates that a tumor may have to be very large for blood biomarkers to reveal its presence, a result that could limit the clinical usefulness of biomarkers, especially if they are secreted not only by tumor cells but also by healthy cells. Given this finding, as more information about how biomarkers behave in the human body becomes available, this model (and more complex versions of it) should help researchers decide which biomarkers are likely to improve early cancer detection and patient outcomes.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050170.
The US National Cancer Institute provides a brief description of what cancer is and how it develops and a fact sheet on tumor markers; it also provides information on all aspects of ovarian and prostate cancer for patients and professionals, including information on screening and testing (in English and Spanish)
The UK charity Cancerbackup also provides general information about cancer and more specific information about ovarian and prostate cancer, including the use of CA125 and PSA for screening and follow-up
The American Society of Clinical Oncology offers a wide range of information on various cancer types, including online published articles on the current status of cancer diagnosis and management from the educational book developed by the annual meeting faculty and presenters. Registration is mandatory, but information is free
doi:10.1371/journal.pmed.0050170
PMCID: PMC2517618  PMID: 18715113
3.  Clinical performance of serum [-2]proPSA derivatives, %p2PSA and PHI, in the detection and management of prostate cancer 
Prostate-specific antigen (PSA) has been widely used as a serum marker for prostate cancer (PCa) screening or progression monitoring, which dramatically increased rate of early detection while significantly reduced PCa-specific mortality. However, a number of limitations of PSA have been noticed. Low specificity of PSA may lead to overtreatment in men who presenting with a total PSA (tPSA) level of < 10 ng/mL. As a type of free PSA (fPSA), [-2]proPSA is differentially expressed in peripheral zone of prostate gland and found to be elevated in serum of men with PCa. Two p2PSA-based derivatives, prostate health index (PHI) and %p2PSA, which were defined as [(p2PSA/fPSA) × √ tPSA] and [(p2PSA/fPSA) × 100] respectively, have been suggested to be increased in PCa and can better distinguish PCa from benign prostatic diseases than tPSA or fPSA. We performed a systematic review of the available scientific evidences to evaluate the potentials of %p2PSA and PHI in clinical application. Mounting evidences suggested that both %p2PSA and PHI possess higher area under the ROC curve (AUC) and better specificity at a high sensitivity for PCa detection when compare with tPSA and %fPSA. It indicated that measurements of %p2PSA and PHI significantly improved the accuracy of PCa detection and diminished unnecessary biopsies. Furthermore, elevations of %p2PSA and PHI are related to more aggressive diseases. %p2PSA and PHI might be helpful in reducing overtreatment on indolent cases or assessing the progression of PCa in men who undergo active surveillance. Further studies are needed before being applied in routine clinical practice.
PMCID: PMC4297331  PMID: 25606581
PSA; prostate cancer; [-2]proPSA; %p2PSA; PHI; biopsy
4.  Free to total serum prostate specific antigen ratio in symptomatic men does not help in differentiating benign from malignant disease of the prostate 
Introduction:
Free to total prostate specific antigen ratio (f/t PSA) has been used to help improving specificity of PSA in the range of 4-10 ng/ml based on the data on population based screening. There is no data on test characteristics of f/t PSA in men presenting with clinical symptoms of benign prostatic hyperplasia (BPH). This study is aimed to determine the usefulness of f/t PSA in symptomatic men.
Methodology:
From January 2006 to June 2012, men of 50-75 years with lower urinary tract symptoms (LUTS), normal rectal examination and PSA between 4-20 ng/ml had free and total PSA assessment. Men with clinical evidence of prostatitis, retention, history of 5α blocker reductase inhibitors and those who had surgery or biopsy on the prostate in last 3 months were excluded. Receiver operating characteristic curves were derived for f/t PSA and total PSA. The effect of age, prostate volume and Gleason score on the f/t PSA was also analyzed. All statistical analyses were performed on SPSS 16 (Chicago, USA).
Results:
Out of 170 men with the mean age of 67.4 ± 6.6 years, 43 (25.3%) had cancer on biopsy. Area under the curve for predicting the presence or absence of prostate cancer in all the men with f/t ratio was 0.63 (confidence interval [CI]: 0.54-0.71). The median value of f/t PSA for men with cancer was 5.5% (1-25%) and 9.2% (1-63%) for those with no cancer. Cut-offs derived at 95% specificity at PSA between 4-10 ng/ml and 4-20 ng/ml were 0.5% and 1% respectively. The specificity of f/t PSA ratio at cut-off levels 7%, 10% and 15% was 73%, 60%, 45% for PSA range of 4-10 ng/ml and 63%, 47% and 35% for PSA range of 4-20 ng/ml PSA. Age, prostate volume and Gleason grade did not show any effect on f/t PSA.
Conclusion:
In men with LUTS the specificity of various f/t PSA ratio cut-offs; described for population based screening, is too low to be used as an aid to defer the decision of biopsy in PSA ranges of 4-20 ng/ml.
doi:10.4103/0970-1591.124202
PMCID: PMC3897049  PMID: 24497678
Free to total prostate specific antigen ratio; prostate cancer; screening
5.  Prostate-Specific Antigen Testing of Older Men 
Background
Elevated serum prostate-specific antigen (PSA) levels are predictive of a future diagnosis of prostate cancer. To test the hypothesis that older men with low PSA levels may require less intensive PSA testing because of a reduced prostate cancer detection rate, we evaluated the association between age, baseline PSA level, and prostate cancer detection.
Methods
We conducted a prospective cohort study among participants in a study of aging who had serial PSA measurements taken from age 60 or 65 years until they either were diagnosed with prostate cancer (cancer case subjects) or reached the age of 75 years (subjects without prostate cancer). The time of cancer detection among cancer case subjects was defined as the measurement date on which a PSA level above 4.0 ng/mL was detected (i.e., PSA conversion). Cancer case subjects and subjects without prostate cancer were analyzed according to baseline PSA level and age.
Results
All cancer case subjects in the 60-year-old cohort had baseline PSA levels above 0.5 ng/mL, and 14 of 15 cancer cases that would have been detected by a PSA conversion among the 65-year-old cohort were associated with baseline PSA levels of 1.1 ng/mL or more. If PSA testing were discontinued in men aged 65 years with PSA levels of 0.5 ng/mL or less, 100% (95% confidence interval [CI] = 78%–100%) of the cancers would still be detected by age 75 years; if PSA testing were discontinued in men aged 65 years who had PSA levels of 1.0 ng/mL or less, 94% (95% CI = 70%–100%) of the cancers would still be detected by age 75 years.
Conclusions
These data suggest that a decrease in the intensity of screening among older men with low PSA values may not lead to an increase in undetected prostate cancer.
PMCID: PMC3474977  PMID: 10528023
6.  Screening for Prostate Cancer: An Update 
The Canadian journal of urology  2008;15(6):4363-4374.
The introduction of total prostate specific antigen (tPSA) testing in serum has revolutionized the detection and management of men with prostate cancer (PCa). This review will highlight some of the exciting new developments in the field of PCa screening in general and from our SPORE research program at Memorial-Sloan Kettering Cancer Center. First, it is important to understand that the inherent variability of tPSA levels affects the interpretation of any single results. Total variation in tPSA includes both analytical (i.e., pre-analytical sample handling, laboratory processing, assay performance, and standardization) and biological variation (i.e., metabolism, renal elimination, medication, physical and sexual activity, size and integrity of the prostate). Second, recent evidence demonstrates that no single tPSA cut-off separates men at high-risk for PCa from men at low-risk or men with “significant” (high-grade, high-volume) cancer from those with low-grade, indolent cancer. Taken together with a man’s age, family history, ethnicity, and digital rectal exam results, tPSA levels add to the overall estimate of the risk of cancer, allowing men to share in the decision about a biopsy. Third, men who will eventually develop PCa have increased tPSA levels years or decades before the cancer is diagnosed. These tPSA levels may reflect the long duration of prostate carcinogenesis and raise the question about a causal role for tPSA in PCa development and progression. tPSA measurements before age 50 could help risk-stratify men for intensity of PCa screening. Fourth, enhancing the diagnostic accuracy of tPSA, especially its specificity, is of particular importance, since higher specificity translates into fewer biopsies in men not affected by PCa. While tPSA velocity has been shown to improve the specificity of tPSA, its sensitivity is too low to avoid prostate biopsy in a patient with an elevated tPSA level. Moreover, prospective screening studies have reported that tPSA velocity does not add diagnostic value beyond tPSA level. At this time, tPSA velocity appears most useful after diagnosis and after treatment, but its value in screening and prognostication remains to be shown. Finally, while free PSA molecular isoforms and human kallikrein-related peptidase 2 (hK2) hold the promise for detection, staging, prognosis, and monitoring of PCa, evidence from large prospective clinical trials remain to be reported.
PMCID: PMC2742707  PMID: 19046489
prostate-specific antigen; human glandular kallikrein; prostate cancer; prognosis; detection
7.  Risk Profiles and Treatment Patterns among Men diagnosed with Prostate Cancer and a Prostate Specific Antigen Level Below 4.0 ng/ml 
Archives of internal medicine  2010;170(14):1256-1261.
Background
Despite controversy over the benefit of prostate specific antigen (PSA) screening, little is known about risk profiles and treatment patterns in men diagnosed with prostate cancer who have a PSA value less than or equal to 4 ng/mL.
Methods
We utilized data from the Surveillance, Epidemiology, End Results system to describe patient characteristics and treatment patterns of 123,934 men with newly diagnosed prostate cancer in 2004–2006. Age-standardized treatment rates were calculated in five-year age strata. Logistic regression was used to quantify the odds ratios (OR) of men with low– and high–risk disease and the use of radical prostatectomy (RP) or radiation therapy (RT).
Results
Men with a PSA of 4.0 ng/ml or less represent 14% of incident prostate cancer cases. Fifty-four percent of men diagnosed with prostate cancer and PSA ≤ 4.0 ng/mL harbor low-risk disease (stage ≤ T2a, PSA level ≤ 10 ng/mL, and Gleason score ≤ 6), but over 75% of them received RP or RT. Men with screen-detected prostate cancer and PSA values ≤ 4 ng/mL were 1.49 (CI 1.38–1.62) and 1.39 (CI 1.30–1.49) times more likely to receive RP and RT, respectively, and were less likely to have high-grade disease than men who had non-screen detected prostate cancer (OR=0.67; 95% CI:0.60–0.76).
Conclusions
Most men diagnosed with prostate cancer with a PSA threshold ≤ 4.0 ng/mL had low-risk disease but underwent aggressive local therapy. Lowering biopsy threshold, while lacking the ability to distinguish indolent cancers from aggressive cancers, may increase overdiagnosis and overtreatment.
doi:10.1001/archinternmed.2010.221
PMCID: PMC3651841  PMID: 20660846
8.  Outcome of Prostate Biopsy in Men Younger than 40 Years of Age with High Prostate-Specific Antigen (PSA) Levels 
Korean Journal of Urology  2010;51(1):21-24.
Purpose
Prostate cancer is rarely diagnosed in men younger than 40 years of age. At present, the available data show a low rate of cancer detection from prostate-specific antigen (PSA) screening of this group of young men. We analyzed the outcome of prostate biopsy results in patients of this age group with a high PSA.
Materials and Methods
Between October 1997 and August 2008, a total of 81 men less than 40 years of age were referred from the Health Care Promotion Center as the result of elevated PSA levels. Six men with prostatitis were excluded. The remaining 75 men were asymptomatic and had normal findings on the digital rectal examination (DRE) and were selected to have a transrectal ultrasound-guided prostate biopsy for suspected prostate cancer. The patients with sustained high PSA levels underwent repeat biopsies.
Results
The median age of the 75 men was 33 years (range, 26-40 years) and the mean PSA level was 6.57 ng/ml (range, 4.32-13.45 ng/ml). The results of the primary biopsy was 1 (1.3%) case of prostate cancer, 70 cases (93%) with benign tissue, 2 cases (2.6%) with inflammation, and 1 case each (1.3%) with high grade intraepithelial neoplasia (HGPIN) and atypical small acinar proliferation (ASAP). Of the 10 men who underwent a second biopsy, all had benign findings. Three of the men who underwent a third biopsy all had benign tissue findings.
Conclusions
The prostate cancer detection rate in young men less than 40 years of age with high PSA levels and normal DREs was very low. Repeat biopsy for sustained high PSA levels in young men less than 40 years of age may not be indicated.
doi:10.4111/kju.2010.51.1.21
PMCID: PMC2855470  PMID: 20414405
Prostate-specific antigen; Digital rectal examination; Biopsy; Young adult; Prostatic neoplasms
9.  Utility of Free/Total Prostate Specific Antigen (f/t PSA) Ratio in Diagnosis of Prostate Carcinoma 
Disease Markers  2004;19(6):287-292.
The discovery that PSA exists in serum in both free and complexed forms led to development of immunoassays specific for different PSA forms. This helped in measuring free PSA in the presence of PSA-ACT (PSA-α antichymotrypsin), hence it was possible to calculate the percent free PSA or free to total PSA ratio, measurement of which was helpful in reducing the number of unnecessary biopsies significantly, while maintaining a high clinical sensitivity for detection of cancer. The study was performed on 103 consecutive male patients (mean age 68 ± 10.8 years SD) comprising of 90 patients with benign disease (87%) and 13 prostate carcinoma patients (13%), who had histologically proven prostate cancer. Patients with total PSA between 2–25 ng/ml were included in the study. 30 normal healthy males with age 58 ± 10 years, served as control. Serum total PSA and free PSA were analyzed using streptavidin biotin EIA method (M/s Roche Diagnostics, Germany). The mean total PSA in normal healthy control subjects was 1.86 ± 1.07 ng/ml. It was increased significantly in diseased condition. Its mean concentration in carcinoma patients was 12.6 ± 5.3 ng/ml and in benign patients it was 6.3 ± 4.6 ng/ml. The free to total PSA ratio in all the three groups was significantly different (p Combination of this ratio cutoff with other parameters like serum total PSA, DRE and TRUS helped in increasing the sensitivity of the test and this also helped in reducing the number of unnecessary biopsies. In 103 men who were biopsied, 13 (12.6%) prostatic carcinoma were identified. Among these 13 cancer patients, 9 patients had abnormal findings in DRE.7 individuals out of these 9, also had free to total PSA ratio lower than 0.16 and would have been biopsied and diagnosed anyway. If we use only f/t PSA ratio less than 0.16, to decide whom to biopsy, we would have biopsied and diagnosed 11/13 cases i.e. sensitivity of 85% but If we decide to biopsy those patients who had abnormal DRE and those who had low f/t PSA ratio, we could identify 13/13 carcinoma i.e. 100% sensitivity.
Combining the f/t PSA ratio with total PSA, DRE and TRUS findings could help in reducing the number of unnecessary biopsies. 37 patients who were negative for malignancy having total PSA in the range of 5–20 ng/ml, normal DRE and TRUS findings, have been biopsied but with combination of total PSA in the range of 5–20 ng/ml, normal findings in digital rectal examination and TRUS and f/t PSA ratio more than 0.16 (cutoff), we could have avoided 16 biopsies which were unnecessary that means there was 43% reduction in unnecessary biopsies.
doi:10.1155/2004/913870
PMCID: PMC3851065  PMID: 15258330
10.  Immediate Risk for Cardiovascular Events and Suicide Following a Prostate Cancer Diagnosis: Prospective Cohort Study 
PLoS Medicine  2009;6(12):e1000197.
Katja Fall and Fang Fang and colleagues find that men newly diagnosed with prostate cancer are at increased risk of cardiovascular events and suicide.
Background
Stressful life events have been shown to be associated with altered risk of various health consequences. The aim of the present study was to investigate whether the emotional stress evoked by a prostate cancer diagnosis increases the immediate risks of cardiovascular events and suicide.
Methods and Findings
We conducted a prospective cohort study by following all men in Sweden who were 30 y or older (n = 4,305,358) for a diagnosis of prostate cancer (n = 168,584) and their subsequent occurrence of cardiovascular events and suicide between January 1, 1961 and December 31, 2004. We used Poisson regression models to calculate relative risks (RRs) and 95% confidence intervals (CIs) of cardiovascular events and suicide among men who had prostate cancer diagnosed within 1 y to men without any cancer diagnosis. The risks of cardiovascular events and suicide were elevated during the first year after prostate cancer diagnosis, particularly during the first week. Before 1987, the RR of fatal cardiovascular events was 11.2 (95% CI 10.4–12.1) during the first week and 1.9 (95% CI 1.9–2.0) during the first year after diagnosis. From 1987, the RR for cardiovascular events, nonfatal and fatal combined, was 2.8 (95% CI 2.5–3.2) during the first week and 1.3 (95% CI 1.3–1.3) during the first year after diagnosis. While the RR of cardiovascular events declined, the RR of suicide was stable over the entire study period: 8.4 (95% CI 1.9–22.7) during the first week and 2.6 (95% CI 2.1–3.0) during the first year after diagnosis. Men 54 y or younger at cancer diagnosis demonstrated the highest RRs of both cardiovascular events and suicide. A limitation of the present study is the lack of tumor stage data, which precluded possibilities of investigating the potential impact of the disease severity on the relationship between a recent diagnosis of prostate cancer and the risks of cardiovascular events and suicide. In addition, we cannot exclude residual confounding as a possible explanation.
Conclusions
Men newly diagnosed with prostate cancer are at increased risks for cardiovascular events and suicide. Future studies with detailed disease characteristic data are warranted.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Prostate cancer—a type of tumor that develops in a walnut-sized structure in the male reproductive system—is the commonest cancer (excluding skin cancer) among men in developed countries. In the USA and the UK, for example, one in six men will develop prostate cancer during their lifetime. Most prostate cancers develop in elderly men and, because these tumors usually grow relatively slowly, many men die with prostate cancer rather than as a result of it. Nevertheless, some prostate cancers are fast-growing and aggressive and prostate cancer is the second leading cause of cancer-related death among men. The symptoms of prostate cancer include problems urinating and excessive urination during the night. Nowadays, however, most prostate cancers are detected before they produce any symptoms by measuring the amount of a protein called the prostate-specific antigen (PSA) in the blood.
Why Was This Study Done?
Widespread PSA screening was introduced 20 years ago in the hope that early detection of prostate cancer would save lives. But, although many more prostate cancers are detected nowadays, the number of prostate cancer deaths has not changed significantly. Experts are divided, therefore, about whether the potential benefits of PSA screening outweigh its risks. Treatments for prostate cancer (for example, surgical removal of the prostate) may be more effective if they are started early but they can cause impotence and urinary incontinence, so should men be treated whose cancer might otherwise never affect their health? In addition, receiving a diagnosis of prostate cancer is stressful and there is growing evidence that stressful life events can increase an individual's risk of becoming ill or dying from a heart attack, stroke, or other “cardiovascular” events and of becoming mentally ill. In this study, therefore, the researchers investigate whether men diagnosed with prostate cancer in Sweden have increased risks of cardiovascular events and suicide during the first week and first year after their diagnosis.
What Did the Researchers Do and Find?
The researchers identified nearly 170, 000 men diagnosed with prostate cancer between 1961 and 2004 among Swedish men aged 30 years or older by searching the Swedish Cancer Register. They obtained information on subsequent fatal and nonfatal cardiovascular events and suicides from the Causes of Death Register and the Inpatient Register (in Sweden, everyone has a unique national registration number that facilitates searches of different health-related Registers). Before 1987, men with prostate cancer were about 11 times as likely to have a fatal cardiovascular event during the first week after their diagnosis as men without prostate cancer; during the first year after their diagnosis, men with prostate cancer were nearly twice as likely to have a cardiovascular event as men without prostate cancer (a relative risk of 1.9). From 1987, the relative risk of combined fatal and nonfatal cardiovascular events associated with a diagnosis of prostate cancer was 2.8 during the first week and 1.3 during the first year after diagnosis. The relative risk of suicide associated with a diagnosis of prostate cancer was 8.4 during the first week and 2.6 during the first year after diagnosis throughout the study period. Finally, men younger than 54 years at diagnosis had higher relative risks of both cardiovascular events and suicide.
What Do These Findings Mean?
These findings suggest that men newly diagnosed with prostate cancer have an increased risk of cardiovascular events and suicide. Because there is no information on tumor size or aggressiveness in the Cancer Register, the researchers could not look at the relationship between disease severity and the likelihood of a cardiovascular event or suicide. Furthermore, because of the study design, men who received a diagnosis of prostate cancer may have had additional characteristics in common that contributed to their increased risk of cardiovascular events and suicide. Nevertheless, these findings strongly suggest that the stress of the diagnosis itself rather than any subsequent treatment has deleterious effects on the health of men receiving a diagnosis of prostate cancer. Thus, strategies should be developed to reduce the risks of cardiovascular events and suicide—increased clinical and psychological monitoring—after a diagnosis of prostate cancer, particularly among young men, and this new information should be considered in the ongoing debate about the risks and benefits of PSA screening.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000197.
The US National Cancer Institute provides information on all aspects of prostate cancer, (in English and Spanish)
The US Centers for Disease Control and Prevention provides information on prostate cancer, including Prostate Cancer Screening, A Decision Guide (some information in multiple languages)
The UK National Health Service Choices Web site provides detailed information on prostate cancer
The UK-based Samaritans charity provides confidential nonjudgmental emotional support, 24 hours a day, for people who are experiencing feelings of distress or despair, including those which could lead to suicide
Outside the UK, Befrienders provides information on help lines for those experiencing distress
doi:10.1371/journal.pmed.1000197
PMCID: PMC2784954  PMID: 20016838
11.  Alcohol consumption and PSA-detected prostate cancer risk—A case-control nested in the ProtecT study 
Alcohol is an established carcinogen but not an established risk factor for prostate cancer, despite some recent prospective studies suggesting increased risk among heavy drinkers. The aim of this study was to investigate the role of alcohol on prostate-specific antigen (PSA) levels and prostate cancer risk. Two thousand four hundred PSA detected prostate cancer cases and 12,700 controls matched on age and general practice were identified through a case-control study nested in the PSA-testing phase of a large UK-based randomized controlled trial for prostate cancer treatment (ProtecT). Linear and multinomial logistic regression models were used to estimate ratios of geometric means (RGMs) of PSA and relative risk ratios (RRRs) of prostate cancer by stage and grade, with 95% confidence intervals (CIs), associated with weekly alcohol intake and drinking patterns. We found evidence of lower PSA (RGM 0.98, 95% CI: 0.98–0.99) and decreased risk of low Gleason-grade (RRR 0.96; 95%CI 0.93–0.99) but increased risk of high-grade prostate cancer (RRR 1.04; 95%CI 0.99–1.08; pdifference=0.004) per 10 units/week increase in alcohol consumption, not explained by current BMI, blood pressure, comorbidities, or reverse causation. This is the first large population-based study to find evidence of lower PSA levels for increasing alcohol consumption, with potential public health implications for the detection of prostate cancer. Our results also support a modestly higher risk of high-grade disease for heavy drinkers, but require independent replication to establish the nature of the association of alcohol with low-grade disease, preferably in cohorts with a heterogeneous case-mix.
What's new?
Alcohol is not an established risk factor for prostate cancer; however, the current work suggests that heavy drinking could cause a small increase in risk of the more aggressive forms. If the results are confirmed to be causal, prostate cancer risk will be added to the many long-term health risks of heavy drinking, and public health strategies will then also reduce high-risk, poorer prognosis prostate cancer. The authors also found that heavy drinkers have lower PSA levels, suggesting that heavy alcohol consumption could be used as a marker to identify men in whom some cancers might be missed.
doi:10.1002/ijc.27877
PMCID: PMC3786564  PMID: 23024014
alcohol; prostate cancer; prostate specific antigen; ProtecT, nested case–control
12.  Reducing Unnecessary Biopsy During Prostate Cancer Screening Using a Four-Kallikrein Panel: An Independent Replication 
Journal of Clinical Oncology  2010;28(15):2493-2498.
Purpose
We previously reported that a panel of four kallikrein forms in blood—total, free, and intact prostate-specific antigen (PSA) and kallikrein-related peptidase 2 (hK2)—can reduce unnecessary biopsy in previously unscreened men with elevated total PSA. We aimed to replicate our findings in a large, independent, representative, population-based cohort.
Patients and Methods
The study cohort included 2,914 previously unscreened men undergoing biopsy as a result of elevated PSA (≥ 3 ng/mL) in the European Randomized Study of Screening for Prostate Cancer, Rotterdam, with 807 prostate cancers (28%) detected. The cohort was randomly divided 1:3 into a training and validation set. Levels of kallikrein markers were compared with biopsy outcome.
Results
Addition of free PSA, intact PSA, and hK2 to a model containing total PSA and age improved the area under the curve from 0.64 to 0.76 and 0.70 to 0.78 for models without and with digital rectal examination results, respectively (P < .001 for both). Application of the panel to 1,000 men with elevated PSA would reduce the number of biopsies by 513 and miss 54 of 177 low-grade cancers and 12 of 100 high-grade cancers. Findings were robust to sensitivity analysis.
Conclusion
We have replicated our previously published finding that a panel of four kallikreins can predict the result of biopsy for prostate cancer in men with elevated PSA. Use of this panel would dramatically reduce biopsy rates. A small number of men with cancer would be advised against immediate biopsy, but these men would have predominately low-stage, low-grade disease.
doi:10.1200/JCO.2009.24.1968
PMCID: PMC2881727  PMID: 20421547
13.  A Prospective Study of Plasma Vitamin D Metabolites, Vitamin D Receptor Polymorphisms, and Prostate Cancer 
PLoS Medicine  2007;4(3):e103.
Background
Vitamin D insufficiency is a common public health problem nationwide. Circulating 25-hydroxyvitamin D3 (25[OH]D), the most commonly used index of vitamin D status, is converted to the active hormone 1,25 dihydroxyvitamin D3 (1,25[OH]2D), which, operating through the vitamin D receptor (VDR), inhibits in vitro cell proliferation, induces differentiation and apoptosis, and may protect against prostate cancer. Despite intriguing results from laboratory studies, previous epidemiological studies showed inconsistent associations of circulating levels of 25(OH)D, 1,25(OH)2D, and several VDR polymorphisms with prostate cancer risk. Few studies have explored the joint association of circulating vitamin D levels with VDR polymorphisms.
Methods and Findings
During 18 y of follow-up of 14,916 men initially free of diagnosed cancer, we identified 1,066 men with incident prostate cancer (including 496 with aggressive disease, defined as stage C or D, Gleason 7–10, metastatic, and fatal prostate cancer) and 1,618 cancer-free, age- and smoking-matched control participants in the Physicians' Health Study. We examined the associations of prediagnostic plasma levels of 25(OH)D and 1,25(OH)2D, individually and jointly, with total and aggressive disease, and explored whether relations between vitamin D metabolites and prostate cancer were modified by the functional VDR FokI polymorphism, using conditional logistic regression. Among these US physicians, the median plasma 25(OH)D levels were 25 ng/ml in the blood samples collected during the winter or spring and 32 ng/ml in samples collected during the summer or fall. Nearly 13% (summer/fall) to 36% (winter/spring) of the control participants were deficient in 25(OH)D (<20 ng/ml) and 51% (summer/fall) and 77% (winter/spring) had insufficient plasma 25(OH)D levels (<32 ng/ml). Plasma levels of 1,25(OH)2D did not vary by season. Men whose levels for both 25(OH)D and 1,25(OH)2D were below (versus above) the median had a significantly increased risk of aggressive prostate cancer (odds ratio [OR] = 2.1, 95% confidence interval [CI] 1.2–3.4), although the interaction between the two vitamin D metabolites was not statistically significant (pinteraction = 0.23). We observed a significant interaction between circulating 25(OH)D levels and the VDR FokI genotype (pinteraction < 0.05). Compared with those with plasma 25(OH)D levels above the median and with the FokI FF or Ff genotype, men who had low 25(OH)D levels and the less functional FokI ff genotype had increased risks of total (OR = 1.9, 95% CI 1.1–3.3) and aggressive prostate cancer (OR = 2.5, 95% CI 1.1–5.8). Among men with plasma 25(OH)D levels above the median, the ff genotype was no longer associated with risk. Conversely, among men with the ff genotype, high plasma 25(OH)D level (above versus below the median) was related to significant 60%∼70% lower risks of total and aggressive prostate cancer.
Conclusions
Our data suggest that a large proportion of the US men had suboptimal vitamin D status (especially during the winter/spring season), and both 25(OH)D and 1,25(OH)2D may play an important role in preventing prostate cancer progression. Moreover, vitamin D status, measured by 25(OH)D in plasma, interacts with the VDR FokI polymorphism and modifies prostate cancer risk. Men with the less functional FokI ff genotype (14% in the European-descent population of this cohort) are more susceptible to this cancer in the presence of low 25(OH)D status.
Results of this study by Haojie Li and colleagues suggest that vitamin D deficiency is common among men in the US, and that vitamin D status and genetic variation in theVDR gene affect prostate cancer risk.
Editors' Summary
Background.
Prostate cancer occurs when cells in the prostate gland (part of the male reproductive system) accumulate genetic changes that allow them to grow into a disorganized mass of cells. Patients whose disease is diagnosed when these cells are still relatively normal can survive for many years, but for patients with aggressive cancers—ones containing fast-growing cells that can migrate around the body—the outlook is poor. Factors that increase prostate cancer risk include increasing age, having a family history of prostate cancer, and being African American. Also, there are hints that some environmental or dietary factors affect prostate cancer risk. One of these factors is vitamin D, of which high levels are found in seafood and dairy products, but which can also be made naturally by the body—more specifically, by sunlight-exposed skin. One reason researchers think vitamin D might protect against prostate cancer is that this cancer is more common in sun-starved northern countries (where people often have a vitamin D deficiency) than in sunny regions. Prostate cancer is also more common in African American men than in those of European descent (when exposed to the same amount of sunlight, individuals with darker skin make less vitamin D than those with lighter skin). Once in the human body, vitamin D is converted into the vitamin D metabolite 25-hydroxyvitamin D3 (25[OH]D) and then into the active hormone 1,25 dihydroxyvitamin D3 (1,25[OH]2D). This binds to vitamin D receptors (VDRs) and inhibits cell proliferation and migration.
Why Was This Study Done?
The effect of 1,25(OH)2D on cells and the observation that related chemicals slow prostate cancer growth in rodents suggest that vitamin D protects against prostate cancer. But circulating levels of vitamin D metabolites in human male populations do not always reflect how many men develop prostate cancer. This lack of correlation may partly be because different forms of the VDR gene exist. One area of variation in the VDR gene is called the FokI polymorphism. Because everyone carries two copies of the VDR gene, individuals may have a FokI FF, FokI Ff, or FokI ff genotype. The f variant (or allele) codes for a receptor that is less responsive to 1,25(OH)2D than the receptor encoded by the FokI F allele. So levels of vitamin D sufficient to prevent cancer in one person may be insufficient in someone with a different FokI genotype. In this study, the researchers have investigated how levels of 25(OH)D and 1,25(OH)2D in combination with different VDR FokI alleles are influencing prostate cancer risk.
What Did the Researchers Do and Find?
The researchers identified 1,066 men who developed prostate cancer between enrollment into the US Physicians' Health Study in 1982 and 2000, and 1,618 cancer-free men of the same ages and smoking levels as “controls.” They measured vitamin D metabolite levels in many of the blood samples taken from these men in 1982 and determined their FokI genotype. Two-thirds of the men had insufficient blood levels of vitamin D metabolites in the winter/spring; almost one-third had a vitamin D deficiency. Men whose blood levels of both metabolites were below average were twice as likely to develop aggressive prostate cancer as those in whom both levels were above average. Compared with men with high blood levels of 25(OH)D and the FokI FF or Ff genotype, men with low 25(OH)D levels and the FokI ff genotype were 2.5 times as likely to develop aggressive prostate cancer. However, men with the ff genotype were not at higher risk if they had sufficient 25(OH)D levels. Among men with the ff genotype, sufficient 25(OH)D levels might therefore protect against prostate cancer, especially against the clinically aggressive form.
What Do These Findings Mean?
These findings confirm that many US men have suboptimal levels of circulating vitamin D. This vitamin is essential for healthy bones, so irrespective of its effects on prostate cancer, vitamin D supplements might improve overall health. In addition, this large and lengthy study reveals an association between low levels of the two vitamin D metabolites and aggressive prostate cancer that is consistent with vitamin D helping to prevent the progression of prostate cancer. It also indicates that the VDR FokI genotype modifies the prostate cancer risk associated with different blood levels of vitamin D. Together, these results suggest that improving vitamin D status through increased exposure to sun and vitamin D supplements might reduce prostate cancer risk, particularly in men with the FokI ff genotype. Because the study participants were mainly of European descent, the researchers caution that these results may not apply to other ethnic groups and note that further detailed studies are needed to understand fully how vitamin D affects prostate cancer risk across the population.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040103.
MedlinePlus encyclopedia has pages on prostate cancer and on vitamin D
Information for patients and physicians is available from the US National Cancer Institute on prostate cancer and on cancer prevention
The Prostate Cancer Foundation's information on prostate cancer discusses the effects of nutrition on the disease
Patient information on prostate cancer is available from Cancer Research UK
Cancerbackup also has patient information on prostate cancer
doi:10.1371/journal.pmed.0040103
PMCID: PMC1831738  PMID: 17388667
14.  Screening for Prostate Cancer With Prostate-Specific Antigen Testing: American Society of Clinical Oncology Provisional Clinical Opinion 
Journal of Clinical Oncology  2012;30(24):3020-3025.
Purpose
An American Society of Clinical Oncology (ASCO) provisional clinical opinion (PCO) offers timely clinical direction to the ASCO membership after publication or presentation of potentially practice-changing data from major studies. This PCO addresses the role of prostate-specific antigen (PSA) testing in the screening of men for prostate cancer.
Clinical Context
Prostate cancer is the second leading cause of cancer deaths among men in the United States. The rationale for screening men for prostate cancer is the potential to reduce the risk of death through early detection.
Recent Data
Evidence from a 2011 Agency for Healthcare Research and Quality systematic review primarily informs this PCO on the benefits and harms of PSA-based screening. An update search was conducted to March 16, 2012, for additional evidence related to the topic.
Results
In one randomized trial, PSA testing in men who would not otherwise have been screened resulted in reduced death rates from prostate cancer, but it is uncertain whether the size of the effect was worth the harms associated with screening and subsequent unnecessary treatment. Although there are limitations to the existing data, there is evidence to suggest that men with longer life expectancy may benefit from PSA testing. Adverse events associated with prostate biopsy are low for the majority of men; however, several population-based studies have shown increasing rates of infectious complications after prostate biopsy, which is a concern.
Provisional Clinical Opinion
On the basis of identified evidence and the expert opinion of the panel (Table 1 provides a description of how recommendations and evidence are rated):
In men with a life expectancy ≤ 10 years,* it is recommended that general screening for prostate cancer with total PSA be discouraged, because harms seem to outweigh potential benefits.
Type and strength of recommendation.
Evidence based: strong.
Strength of evidence.
Moderate: based on five randomized clinical trials (RCTs) with intermediate to high risk of bias, moderate follow-up, and limited data on subgroup populations.
In men with a life expectancy > 10 years,* it is recommended that physicians discuss with their patients whether PSA testing for prostate cancer screening is appropriate for them. PSA testing may save lives but is associated with harms, including complications, from unnecessary biopsy, surgery, or radiation treatment.
Type and strength of recommendation.
Evidence based: strong.
Strength of evidence.
For benefit, moderate; for harm, strong: based on five RCTs (and several cohort studies) with intermediate to high risk of bias, moderate follow-up, indirect data, inconsistent results, and limited data on subgroup populations.
It is recommended that information written in lay language be available to clinicians and their patients to facilitate the discussion of the benefits and harms associated with PSA testing before the routine ordering of a PSA test.
Type and strength of recommendation.
Informal consensus: strong.
Strength of evidence.
Indeterminate: evidence was not systematically reviewed to inform this recommendation; however, randomized trials are available on the topic.
*Calculation of life expectancy is based on a variety of individual factors and circumstances. A number of life expectancy calculators (eg, http://www.socialsecurity.gov/OACT/population/longevity.html) are available in the public domain; however, ASCO does not endorse any one calculator over another.
doi:10.1200/JCO.2012.43.3441
PMCID: PMC3776923  PMID: 22802323
15.  Development of a New Method for Monitoring Prostate-Specific Antigen Changes in Men with Localised Prostate Cancer: A Comparison of Observational Cohorts 
European urology  2009;57(3):446-452.
Background
Prostate-specific antigen (PSA) measurements are increasingly used to monitor men with localised prostate cancer (PCa), but there is little consensus about the method to use.
Objective
To apply age-specific predictions of PSA level (developed in men without cancer) to one cohort of men with clinically identified PCa and one cohort of men with PSA-detected PCa. We hypothesise that among men with clinically identified cancer, the annual increase in PSA level would be steeper than in men with PSA-detected cancer.
Design, setting, and participants
The Scandinavian Prostatic Cancer Group 4 (SPCG-4) cohort consisted of 321 men assigned to the watchful waiting arm of the SPCG-4 trial. The UK cohort consisted of 320 men with PSA-detected PCa in the Prostate Testing for Cancer and Treatment (ProtecT) study in nine UK centres between 1999 and 2007 who opted for monitoring rather than treatment. Multilevel models describing changes in PSA level were fitted to the two cohorts, and average PSA level at age 50, change in PSA level with age, and predicted PSA values were derived.
Measurements
PSA level.
Results and limitations
In the SPCG-4 cohort, mean PSA at age 50 was similar to the cancer-free cohort but with a steeper yearly increase in PSA level (16.4% vs 4.0%). In the UK cohort, mean PSA level was higher than that in the cancer-free cohort (due to a PSA biopsy threshold of 3.0 ng/ml) but with a similar yearly increase in PSA level (4.1%). Predictions were less accurate for the SPCG-4 cohort (median observed minus predicted PSA level: −2.0 ng/ml; interquartile range [IQR]: −7.6–0.7 ng/ml) than for the UK cohort (median observed minus predicted PSA level: −0.8 ng/ml; IQR: −2.1–0.1 ng/ml).
Conclusions
In PSA-detected men, yearly change in PSA was similar to that in cancer-free men, whereas in men with symptomatic PCa, the yearly change in PSA level was considerably higher. Our method needs further evaluation but has promise for refining active monitoring protocols.
doi:10.1016/j.eururo.2009.03.023
PMCID: PMC2910432  PMID: 19303695
active surveillance; localised prostate cancer; PSA doubling time; PSA velocity; reference ranges
16.  Ethnicity Is an Independent Determinant of Age-Specific PSA Level: Findings from a Multiethnic Asian Setting 
PLoS ONE  2014;9(8):e104917.
Objectives
To study the baseline PSA profile and determine the factors influencing the PSA levels within a multiethnic Asian setting.
Materials and Methods
We conducted a cross-sectional study of 1054 men with no clinical evidence of prostate cancer, prostate surgery or 5α-reductase inhibitor treatment of known prostate conditions. The serum PSA concentration of each subject was assayed. Potential factors associated with PSA level including age, ethnicity, height, weight, family history of prostate cancer, lower urinary tract voiding symptoms (LUTS), prostate volume and digital rectal examination (DRE) were evaluated using univariable and multivariable analysis.
Results
There were 38 men (3.6%) found to have a PSA level above 4 ng/ml and 1016 (96.4%) with a healthy PSA (≤4 ng/ml). The median PSA level of Malay, Chinese and Indian men was 1.00 ng/ml, 1.16 ng/ml and 0.83 ng/ml, respectively. Indians had a relatively lower median PSA level and prostate volume than Malays and Chinese, who shared a comparable median PSA value across all 10-years age groups. The PSA density was fairly similar amongst all ethnicities. Further analysis showed that ethnicity, weight and prostate volume were independent factors associated with age specific PSA level in the multivariable analysis (p<0.05).
Conclusion
These findings support the concept that the baseline PSA level varies between different ethnicities across all age groups. In addition to age and prostate volume, ethnicity may also need to be taken into account when investigating serum PSA concentrations in the multiethnic Asian population.
doi:10.1371/journal.pone.0104917
PMCID: PMC4128728  PMID: 25111507
17.  Interpretation of the prostate-specific antigen history in assessing life-threatening prostate cancer 
BJU international  2010;106(9):1284-1292.
Objective
To present an effective approach to the early detection of lethal prostate cancer using longitudinal data on prostate-specific antigen (PSA) and its rate of change, i.e. PSA velocity (PSAV). This longitudinal approach might also be extendible to other biomarkers.
Subjects and methods
PSAV was calculated using five techniques for 634 subjects with at least three PSA measurements in a longitudinal ageing study, censoring PSA levels of > 10 ng/mL. The efficacy for predicting death from prostate cancer was assessed with concordance indices and by using net reclassification improvement (NRI), which indicated the net increase in sensitivity and specificity when adding a biomarker to a base Cox proportional hazards model. The PSAV techniques were compared for the 5–10 years before the clinical diagnosis of prostate cancer. The most effective technique was then applied at the transition point when each man's PSA history curve transformed from linear to exponentially increasing, and its predictive value was compared to that of concurrent PSA level.
Results
A PSA transition point was found in 522 (82%) of the 634 men, including all 11 who died from prostate cancer. At the transition point, the mean PSA level was 1.4 ng/mL, and PSAV but not PSA level was significantly higher among men who died from prostate cancer than among men who did not (P = 0.021 vs P = 0.112; Wilcoxon two-sample test). At the transition point, adding PSAV to a base model consisting of age and date of diagnosis improved the concordance index by 0.05, and significantly improved the overall sensitivity and specificity (NRI, P = 0.028), while adding PSA level to the same base model resulted in little improvement (concordance index increase < 0.01 and NRI P = 0.275).
Conclusion
When the shape of a man's PSA history curve changes from linear to exponential, PSAV might help in the early identification of life-threatening prostate cancer at a time when PSA values are still low in most men.
doi:10.1111/j.1464-410X.2010.09363.x
PMCID: PMC2928882  PMID: 20477823
PSA; prostate cancer; kinetics; velocity
18.  Comparative effectiveness of alternative PSA-based prostate cancer screening strategies 
Annals of internal medicine  2013;158(3):145-153.
Background
The US Preventive Services Task Force recently concluded that the harms of existing prostate-specific antigen (PSA) screening strategies outweigh benefits.
Objective
To evaluate comparative effectiveness of alternative PSA screening strategies.
Design
Microsimulation model of prostate cancer incidence and mortality quantifying harms and lives saved for alternative PSA screening strategies.
Data Sources
National and trial data on PSA growth, screening and biopsy patterns, incidence, treatment distributions, treatment efficacy, and mortality.
Target Population
A contemporary cohort of US men.
Time Horizon
Lifetime.
Perspective
Societal.
Intervention
35 screening strategies that vary by start/stop ages, inter-screening intervals, and thresholds for biopsy referral.
Outcome Measurements
PSA tests, false positive tests, cancers detected, overdiagnoses, prostate cancer deaths, lives saved, and months of life saved.
Results of Base-Case Analysis
Without screening, the risk of prostate cancer death is 2.86%. A reference strategy that screens men aged 50–74 annually with a PSA threshold for biopsy referral of 4 μg/L reduces the risk of prostate cancer death to 2.15% with risk of overdiagnosis of 3.3%. A strategy that uses higher PSA thresholds for biopsy referral in older men achieves a similar risk of prostate cancer death (2.23%) but reduces the risk of overdiagnosis to 2.3%. A strategy that screens biennially with longer inter-screen intervals for men with low PSA levels achieves similar risks of prostate cancer death (2.27%) and overdiagnosis (2.4%) but reduces total tests by 59% and false positive tests by 50%.
Results of Sensitivity Analysis
Varying incidence inputs or reducing the survival improvement due to screening did not change conclusions.
Limitations
The model is a simplification of prostate cancer natural history, and the survival improvement due to screening is uncertain.
Conclusions
PSA screening strategies that use higher thresholds for biopsy referral for older men and that screen men with low PSA levels less frequently can reduce harms while preserving lives saved compared to standard screening.
Primary Funding Source
National Cancer Institute.
doi:10.7326/0003-4819-158-3-201302050-00003
PMCID: PMC3738063  PMID: 23381039
Public health policy; decision analysis; prostate cancer screening; simulation modeling
19.  [−2 ] PRO-PSA IS MORE ACCURATE THAN TOTAL AND FREE PSA IN DIFFERENTIATING PROSTATE CANCER FROM BENIGN DISEASE IN A PROSPECTIVE PROSTATE CANCER SCREENING STUDY*, ** 
The Journal of urology  2010;183(4):1355-1359.
Purpose
Due to the limited specificity of prostate-specific antigen (PSA) for prostate cancer (CaP) screening, there is an ongoing search for adjunctive biomarkers. Retrospective studies have suggested that an isoform of proenzyme PSA called [−2] proPSA (p2PSA) may enhance the specificity of PSA-based screening. The objective of our study was to examine the utility of p2PSA in a prospective CaP screening study.
Materials and Methods
From a population of 2034 men undergoing CaP screening, we examined the relationship between p2PSA and CaP detection. Specifically, we compared the utility of total PSA, the ratio of free PSA (fPSA) to total PSA (%fPSA), the ratio of p2PSA to fPSA (%p2PSA) and a formula combining PSA, fPSA and p2PSA (called Beckman Coulter prostate health index or phi®) to predict CaP among men from the study undergoing prostate biopsy with PSA levels of 2.5–10 ng/ml and non-suspicious digital rectal examination (DRE).
Results
Despite similar total PSA levels (p=0.88), both %fPSA (p=0.02) and %p2PSA (p=0.0006) distinguished between positive and negative biopsy results. On receiver operating characteristic (ROC) analysis, %p2PSA (AUC 0.76) outperformed both PSA (AUC 0.50) and %fPSA (AUC 0.68) for differentiating between CaP and benign disease. Setting the sensitivity at 88.5%, p2PSA led to a substantial improvement in specificity, positive and negative predictive values. The Beckman Coulter phi® (AUC 0.77) had the best overall performance characteristics.
Conclusions
This is the first prospective study to demonstrate that p2PSA provides improved discrimination between CaP and benign disease in screened men with PSA levels from 2.5 to 10 ng/ml and negative DRE.
doi:10.1016/j.juro.2009.12.056
PMCID: PMC3537165  PMID: 20171670
prostate-specific antigen; PSA; free PSA; PSA isoforms; proPSA
20.  Urinary PSA: a potential useful marker when serum PSA is between 2.5 ng/mL and 10 ng/mL 
Introduction
Our objective was to evaluate the usefulness of urinary prostate specific antigen (PSA) in the differential diagnosis of benign prostatic hyperplasia (BPH) and prostate cancer.
Methods
We undertook a prospective study and obtained informed consent from 170 men. They provided blood samples to measure serum PSA and 50 mL of first-voided urine to measure urinary PSA. Seventy-seven men were diagnosed with BPH; 42 patients had newly diagnosed prostate cancer; and 51 were selected as age-matched control subjects. Data were analyzed using Wilcoxon signed rank tests, receiver operating characteristic (ROC) curves and logistic regression.
Results
Prostate volume was 35 cm3 and 45 cm3 (p < 0.05), serum PSA was 9.7 ng/mL and 4.5 ng/mL (p < 0.001) and PSA density was 0.28 and 0.11 (p < 0.01) for prostate cancer and BPH patients, respectively. Overall, urinary PSA was not significantly different, but PSA ratio (urinary:serum) was significantly different at 6.7 and 30.6 (p < 0.001) for prostate cancer and BPH patients, respectively. A subgroup with serum PSA between 2.5 ng/mL and 10.0 ng/mL was selected and urinary PSA was significant: 52.6 ng/mL (n = 29) and 123.2 ng/mL (n = 35) (p < 0.05) for prostate cancer and BPH patients, respectively. PSA ratios were also significant (p = 0.007). ROC curves identified a cutoff for urinary PSA at > 150 ng/mL, with a sensitivity of 92.5%. When comparing prostate cancer patients with age-matched control subjects, serum PSA, urinary PSA and PSA ratio were different (p = 0.004).
Conclusion
Our study supports urinary PSA as a useful marker in the differential diagnosis of prostate cancer and BPH, especially when serum PSA is between 2.5 ng/mL and 10 ng/mL. Low urinary PSA and PSA ratios point toward prostate cancer. A urinary PSA threshold of > 150 ng/mL may be used to decrease the number of prostatic biopsies.
PMCID: PMC2422995  PMID: 18542821
21.  Role of Prostate Volume in the Early Detection of Prostate Cancer in a Cohort with Slowly Increasing Prostate Specific Antigen 
Yonsei Medical Journal  2013;54(5):1202-1206.
Purpose
To investigate the relationship between prostate volume and the increased risk for being diagnosed with prostate cancer (PCa) in men with slowly increasing prostate specific antigen (PSA).
Materials and Methods
A cohort of 1035 men who visited our hospital's health promotion center and were checked for serum PSA levels more than two times between January 2001 and November 2011 were included. Among them, 116 patients had a change in PSA levels from less than 4 ng/mL to more than 4 ng/mL and underwent transrectal ultrasound guided prostate biopsy. Median age was 55.9 years and 26 (22.4%) had PCa. We compared the initial PSA level, the last PSA level, age, prostate volume, PSA density (PSAD), PSA velocity, and follow-up period between men with and without PCa. The mean follow-up period was 83.7 months.
Results
Significant predictive factors for the detection of prostate cancer identified by univariate analysis were prostate volume, follow-up period and PSAD. In the multivariate analysis, prostate volume (p<0.001, odds ratio: 0.890) was the most significant factor for the detection of prostate cancer. In the receiver operator characteristic curve of prostate volume, area under curve was 0.724. At the cut-off value of 28.8 mL for prostate volume, the sensitivity and specificity were 61.1% and 73.1% respectively.
Conclusion
In men with PSA values more than 4 ng/mL during the follow-up period, a small prostate volume was the most important factor in early detection of prostate cancer.
doi:10.3349/ymj.2013.54.5.1202
PMCID: PMC3743199  PMID: 23918570
Prostatic neoplasms; prostate-specific antigen; early diagnosis; organ size
22.  Genome-wide Association Study Identifies Loci at ATF7IP and KLK2 Associated with Percentage of Circulating Free PSA1 2 
Neoplasia (New York, N.Y.)  2013;15(1):95-101.
Background
Percentage of free-to-total prostate-specific antigen (%fPSA) is an independent predictor of risk for prostate cancer among men with modestly elevated level of total PSA (tPSA) in blood. Physiological and pathological factors have been shown to influence the %fPSA value and diagnostic accuracy.
Materials/Methods
To evaluate genetic determinants of %fPSA, we conducted a genome-wide association study of serum %fPSA by genotyping 642,584 single nucleotide polymorphisms (SNPs) in 3192 men of European ancestry, each with a tPSA level of 2.5 to 10 ng/ml, that were recruited in the REduction by DUtasteride of Prostate Cancer Events study. Single nucleotide polymorphisms (SNPs) with P < 10-5 were further evaluated among the controls of a population-based case-control study in Sweden (2899 prostate cancer cases and 1722 male controls), including 464 controls having tPSA levels of 2.5 to 10 ng/ml.
Results
We identified two loci that were associated with %fPSA at a genome-wide significance level (P <5 x 10-8). The first associated SNP was rs3213764 (P = 6.45 x 10-10), a nonsynonymous variant (K530R) in the ATF7IP gene at 12p13. This variant was also nominally associated with tPSA (P = .015). The second locus was rs1354774 (P = 1.25 x 10-12), near KLK2 at 19q13, which was not associated with tPSA levels, and is separate from the rs17632542 locus at KLK3 that was previously associated with tPSA levels and prostate cancer risk. Neither rs3213764 nor rs1354774 was associated with prostate cancer risk or aggressiveness.
Conclusions
These findings demonstrate that genetic variants at ATF7IP and KLK2 contribute to the variance of %fPSA.
PMCID: PMC3556942  PMID: 23359319
23.  Prostate-specific antigen and prostate-specific antigen density cutoff points among Indonesian population suspected for prostate cancer 
Prostate International  2013;1(1):23-30.
Purpose:
Racial differences exist in the incidence of prostate cancer (PCa). Although many studies have looked at the performance of prostate-specific antigen (PSA) and PSA density (PSAD) in the detection of PCa, only a few have looked at it in relation to Indonesian men. The objective of this study is to find out better PSA and PSAD cutoff point in the detection of PCa in Indonesian men.
Methods:
A total of 404 consecutive Indonesian men underwent prostate biopsy for suspicion of PCa from 2008 to 2011. The biopsy criteria include one or more of the following: serum PSA more than 10 ng/mL, PSAD more than 0.15 if PSA 4–10 ng/mL, hypoechoic lesion during transrectal sonography and/or abnormal digital rectal examination.
Results:
Forty five out of 404 (11.1%) had positive biopsies. The mean age, prostate volume, PSA and PSAD were respectively 64.06 years, 43.03 mL, 45.59 ng/mL and 1.15. Of the 404, 131 cases (32.4%) were confirmed to be urinary retention. Positive urine culture found in 182 cases (45%). The cutoff point to detect PCa as estimated by the receiver operating characteristics was 6.95 ng/mL for PSA (sensitivity 97.8%, specificity 19.6%) and 0.7072 for PSAD (sensitivity 62.2%, specificity 78.7%). Positive predictive value for this PSA and PSAD cutoff point were 11.6% and 27.5% respectively (P=0.004 and P=0.000). There was a significant correlation between hypoechoic lesion and positive biopsy results (P =0.000). Urinary retention elevates PSA cutoff point to 14.55 (sensitivity 90.9%, specificity 50%), while positive urine culture alters almost no PSA cutoff elevation.
Conclusions:
PSA and PSAD cutoff point for Indonesian men in this series is relatively different from international consensus. Furthermore, these data show that PSA and PSAD cutoff point must be adjusted to racial variation to discriminate between malignant and benign disease. Urinary retention is a significant factor for PSA cutoff increase.
doi:10.12954/PI.12003
PMCID: PMC3821515  PMID: 24223398
Prostate neoplasms; Prostate-specific antigen; Prostate specific antigen density; Indonesia
24.  The Prostate Cancer Intervention Versus Observation Trial:VA/NCI/AHRQ Cooperative Studies Program #407 (PIVOT): Design and Baseline Results of a Randomized Controlled Trial Comparing Radical Prostatectomy With Watchful Waiting for Men With Clinically Localized Prostate Cancer 
Prostate cancer is the most common noncutaneous malignancy and the second leading cause of cancer death in men. In the United States, 90% of men with prostate cancer are more than age 60 years, diagnosed by early detection with the prostate-specific antigen (PSA) blood test, and have disease believed confined to the prostate gland (clinically localized). Common treatments for clinically localized prostate cancer include watchful waiting (WW), surgery to remove the prostate gland (radical prostatectomy), external-beam radiation therapy and interstitial radiation therapy (brachytherapy), and androgen deprivation. Little is known about the relative effectiveness and harms of treatments because of the paucity of randomized controlled trials. The Department of Veterans Affairs/National Cancer Institute/Agency for Healthcare Research and Quality Cooperative Studies Program Study #407:Prostate Cancer Intervention Versus Observation Trial (PIVOT), initiated in 1994, is a multicenter randomized controlled trial comparing radical prostatectomy with WW in men with clinically localized prostate cancer. We describe the study rationale, design, recruitment methods, and baseline characteristics of PIVOT enrollees. We provide comparisons with eligible men declining enrollment and men participating in another recently reported randomized trial of radical prostatectomy vs WW conducted in Scandinavia. We screened 13 022 men with prostate cancer at 52 US medical centers for potential enrollment. From these, 5023 met initial age, comorbidity, and disease eligibility criteria, and a total of 731 men agreed to participate and were randomized. The mean age of enrollees was 67 years. Nearly one-third were African American. Approximately 85% reported that they were fully active. The median PSA was 7.8ng/mL (mean 10.2ng/mL). In three-fourths of men, the primary reason for biopsy leading to a diagnosis of prostate cancer was a PSA elevation or rise. Using previously developed tumor risk categorizations incorporating PSA levels, Gleason histologic grade, and tumor stage, it was found that approximately 40% had low-risk, 34% had medium-risk, and 21% had high-risk prostate cancer based on local histopathology. Comparison to our national sample of eligible men declining PIVOT participation as well as to men enrolled in the Scandinavian trial indicated that PIVOT enrollees are representative of men being diagnosed and treated in the United States and quite different from men in the Scandinavian trial. PIVOT enrolled an ethnically diverse population representative of men diagnosed with prostate cancer in the United States. Results will yield important information regarding the relative effectiveness and harms of surgery compared with WW for men with predominately PSA-detected clinically localized prostate cancer.
doi:10.1093/jncimonographs/lgs041
PMCID: PMC3540866  PMID: 23271771
25.  Detection of Life-Threatening Prostate Cancer With Prostate-Specific Antigen Velocity During a Window of Curability 
Background
Prostate-specific antigen (PSA) level is typically used as a dichotomous test for prostate cancer, resulting in overdiagnosis for a substantial number of men. The rate at which serum PSA levels change (PSA velocity) may be an important indicator of the presence of life-threatening disease.
Methods
PSA velocity was determined in 980 men (856 without prostate cancer, 104 with prostate cancer who were alive or died of another cause, and 20 who died of prostate cancer) who were participants in the Baltimore Longitudinal Study of Aging for up to 39 years. The relative risks (RRs) of prostate cancer death and prostate cancer–specific survival stratified by PSA velocity were evaluated in the three groups of men by Cox regression and Kaplan–Meier analyses. Statistical tests were two-sided.
Results
PSA velocity measured 10–15 years before diagnosis (when most men had PSA levels below 4.0 ng/mL) was associated with cancer-specific survival 25 years later; survival was 92% (95% confidence interval [CI] = 84% to 96%) among men with PSA velocity of 0.35 ng/mL per year or less and 54% (95% CI = 15% to 82%) among men with PSA velocity above 0.35 ng/mL per year (P<.001). Furthermore, men with PSA velocity above 0.35 ng/mL per year had a higher relative risk of prostate cancer death than men with PSA velocity of 0.35 ng/mL per year or less (RR = 4.7, 95% CI = 1.3 to 16.5; P = .02); the rates per 100 000 person-years were 1240 for men with a PSA velocity above 0.35 ng/mL per year and 140 for men with a PSA velocity of 0.35 ng/mL per year or less.
Conclusions
PSA velocity may help identify men with life-threatening prostate cancer during a period when their PSA levels are associated with the presence of curable disease.
doi:10.1093/jnci/djj410
PMCID: PMC2645644  PMID: 17077354

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