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1.  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
2.  Can microfocal prostate cancer be regarded as low-risk prostate cancer? 
Prostate International  2013;1(4):158-162.
Purpose:
Prostate specific antigen (PSA) screening for prostate cancer has become widespread, the prostate biopsy technique has evolved, and the occurrence of low-risk prostate cancer has been increasing. Even low-risk patients may demonstrate disease upgrading or upstaging. We aimed to evaluate the clinical importance of a single microfocal prostate cancer at biopsy in patients subsequently treated with radical prostatectomy.
Methods:
A total of 337 cases of patients who underwent radical prostatectomy after prostate biopsies were retrospectively reviewed. Microfocal prostate cancer was defined as Gleason score 6 and a single positive core with ≤5% cancer involvement after the standard 12-core extended biopsy.
Results:
Of the 337 prostatectomy specimens, 22 (6.5%) were microfocal prostate cancer based on prostate biopsy. On final pathology, microfocal patients were found to have significant 45% Gleason score upgrading (P=0.02) and 27% positive surgical margins (P=0.04) despite low PSA, compared with the nonmicrofocal prostate cancer group. Gleason upgrading was significantly higher in the microfocal prostate cancer group (P=0.02), whereas Gleason downgrading was significantly higher in the nonmicrofocal prostate cancer group (P<0.01). Furthermore, biochemical recurrence rate was no different between microfocal and nonmicrofocal prostate cancer at mean 31 months (P=0.18). Overall, 13 of 22 cases (53.1%) in the microfocal prostate cancer group showed Gleason upgrading or stage upgrading.
Conclusions:
Based on higher rates of Gleason score upgrading or stage upgrading cases in microfocal prostate cancer group, compared with nonmicrofocal prostate cancer group, active surveillance should be cautiously applied to these patients.
doi:10.12954/PI.13028
PMCID: PMC3879053  PMID: 24392440
Prostate neoplasms; Biopsy; Low-risk prostate cancer; Prostatectomy
3.  Active Surveillance: The Canadian Experience With an “Inclusive Approach” 
Active surveillance has evolved to become a standard of care for favorable-risk prostate cancer. This is a summary of the rationale, method, and results of active surveillance beginning in 1995 with the first prospective trial of this approach. This was a prospective, single-arm cohort study. Patients were managed with an initial expectant approach. Definitive intervention was offered to those patients with a prostate-specific antigen (PSA) doubling time of less than 3 years, Gleason score progression (to 4+3 or greater), or unequivocal clinical progression. Survival analysis and Cox proportional hazard model were applied to the data. Since November 1995, 450 patients have been managed with active surveillance. The cohort included men under 70 with favorable-risk disease and men of age more than 70 with favorable- or intermediate-risk cancer (Gleason score 3+4 or PSA 10–15). Median follow-up is 6.8 years (range 1–16 years). Overall survival is 78.6%. Ten-year prostate cancer actuarial survival is 97.2%. Five of 450 patients (1.1%) have died of prostate cancer. Thirty percent of patients have been reclassified as higher-risk patients and offered definitive therapy. The commonest indication for treatment was a PSA doubling time less than 3 years (48%) or Gleason upgrading (26%). Of 117 patients treated radically, the PSA failure rate was 50%. This represents 13% of the total cohort. Most PSA failures occurred early; at 2 years, 44% of the treated patients had PSA failure. The hazard ratio for non–prostate cancer mortality to prostate cancer mortality was 18.6 at 10 years. In conclusion, we observed a very low rate of prostate cancer mortality in an intermediate time frame. Among the one-third of patients who were reclassified as higher risk and retreated, PSA failure was relatively common. However, other-cause mortality accounted for almost all of the deaths. Further studies are warranted to improve the identification of patients who harbor more aggressive disease in spite of favorable clinical parameters at diagnosis [reproduced from Klotz (1) with permission from Wolters Kluwer Health].
doi:10.1093/jncimonographs/lgs042
PMCID: PMC3540875  PMID: 23271779
4.  Serum insulin level, disease stage, prostate specific antigen (PSA) and Gleason score in prostate cancer 
British Journal of Cancer  2002;87(7):726-728.
In the present study, we assessed the relationship of serum insulin levels and three surrogate markers of recurrence, T stage, PSA, and Gleason score, in men with localized prostate cancer. Participants in our study were found through urology and radiation oncology clinics, and all eligible patients were asked to take part. All patients were asymptomatic and had been initially diagnosed on the basis of rising PSA or abnormal physical examination. Histological confirmation of diagnosis was obtained for all subjects. Serum insulin levels were determined by chemoluminescent assay with a standard, commercially available instrument. Patients were divided into three previously defined risk groups: Low risk: PSA ⩽10, stage ⩽T2a, or Gleason grade ⩽6. Medium risk: 10 7, tumour in seminal vesicle biopsy, PSA >15 or stage T2c or T3. One hundred and sixty-three men with prostate cancer were studied. There was a significant increase in serum insulin with risk group (P=0.003, one way anova). Tukey's multiple range test showed that the insulin levels of high risk patients were significantly higher than the insulin levels of medium and low risk patients (P=0.05) but the insulin levels of medium and low risk patients were not significantly different from one another. Multivariate linear regression, with insulin as the dependent variable, Gleason score, PSA, and T stage (T1, T2, T3) as the independent variables, was significant overall (P<0.001, r2=0.120). Increased T stage was independently correlated with increased serum insulin levels (P<0.001). Gleason score was negatively, insignificantly correlated with serum insulin level (P=0.059). The positive correlation of PSA and insulin level was not significant (P=0.097). To assure normal distribution of insulin and PSA values, the regression was repeated with log (insulin) as the dependent variable, log (PSA), T stage (T1, T2, T3), and Gleason score as independent variables. The regression was significant overall (P=0.002, r2 =0.095). Increased T stage was independently correlated with increased log (insulin level) (P=0.026). Gleason score was negatively, insignificantly correlated with log (insulin) level (P=0.728). The positive correlation of log (PSA) and log (insulin) levels was significant (P=0.010). The relationship between increased insulin level and advanced tumour stage in prostate cancer we describe here is biologically quite plausible, since insulin is a growth factor. Further studies may document whether serum insulin levels might be a useful biomarker of prostate cancer stage.
British Journal of Cancer (2002) 87, 726–728. doi:10.1038/sj.bjc.6600526 www.bjcancer.com
© 2002 Cancer Research UK
doi:10.1038/sj.bjc.6600526
PMCID: PMC2364268  PMID: 12232754
prostate cancer progression; insulin; growth factors
5.  Is a Decreased Serum Testosterone Level a Risk Factor for Prostate Cancer? A Cohort Study of Korean Men 
Korean Journal of Urology  2010;51(12):819-823.
Purpose
To investigate patients who had transrectal ultrasonography (TRUS)-guided prostate biopsy to define the role of the serum testosterone level in predicting prostate cancer risk and its association with a high Gleason score.
Materials and Methods
A total of 568 patients who underwent prostate biopsy were entered in this study. We divided the patients into two groups according to serum testosterone level (median level, 3.85 ng/ml): the high-testosterone group (n=285) and the low-testosterone group (n=283). Multivariate regression analysis was used to define the effect of age, prostate volume, serum prostate-specific antigen (PSA) level and PSA density, and serum testosterone level on the risk of prostate cancer and a high Gleason score.
Results
Baseline characteristics did not differ significantly between the two groups. Compared with the high-testosterone group, the low-testosterone group had a significantly higher prostate cancer incidence (38.9% vs. 29.5%, p=0.018). Factors associated with an increased risk of prostate cancer were increased age (odds ratio [OR]=1.08, 95% confidence interval [CI]=1.25-3.16, p=0.001), a high serum PSA level (OR=3.35, 95% CI=2.63-4.25, p=0.001), a low prostate volume (OR=0.183, 95% CI=0.11-0.30, p=0.001), and a low serum testosterone level (OR=1.99, 95% CI=1.25-3.16, p=0.001). Among these, only the serum PSA level was a strong predictor of high-grade prostate cancer (Gleason score ≥7) (OR=2.19, 95% CI=1.57-2.95, p=0.001).
Conclusions
Patients with lower levels of serum testosterone had a higher risk of prostate cancer than did patients with high serum testosterone. Even though a lower serum testosterone level was a predictor of prostate cancer risk, it was not associated with an increased risk of high-grade prostate cancer.
doi:10.4111/kju.2010.51.12.819
PMCID: PMC3016426  PMID: 21221200
Prostatic neoplasms; Risk factors; Testosterone
6.  Active Surveillance Compared With Initial Treatment for Men With Low-Risk Prostate Cancer 
Context
In the United States, 192 000 men were diagnosed as having prostate cancer in 2009, the majority with low-risk, clinically localized disease. Treatment of these cancers is associated with substantial morbidity. Active surveillance is an alternative to initial treatment, but long-term outcomes and effect on quality of life have not been well characterized.
Objective
To examine the quality-of-life benefits and risks of active surveillance compared with initial treatment for men with low-risk, clinically localized prostate cancer.
Design and Setting
Decision analysis using a simulation model was performed: men were treated at diagnosis with brachytherapy, intensity-modulated radiation therapy (IMRT), or radical prostatectomy or followed up by active surveillance (a strategy of close monitoring of newly diagnosed patients with serial prostate-specific antigen measurements, digital rectal examinations, and biopsies, with treatment at disease progression or patient choice). Probabilities and utilities were derived from previous studies and literature review. In the base case, the relative risk of prostate cancer–specific death for initial treatment vs active surveillance was assumed to be 0.83. Men incurred short- and long-term adverse effects of treatment.
Patients
Hypothetical cohorts of 65-year-old men newly diagnosed as having clinically localized, low-risk prostate cancer (prostate-specific antigen level <10 ng/mL, stage ≤T2a disease, and Gleason score ≤6).
Main Outcome Measure
Quality-adjusted life expectancy (QALE).
Results
Active surveillance was associated with the greatest QALE (11.07 quality-adjusted life-years [QALYs]), followed by brachytherapy (10.57 QALYs), IMRT (10.51 QALYs), and radical prostatectomy (10.23 QALYs). Active surveillance remained associated with the highest QALE even if the relative risk of prostate cancer–specific death for initial treatment vs active surveillance was as low as 0.6. However, the QALE gains and the optimal strategy were highly dependent on individual preferences for living under active surveillance and for having been treated.
Conclusions
Under a wide range of assumptions, for a 65-year-old man, active surveillance is a reasonable approach to low-risk prostate cancer based on QALE compared with initial treatment. However, individual preferences play a central role in the decision whether to treat or to pursue active surveillance.
doi:10.1001/jama.2010.1720
PMCID: PMC3055173  PMID: 21119084
7.  Contemporary Trends in Low-Risk Prostate Cancer: Risk Assessment and Treatment 
The Journal of urology  2007;178(3 Pt 2):S14-S19.
Purpose
To update national risk trends in prostate cancer with a focus on low-risk tumors, to re-examine trends in primary treatment for low-risk tumors, and to attempt to substratify low-risk patients based on pretreatment clinical data.
Materials and Methods
Data were abstracted from the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) registry. 10,385 men were diagnosed between 1990 and 2006 with localized disease. Low risk was defined as a prostate-specific antigen (PSA) level ≤10 ng/mL, a Gleason score ≤6, and a clinical T stage ≤2a. Temporal trends were assessed for patient distribution among risk groups and within the low-risk group for individual risk factors, Kattan nomogram prediction, Cancer of the Prostate Risk Assessment (CAPRA) score, and primary treatment. The ability of the CAPRA score to substratify low-risk prostatectomy patients was evaluated with survival analysis.
Results
The proportion of low-risk tumors in CaPSURE nearly doubled from 27.5% in 1990-1994 to 46.4% in 2000-2001, but has been relatively constant since. A growing proportion of low-risk tumors are cT1c, and virtually all are Gleason score 6. PSA and the percentage of positive biopsies have decreased throughout the study period, as did the mean CAPRA score. The use of active surveillance increased from a nadir of 6.2% in 2000-2001 to 10.2% in 2004-2006. The use of prostatectomy has also increased, whereas use of androgen deprivation and radiation has declined. Likelihood of recurrence increases significantly with rising CAPRA score.
Conclusions
Low-risk patients can be further substratified to identify those at very low-risk based on clinical variables. The use of surveillance is increasing, but overtreatment remains a concern among these patients.
doi:10.1016/j.juro.2007.03.135
PMCID: PMC2987559  PMID: 17644125
Prostatic neoplasms; Risk factors; Prognosis; Treatment; CAPRA; CaPSURE
8.  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
9.  Evaluation of Multiple Risk-Associated Single Nucleotide Polymorphisms Versus Prostate-Specific Antigen at Baseline to Predict Prostate Cancer in Unscreened Men 
European Urology  2011;61(3):471-477.
Background
Although case-control studies have identified numerous single nucleotide polymorphisms (SNPs) associated with prostate cancer, the clinical role of these SNPs remains unclear.
Objective
Evaluate previously identified SNPs for association with prostate cancer and accuracy in predicting prostate cancer in a large prospective population-based cohort of unscreened men.
Design, setting, and participants
This study used a nested case-control design based on the Malmö Diet and Cancer cohort with 943 men diagnosed with prostate cancer and 2829 matched controls. Blood samples were collected between 1991 and 1996, and follow-up lasted through 2005.
Measurements
We genotyped 50 SNPs, analyzed prostate-specific antigen (PSA) in blood from baseline, and tested for association with prostate cancer using the Cochran-Mantel-Haenszel test. We further developed a predictive model using SNPs nominally significant in univariate analysis and determined its accuracy to predict prostate cancer.
Results and limitations
Eighteen SNPs at 10 independent loci were associated with prostate cancer. Four independent SNPs at four independent loci remained significant after multiple test correction (p < 0.001). Seven SNPs at five independent loci were associated with advanced prostate cancer defined as clinical stage ≥T3 or evidence of metastasis at diagnosis. Four independent SNPs were associated with advanced or aggressive cancer defined as stage ≥T3, metastasis, Gleason score ≥8, or World Health Organization grade 3 at diagnosis. Prostate cancer risk prediction with SNPs alone was less accurate than with PSA at baseline (area under the curve of 0.57 vs 0.79), with no benefit from combining SNPs with PSA. This study is limited by our reliance on clinical diagnosis of prostate cancer; there are likely undiagnosed cases among our control group.
Conclusions
Only a few previously reported SNPs were associated with prostate cancer risk in the large prospective Diet and Cancer cohort in Malmö, Sweden. SNPs were less useful in predicting prostate cancer risk than PSA at baseline.
doi:10.1016/j.eururo.2011.10.047
PMCID: PMC3269546  PMID: 22101116
Prostate cancer; Biomarkers; SNPs; PSA; Sensitivity and specificity
10.  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
11.  Outcomes of Localized Prostate Cancer Following Conservative Management 
Context:
Most newly diagnosed prostate cancer is clinically localized, and major treatment options include surgery, radiation, or conservative management. Although conservative management can be a reasonable choice, there is little contemporary PSA era data on outcomes with this approach.
Objective:
To evaluate the outcomes of clinically localized prostate cancer managed without initial attempted curative therapy in the PSA era.
Design:
A population-based cohort study with a median follow-up 8.3 years (through December 31, 2007). Competing risk analyses were performed to assess outcomes.
Setting:
Areas covered by the Surveillance, Epidemiology and End Results (SEER) program.
Participants:
Men diagnosed with stage T1/T2 prostate cancer after age 65 between 1992 and 2002 managed without surgery or radiation within 6 months of cancer diagnosis.
Main Outcome Measure:
10-year overall survival, cancer-specific survival, and major cancer related interventions.
Results:
With a median age of 78 years at cancer diagnosis, ten-year prostate cancer-specific mortality was 8.3% (95% CI 4.2% – 12.8%), 9.1% (95% CI 8.3% - 10.1%), and 25.6% (95% CI 23.7% - 28.3%) for men with well-, moderately-, and poorly-differentiated tumors, respectively. The corresponding 10-year risks of dying of competing causes were 59.8% (95% CI 53.2% - 67.8%), 57.2% (95% CI 52.6% - 63.9%) and 56.5% (95% CI 53.6% - 58.8%), respectively. Ten-year disease specific mortality for men aged 66-74 years diagnosed with moderately-differentiated disease was 60% - 74% lower than earlier studies: 6% (95% confidence interval [CI] 4% - 8%) in the contemporary PSA era (1992-2002) compared to results of previous studies (15% - 23%) in earlier eras (1949-1992). Improved survival was also observed in poorly-differentiated disease. The use of chemotherapy (1.6%), or major interventions for spinal cord compression (0.9%), was uncommon.
Conclusion:
Results following conservative management of clinically localized prostate cancer diagnosed in 1992 – 2002 are better than outcomes among patients diagnosed in the 1970s and 1980s. This may be due, in part, to additional lead time, overdiagnosis related to PSA testing, grade migration, or advances in medical care.
doi:10.1001/jama.2009.1348
PMCID: PMC2822438  PMID: 19755699
prostatic neoplasm; survival; population-based study
12.  Prostate cancer outcome in Burkina Faso 
Infectious Agents and Cancer  2011;6(Suppl 2):S6.
Introduction
African-American black men race is one of non-modifiable risk factors confirmed for prostate cancer. Many studies have been done in USA among African- American population to evaluate prostate cancer disparities. Compared to the USA very few data are available for prostate cancer in Sub-Saharan African countries. The objective of this study was to describe incident prostate cancer (PC) diagnosis characteristics in Burkina Faso (West Africa).
Methods
We performed a prospective non randomized patient’s cohort study of new prostate cancer cases diagnosed by histological analysis of transrectal prostate biopsies in Burkina Faso. Study participants included 166 patients recruited at the urology division of the university hospital of Ouagadougou. Age of the patients, clinical symptoms, digital rectal examination (DRE) result, serum prostate-specific antigen (PSA) level, histological characteristics and TNM classification were taking in account in this study.
Results
166 transrectal prostate biopsies (TRPB) were performed based on high PSA level or abnormal DRE. The prostate cancer rate on those TRPB was 63, 8 % (n=106). The mean age of the patients was 71, 5 years (52 to 86). Urinary retention was the first clinical patterns of reference in our institution (55, 7 %, n = 59). Most patients, 56, 6 % (n = 60) had a serum PSA level over than 100 ng/ml. All the patients had adenocarcinoma on histological study of prostate biopsy cores. The majority of cases (54, 7 % n = 58) had Gleason score equal or higher than 7.
Conclusion
Prostate cancer is diagnosed at later stages in our country. Very high serum PSA level and poorly differentiated tumors are the two major characteristics of PC at the time of diagnosis.
doi:10.1186/1750-9378-6-S2-S6
PMCID: PMC3194185  PMID: 21992406
13.  Use of Advanced Treatment Technologies Among Men at Low Risk of Dying From Prostate Cancer 
JAMA : the journal of the American Medical Association  2013;309(24):10.1001/jama.2013.6882.
Importance
The use of advanced treatment technologies (ie, intensity-modulated radiotherapy [IMRT] and robotic prostatectomy) for prostate cancer is increasing. The extent to which these advanced treatment technologies have disseminated among patients at low risk of dying from prostate cancer is uncertain.
Objective
To assess the use of advanced treatment technologies, compared with prior standards (ie, traditional external beam radiation treatment [EBRT] and open radical prostatectomy) and observation, among men with a low risk of dying from prostate cancer.
Design, Setting, and Patients
Using Surveillance, Epidemiology, and End Results (SEER)-Medicare data, we identified a retrospective cohort of men diagnosed with prostate cancer between 2004 and 2009 who underwent IMRT (n=23 633), EBRT (n=3926), robotic prostatectomy (n=5881), open radical prostatectomy (n=6123), or observation (n=16 384). Follow-up data were available through December 31, 2010.
Main Outcomes and Measures
The use of advanced treatment technologies among men unlikely to die from prostate cancer, as assessed by low-risk disease (clinical stage ≤T2a, biopsy Gleason score ≤6, and prostate-specific antigen level ≤10 ng/mL), high risk of noncancer mortality (based on the predicted probability of death within 10 years in the absence of a cancer diagnosis), or both.
Results
In our cohort, the use of advanced treatment technologies increased from 32% (95% CI, 30%–33%) to 44% (95% CI, 43%–46%) among men with low-risk disease (P<.001) and from 36% (95% CI, 35%–38%) to 57% (95% CI, 55%–59%) among men with high risk of noncancer mortality (P<.001). The use of these advanced treatment technologies among men with both low-risk disease and high risk of noncancer mortality increased from 25% (95% CI, 23%–28%) to 34% (95% CI, 31%–37%) (P<.001). Among all patients diagnosed in SEER, the use of advanced treatment technologies for men unlikely to die from prostate cancer increased from 13% (95% CI, 12%–14%), or 129.2 per 1000 patients diagnosed with prostate cancer, to 24% (95% CI, 24%–25%), or 244.2 per 1000 patients diagnosed with prostate cancer (P<.001).
Conclusion and Relevance
Among men diagnosed with prostate cancer between 2004 and 2009 who had low-risk disease, high risk of noncancer mortality, or both, the use of advanced treatment technologies has increased.
doi:10.1001/jama.2013.6882
PMCID: PMC3857348  PMID: 23800935
14.  Evaluation of the Prostate Cancer Prevention Trial Risk Calculator in a High-Risk Screening Population 
BJU international  2009;105(3):334-337.
Introduction
Clinical factors in addition to PSA have been evaluated to improve risk assessment for prostate cancer. The Prostate Cancer Prevention Trial (PCPT) risk calculator provides an assessment of prostate cancer risk based on age, PSA, race, prior biopsy, and family history. This study evaluated the risk calculator in a screening cohort of young, racially diverse, high-risk men with a low baseline PSA enrolled in the Prostate Cancer Risk Assessment Program.
Patients and Methods
Eligibility for PRAP include men ages 35-69 who are African-American, have a family history of prostate cancer, or have a known BRCA1/2 mutation. PCPT risk scores were determined for PRAP participants, and were compared to observed prostate cancer rates.
Results
624 participants were evaluated, including 382 (61.2%) African-American men and 375 (60%) men with a family history of prostate cancer. Median age was 49.0 years (range 34.0-69.0), and median PSA was 0.9 (range 0.1-27.2). PCPT risk score correlated with prostate cancer diagnosis, as the median baseline risk score in patients diagnosed with prostate cancer was 31.3%, versus 14.2% in patients not diagnosed with prostate cancer (p<0.0001). The PCPT calculator similarly stratified the risk of diagnosis of Gleason score ≥7 disease, as the median risk score was 36.2% in patients diagnosed with Gleason ≥7 prostate cancer versus 15.2% in all other participants (p<0.0001).
Conclusion
PCPT risk calculator score was found to stratify prostate cancer risk in a cohort of young, primarily African-American men with a low baseline PSA. These results support further evaluation of this predictive tool for prostate cancer risk assessment in high-risk men.
doi:10.1111/j.1464-410X.2009.08793.x
PMCID: PMC2809782  PMID: 19709072
Prostate Cancer; prostate biopsy; prostate cancer prevention
15.  Up-to-date results of carbon-ion radiotherapy for prostate cancer 
Journal of Radiation Research  2014;55(Suppl 1):i28-i29.
Carbon ion radiotherapy (C-ion RT) for prostate cancer was started in 1995 using the Heavy-Ion Medical Accelerator in Chiba (HIMAC) at the National Institute of Radiological Sciences (NIRS), Japan. After preceding phase I/II dose-escalation studies of 20 fractions over 5 weeks, a phase II study was initiated in April 2000 using the treatment techniques and the recommended dose fractionations established by the phase I/II studies. This study was also successfully completed in October 2003 when the C-ion RT for solid tumors, including the prostate cancer, was approved as ‘Advanced Medicine’ by the Ministry of Health, Labor, and Welfare. Since then, more than 1400 patients have been treated with C-ion RT as of February 2012, and advancement of hypofractionation has also been achieved. In this paper, the treatment outcomes in 1144 patients who underwent the established C-ion RT between April 2000 and July 2012 were analyzed.
Out of 1144 patients, 585 patients were categorized as high-risk group, which includes patients having at least one of the following conditions: T3 clinical stage, Gleason's score of 8 or higher and PSA of 20 or higher. One hundred and ninety-seven patients who met the conditions such as clinical stage of T2a or lower, Gleason's score of 6 or lower and PSA of <20 were categorized as low-risk group. Three hundred and sixty-two patients who were not included in either high- or low-risk group were categorized as intermediate-risk group. All patients were pathologically proven to have adenocarcinoma of the prostate, and Gleason's score was determined by the chief pathologist of our study group. Written consent was obtained from all patients included in the clinical study. Patients with the following conditions were not registered in the clinical trial: having distant metastases, having synchronous primary malignancy, not histologically proven cancer, without informed consent, post-operative/post-irradiation recurrence.
All patients were treated with three field irradiations (vertical one field and horizontal opposing two fields). The prostate and proximal part of the seminal vesicle were contoured as clinical target volume (CTV), and planning target volume (PTV) was set with 5–10 mm margins around the CTV. On the way of radiotherapy, a part of irradiation field of the posterior side was cut to reduce the rectal dose. The 197 patients in the low-risk group did not undergo androgen deprivation therapy (ADT), whereas the 947 patients of intermediate- and high-risk groups underwent ADT. The patients of intermediate-risk group underwent about 6 months of neoadjuvant ADT, and the patients of high-risk group also underwent about 6 months of neoadjuvant ADT and sequential adjuvant ADT for more than 18 months. The median age of all patients was 68 years, and the median follow-up time was 48.7 months (range: 3.6–151.1 months).
The 5-year overall survival rate and biochemical relapse-free rate of the entire groups was 95.7% and 91.0%, respectively. T-stage and Gleason's score were significant prognostic factors for both the biochemical control and patient survival and initial PSA was also a predictive factor for survival. Regarding the late radiation toxicity, the incidence of rectal toxicity of grade 2 or worse was 1.1% and that of genitourinary toxicity was 6.5%. These outcomes seemed to be better than those of the past publications [ 1– 4]. In addition, the incidence of toxicity in patients treated with more hypofractionated C-ion RT of 16 fractions over 4 weeks was lower than those of 20 fraction treatment. These favorable outcomes can be thought as apparent evidence of physical and biological advantages of the hypofractionated C-ion RT.
doi:10.1093/jrr/rrt177
PMCID: PMC3941550
carbon-ion radiation therapy; prostate cancer; hypofractionation
16.  Prostate cancer mortality following active surveillance versus immediate radical prostatectomy 
Propose
Active surveillance (AS) has been endorsed for low-risk prostate cancer, but information about long-term outcomes and comparative effectiveness of AS is lacking. The purpose of this study is to project prostate cancer mortality under AS followed by radical prostatectomy (RP) versus under immediate RP.
Experimental Design
A simulation model was developed to combine information on time from diagnosis to treatment under AS and associated disease progression from a Johns Hopkins AS cohort (n=769), time from RP to recurrence from cases in the CaPSURE database with T-stage ≤ T2a (n=3,470), and time from recurrence to prostate cancer death from a T-stage ≤ T2a Johns Hopkins cohort of patients whose disease recurred after RP (n=963). Results were projected for a hypothetical cohort aged 40–90 years with low-risk prostate cancer (T-stage ≤ T2a, Gleason score ≤ 6, and PSA level ≤ 10 ng/mL).
Results
The model projected that 2.8% of men on AS and 1.6% of men with immediate RP would die of their disease in 20 years. Corresponding lifetime estimates were 3.4% for AS and 2.0% for immediate RP. The average projected increase in life expectancy associated with immediate RP was 1.8 months. On average, the model projected that men on AS would remain free of treatment for an additional 6.4 years relative to men treated immediately.
Conclusions
AS is likely to produce a very modest decline in prostate-cancer-specific survival among men diagnosed with low-risk prostate cancer but could lead to significant benefits in terms of quality of life.
doi:10.1158/1078-0432.CCR-12-1502
PMCID: PMC3604990  PMID: 23008476
Active surveillance; radical prostatectomy; prostaticneoplasms; Gleason score
17.  Outcomes of Active Surveillance for Men With Intermediate-Risk Prostate Cancer 
Journal of Clinical Oncology  2010;29(2):228-234.
Purpose
Active surveillance (AS) is an option for the initial management of early-stage prostate cancer. Current risk stratification schema identify patients with low-risk disease who are presumed to be most suitable for AS. However, some men with higher risk disease also elect AS; outcomes for such men have not been widely reported.
Patients and Methods
Men managed with AS at University of California, San Francisco, were classified as low- or intermediate-risk based on serum prostate-specific antigen (PSA), Gleason grade, extent of biopsy involvement, and T stage. Clinical and demographic characteristics, and progression in terms of Gleason score, PSA kinetics, and active treatment were compared between men with low- and intermediate-risk tumors.
Results
Compared to men with low-risk tumors, those with intermediate-risk tumors were older (mean, 64.9 v 62.3 years) with higher mean PSA values (10.9 v 5.1 ng/mL), and more tumor involvement (mean, 20.4% v 15.3% positive biopsy cores; all P < .01). Within 4 years of the first positive biopsy, the clinical risk group did not differ in terms of the proportions experiencing progression-free survival, (low [54%] v intermediate [61%]; log-rank P = .22) or the proportions who underwent active treatment (low [30%] v intermediate [35%]; log-rank P = .88). Among men undergoing surgery, none were node positive and none had biochemical recurrence within 3 years.
Conclusion
Selected men with intermediate-risk features be appropriate candidates for AS, and are not necessarily more likely to progress. AS for these men may provide an opportunity to further reduce overtreatment of disease that is unlikely to progress to advanced cancer.
doi:10.1200/JCO.2010.31.4252
PMCID: PMC3058278  PMID: 21115873
18.  Treatment of local–regional prostate cancer detected by PSA screening: benefits and harms according to prognostic factors 
British Journal of Cancer  2013;108(10):1971-1977.
Background:
Men with screen-detected prostate cancer can choose to undergo immediate curative treatment or enter into an expectant management programme. We quantified how the benefits and harms of immediate treatment vary according to the prognostic factors of clinical T-stage, Gleason score, and patient age.
Methods:
A microsimulation model based on European Randomized Study of Screening for Prostate Cancer data was used to predict the benefits and harms of immediate treatment versus delayed treatment of local–regional prostate cancer in men aged 55–74 years. Benefits included life-years gained and reduced probability of death from prostate cancer. Harms included lead time and probability of overdiagnosis.
Results:
The ratio of mean lead time to mean life-years gained ranged from 1.8 to 31.2, and the additional number of treatments required per prostate cancer death prevented ranged from 0.3 to 11.6 across the different prognostic groups. Both harm–benefit ratios were lowest, most favourable, for men aged 55–59 years and diagnosed with moderate-risk prostate cancer. Ratios were high for men aged 70–74 years regardless of clinical T-stage and Gleason score.
Conclusion:
Men aged 55–59 years with moderate-risk prostate cancer are predicted to derive greatest benefit from immediate curative treatment. Immediate treatment is least favourable for men aged 70–74 years with either low-risk or high-risk prostate cancer.
doi:10.1038/bjc.2013.198
PMCID: PMC3670486  PMID: 23674085
prostate cancer; screening; overdiagnosis; lead time; life expectancy
19.  Early results of prostate cancer radiation therapy: an analysis with emphasis on research strategies to improve treatment delivery and outcomes 
BMC Cancer  2013;13:23.
Background
There is scant data regarding disease presentation and treatment response among black men living in Africa. In this study we evaluate disease presentation and early clinical outcomes among Ghanaian men with prostate cancer treated with external beam radiotherapy (EBRT).
Methods
A total of 379 men with prostate cancer were referred to the National Center for Radiotherapy, Ghana from 2003 to 2009. Data were collected regarding patient-and tumor-related factors such as age, prostate specific antigen (PSA), Gleason score (GS), clinical stage (T), and use of androgen deprivation therapy (ADT). For patients who received EBRT, freedom from biochemical failure (FFbF) was evaluated using the Kaplan-Meier method.
Results
Of 379 patients referred for treatment 69.6% had initial PSA (iPSA) > 20 ng/ml, and median iPSA was 39.0 ng/ml. A total of 128 men, representing 33.8% of the overall cohort, were diagnosed with metastatic disease at time of referral. Among patients with at least 2 years of follow-up after EBRT treatment (n=52; median follow-up time: 38.9 months), 3- and 5-year actuarial FFbF was 73.8% and 65.1% respectively. There was significant association between higher iPSA and GS (8–10 vs. ≤7, p < 0.001), and T stage (T3/4 vs. T1/2, p < 0.001).
Conclusions
This is the largest series reporting on outcomes after prostate cancer treatment in West Africa. That one-third of patients presented with metastatic disease suggests potential need for earlier detection to permit curative-intent therapy. Data from this study will aid in the strategic development of prostate cancer research roadmap in Ghana.
doi:10.1186/1471-2407-13-23
PMCID: PMC3558339  PMID: 23324165
African men; Prostate cancer; External beam RT; Biochemical failure
20.  Clusterin as a possible predictor for biochemical recurrence of prostate cancer following radical prostatectomy with intermediate Gleason scores: a preliminary report 
Disease recurrence following radical prostatectomy is a major concern in prostate cancer patients. Gleason scores are useful in predicting recurrence. Low Gleason scores are usually associated with long disease-free intervals, while high Gleason scores are suggestive of early recurrence. However, prediction of recurrence has been difficult with intermediate Gleason scores. Clusterin is a ubiquitous secretory sulfated glycoprotein. It is also an antiapoptotic mediator in prostate cancer. The objective of the present study is to determine if clusterin can serve as a predictive biomarker for recurrence of prostate cancer with intermediate Gleason scores in patients following radical prostatectomy. Prostatic specimens with Gleason score of 6 (3 + 3) or 7 (3 + 4) were obtained from the archival bank. Three groups of specimens were investigated. The first group was from nine patients who developed recurrent disease according to a persistent rise of serum PSA within 3 years following radical prostatectomy. Those in the second group and the third group were from patients who showed no evidence of disease recurrence for at least 5 y (11 patients) and 10 y (eight patients), respectively following the surgery. Histological sections were subjected to immunohistochemical staining using a monoclonal antibody specific for clusterin. The staining intensity was scored as 0, 1, 2, and 3, with 0 being no staining, 1 showing less than 25% positive staining, 2 being 25–50% positive, and 3 showing greater than 75% positive staining. One-way ANOVA with Bonferroni correction was used for statistical analysis. Evaluation of the scores of clusterin staining was carried out according to four specific areas in each specimen. They were (a) benign epithelial cells, (b) malignant epithelial cells (cancer epithelia), (c) stromal cells surrounding benign cells, and (d) stromal cells surrounding malignant cells (cancer stroma). Staining score in prostatic epithelial cells, benign as well as malignant, showed no significant relationship among the three patient groups. However, when staining scores in stromal cells were compared, there was a significant difference between patients with recurrent disease and those showed no evidence of disease recurrence for at least 10 y. Results of this preliminary study support the important role of clusterin in the stromal component for prostate cancer progression. Clusterin immunostaining may be useful to aid the prediction of chance of disease recurrence in patients with Gleason score 6 or 7 prostate cancer following radical prostatectomy. Further studies with a large number of cases are warranted to verify this preliminary finding.
doi:10.1038/sj.pcan.4500722
PMCID: PMC1400553  PMID: 15343364
clusterin immunostaining; stromal cells; Gleason scores; PSA recurrence
21.  Association of prostate cancer risk variants with clinicopathologic characteristics of the disease 
Purpose
Fifteen independent genetic variants have been implicated in prostate cancer risk by recent genome-wide association studies. However, their association with clinicopathologic features of prostate cancer is uncertain.
Experimental Design
We systematically evaluated these 15 variants in 1,563 prostate cancer patients undergoing radical prostatectomy, taking advantage of the uniform tumor stage and grade information available for each of these cases. Associations of these variants with aggressiveness, pathologic Gleason scores, pathologic stage, age at diagnosis, or serum PSA levels were tested.
Results
After adjusting for multiple testing, none of the SNPs was individually or cumulatively associated with aggressiveness or individual clinicopathologic variables of prostate cancer such as Gleason scores, pathologic stage, or age at diagnosis of prostate cancer. The reported risk allele (G) for SNP rs2735839 in the KLK3 gene at 19q13 was more frequent in less aggressive prostate cancer patients (0.89) than in more aggressive prostate cancer patients (0.86), nominal P = 0.03, or in controls (0.86), nominal P = 0.04. Considering that this allele was also significantly associated with higher serum PSA levels among controls (nominal P = 0.003), the observed trend of higher frequency of this risk allele between less and more aggressive prostate cancer, or between less aggressive and controls may be due to detection bias of PSA screening.
Conclusions
Prostate cancer risk variants recently discovered from genome-wide case-control association studies are not associated with clinicopathologic variables in this population. Case-case studies are urgently needed in order to discover genetic variants that predict tumor aggressiveness.
doi:10.1158/1078-0432.CCR-08-0934
PMCID: PMC2810539  PMID: 18794092
association; prostate cancer; genetics; aggressiveness; Gleason score; stage; KLK3
22.  miR-19, miR-345, miR-519c-5p Serum Levels Predict Adverse Pathology in Prostate Cancer Patients Eligible for Active Surveillance 
PLoS ONE  2014;9(6):e98597.
Serum microRNAs hold great promise as easily accessible and measurable biomarkers of disease. In prostate cancer, serum miRNA signatures have been associated with the presence of disease as well as correlated with previously validated risk models. However, it is unclear whether miRNAs can provide independent prognostic information beyond current risk models. Here, we focus on a group of low-risk prostate cancer patients who were eligible for active surveillance, but chose surgery. A major criteria for the low risk category is a Gleason score of 6 or lower based on pre-surgical biopsy. However, a third of these patients are upgraded to Gleason 7 on post surgical pathological analysis. Both in a discovery and a validation cohort, we find that pre-surgical serum levels of miR-19, miR-345 and miR-519c-5p can help identify these patients independent of their pre-surgical age, PSA, stage, and percent biopsy involvement. A combination of the three miRNAs increased the area under a receiver operator characteristics curve from 0.77 to 0.94 (p<0.01). Also, when combined with the CAPRA risk model the miRNA signature significantly enhanced prediction of patients with Gleason 7 disease. In-situ hybridizations of matching tumors showed miR-19 upregulation in transformed versus normal-appearing tumor epithelial, but independent of tumor grade suggesting an alternative source for the increase in serum miR-19a/b levels or the release of pre-existing intracellular miR-19a/b upon progression. Together, these data show that serum miRNAs can predict relatively small steps in tumor progression improving the capacity to predict disease risk and, therefore, potentially drive clinical decisions in prostate cancer patients. It will be important to validate these findings in a larger multi-institutional study as well as with independent methodologies.
doi:10.1371/journal.pone.0098597
PMCID: PMC4043973  PMID: 24893170
23.  How reliable is 12-core prostate biopsy procedure in the detection of prostate cancer? 
Introduction:
Prostate biopsies incur the risk of being false-negative and this risk has not yet been evaluated for 12-core prostate biopsy. We calculated the false-negative rate of 12-core prostate biopsy and determined the patient characteristics which might affect detection rate.
Methods:
We included 90 prostate cancer patients (mean age of 64, range: 49–77) diagnosed with transrectal ultrasound guided 12-core prostate biopsy between December 2005 and April 2008. All patients underwent radical retropubic prostatectomy and the 12-core prostate biopsy procedure was repeated on surgical specimen ex-vivo. Results of preoperative and postoperative prostate biopsies were compared. We analyzed the influence of patient age, prostate weight, serum prostate-specific antigen (PSA) level, free/total PSA ratio, PSA density and Gleason score on detection rate.
Results:
In 67.8% of patients, prostate cancer was detected with repeated ex-vivo biopsies using the same mapping postoperatively. We found an increase in PSA level, PSA density and biopsy Gleason score; patient age, decreases in prostate weight and free/total PSA ratio yielded higher detection rates. All cores, except the left-lateral cores, showed mild-moderate or moderate internal consistency. Preoperative in-vivo biopsy Gleason scores remained the same, decreased and increased in 43.3%, 8.9% and 47.8% of patients, respectively, on final specimen pathology.
Conclusions:
The detection rate of prostate cancer with 12-core biopsy in patients (all of whom had prostate cancer) was considerably low. Effectively, repeat biopsies can still be negative despite the patient’s reality of having prostate cancer. The detection rate is higher if 12-core biopsies are repeated in younger patients, patients with high PSA levels, PSA density and Gleason scores, in addition in patients with smaller prostates, lower free/total PSA ratios.
doi:10.5489/cuaj.11224
PMCID: PMC3668408  PMID: 22398204
24.  Prostate gland biopsies and prostatectomies: an Ontario community hospital experience 
Objective
Transrectal ultrasound–guided core biopsies of the prostate gland and prostatectomies have become common procedures at many community hospitals in Canada, especially in the era of serum prostate-specific antigen (PSA) screening for prostate cancer. The Gleason grading of prostate cancer in biopsies and prostatectomies is a major determinant used for treatment planning. There is evidence in the literature that suggests important discordance between community hospital pathologists and urological pathologists with respect to the Gleason grading of prostate cancer. Our objective was to determine the diagnostic rates and Gleason scoring patterns for prostate gland biopsies and prostatectomies at our institution compared with the literature.
Methods
We conducted a retrospective review of all prostate gland biopsies and prostatectomies performed at the Grey Bruce Health Services from January 2005 to September 2005. We collected data from 194 biopsies and 44 prostatectomies. We obtained prebiopsy serum PSA levels and digital rectal exam results for all patients from urologists’ office records.
Results
The average age for men having biopsies was 65.8 (standard deviation [SD] 8.6) years, and the average prebiopsy serum PSA level was 8.7 (median 7.1, SD 6.2) μg/L. The rates of diagnosis from prostate gland biopsies of benign (17.6%), high-grade prostatic intraepithelial neoplasia (11.0%), atypical small acinar proliferation suspicious for invasive malignancy (13.2%) and invasive prostatic adenocarcinoma (58.2%) at our institution were significantly different than those reported in the literature (p < 0.001). We observed a significant variation in the rates of these diagnoses among the community hospital pathologists in our study (p = 0.004). There was a strong correlation between the increasing number of positive core biopsy sites and increasing Gleason scores in biopsies (p < 0.001). There was also a strong correlation between increasing pre-biopsy serum PSA levels and increasing Gleason scores in biopsies (p < 0.001). A substantial proportion (21.9%) of the biopsies given the Gleason score of 6 had a Gleason score of 7 in the prostatectomy specimen.
Conclusion
Our results showed a significant difference in prostate gland biopsy categorical diagnoses compared with the literature. There were also significant differences in categorical diagnoses of prostate gland biopsies among the community hospital pathologists in our study. The data identify a strong positive correlation between the increasing number of positive core biopsy sites and increasing Gleason scores in biopsies, as well as a strong positive correlation between increasing prebiopsy serum PSA levels and increasing Gleason scores in biopsies that revealed cancer. We would encourage other community hospital pathologists, in collaboration with their urologists, to review periodically their prostate gland pathology practices in an attempt to improve the uniformity of diagnoses.
PMCID: PMC2572237  PMID: 18953449
25.  Mortality results from the Göteborg Randomised Prostate Cancer Screening Trial 
The lancet oncology  2010;11(8):725-732.
Summary
Background
Prostate cancer is one of the leading causes of death from malignant disease among men in the Western world. One strategy to decrease the risk of dying from this disease is screening with Prostate-Specific Antigen (PSA); however, the extent of benefit and harm with such screening is under continuous debate.
Methods
In December 1994, 20 000 men born 1930 to 1944, randomly sampled from the Population Register, were computer randomised in a 1:1 ratio to a screening group invited for biennial PSA testing or to a control group not invited. In each arm, 48 men were excluded from analysis due to either death or emigration before randomization date or prevalent prostate cancer. The primary endpoint was prostate cancer specific mortality analyzed according to the intention-to-screen principle. Men in the screening group were invited up to the upper age limit (median 69, range 67–71 years) and only men with elevated PSA were offered additional tests such as digital rectal examination and prostate biopsies. The study is still ongoing inviting men who have not yet reached the upper age limit. This is the first planned report on cumulative prostate cancer incidence and mortality calculated up to Dec 31 2008. This study is registered [as an International Standard Randomised Controlled Trial], number [ISRCTN49127736].
Findings
Among men randomised to screening 7578/9952 (76%) attended at least once (attendees). During a median follow-up of 14 years, 1138 men in the screening group and 718 in the control group were diagnosed with prostate cancer resulting in a cumulative incidence of prostate cancer of 12.7% in the screening arm and 8.2% in the control arm (hazard ratio 1.64; 95% confidence interval [CI] 1.50–1.80; p<0.0001). The absolute cumulative risk reduction of death from prostate cancer at 14 years was 0.40% (95% CI 0.17–0.64%), from 0.90% in the control group to 0.50% in the screening group. The incidence rate ratio for death from prostate cancer was 0.56 (95% CI 0.39–0.82; p=0.002) in the screening compared to the control group. The incidence rate ratio of attendees compared to the control group was 0.44 (95% CI 0.28–0.68; p=0.0002). Overall, 293 men needed to be invited for screening and 12 to be diagnosed to prevent one prostate cancer death.
Interpretation
The benefit of prostate cancer screening compares favourably to other cancer screening programs and in this study prostate cancer mortality was reduced almost by half over 14 years. However, the risk of over diagnosis is substantial and the number needed to treat is at least as high as in breast cancer screening.
Funding
The Swedish Cancer Society, the Swedish Research Council and the National Cancer Institute.
doi:10.1016/S1470-2045(10)70146-7
PMCID: PMC4089887  PMID: 20598634

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