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1.  Molecular sampling of prostate cancer: a dilemma for predicting disease progression 
Background
Current prostate cancer prognostic models are based on pre-treatment prostate specific antigen (PSA) levels, biopsy Gleason score, and clinical staging but in practice are inadequate to accurately predict disease progression. Hence, we sought to develop a molecular panel for prostate cancer progression by reasoning that molecular profiles might further improve current clinical models.
Methods
We analyzed a Swedish Watchful Waiting cohort with up to 30 years of clinical follow up using a novel method for gene expression profiling. This cDNA-mediated annealing, selection, ligation, and extension (DASL) method enabled the use of formalin-fixed paraffin-embedded transurethral resection of prostate (TURP) samples taken at the time of the initial diagnosis. We determined the expression profiles of 6100 genes for 281 men divided in two extreme groups: men who died of prostate cancer and men who survived more than 10 years without metastases (lethals and indolents, respectively). Several statistical and machine learning models using clinical and molecular features were evaluated for their ability to distinguish lethal from indolent cases.
Results
Surprisingly, none of the predictive models using molecular profiles significantly improved over models using clinical variables only. Additional computational analysis confirmed that molecular heterogeneity within both the lethal and indolent classes is widespread in prostate cancer as compared to other types of tumors.
Conclusions
The determination of the molecularly dominant tumor nodule may be limited by sampling at time of initial diagnosis, may not be present at time of initial diagnosis, or may occur as the disease progresses making the development of molecular biomarkers for prostate cancer progression challenging.
doi:10.1186/1755-8794-3-8
PMCID: PMC2855514  PMID: 20233430
2.  Radical Prostatectomy or Watchful Waiting in Early Prostate Cancer 
The New England journal of medicine  2014;370(10):932-942.
BACKGROUND
Radical prostatectomy reduces mortality among men with localized prostate cancer; however, important questions regarding long-term benefit remain.
METHODS
Between 1989 and 1999, we randomly assigned 695 men with early prostate cancer to watchful waiting or radical prostatectomy and followed them through the end of 2012. The primary end points in the Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4) were death from any cause, death from prostate cancer, and the risk of metastases. Secondary end points included the initiation of androgen-deprivation therapy.
RESULTS
During 23.2 years of follow-up, 200 of 347 men in the surgery group and 247 of the 348 men in the watchful-waiting group died. Of the deaths, 63 in the surgery group and 99 in the watchful-waiting group were due to prostate cancer; the relative risk was 0.56 (95% confidence interval [CI], 0.41 to 0.77; P = 0.001), and the absolute difference was 11.0 percentage points (95% CI, 4.5 to 17.5). The number needed to treat to prevent one death was 8. One man died after surgery in the radical-prostatectomy group. Androgen-deprivation therapy was used in fewer patients who underwent prostatectomy (a difference of 25.0 percentage points; 95% CI, 17.7 to 32.3). The benefit of surgery with respect to death from prostate cancer was largest in men younger than 65 years of age (relative risk, 0.45) and in those with intermediate-risk prostate cancer (relative risk, 0.38). However, radical pros-tatectomy was associated with a reduced risk of metastases among older men (relative risk, 0.68; P = 0.04).
CONCLUSIONS
Extended follow-up confirmed a substantial reduction in mortality after radical prostatectomy; the number needed to treat to prevent one death continued to decrease when the treatment was modified according to age at diagnosis and tumor risk. A large proportion of long-term survivors in the watchful-waiting group have not required any palliative treatment. (Funded by the Swedish Cancer Society and others.)
doi:10.1056/NEJMoa1311593
PMCID: PMC4118145  PMID: 24597866
3.  Eosinophils in the blood of hematopoietic stem cell transplanted patients are activated and have different molecular marker profiles in acute and chronic graft-versus-host disease 
While increased numbers of eosinophils may be detected in patients with graft-versus-host disease (GVHD) following hematopoietic stem cell transplantation, it is not known if eosinophils play a role in GVHD. The aims of this study were to determine: whether eosinophils are activated during GVHD; whether the patterns of activation are similar in acute and chronic GVHD; and the ways in which systemic corticosteroids affect eosinophils. Transplanted patients (n = 35) were investigated for eosinophil numbers and the expression levels of 16 eosinophilic cell surface markers using flow cytometry; all the eosinophil data were analyzed by the multivariate method OPLS-DA. Different patterns of molecule expression were observed on the eosinophils from patients with acute, chronic, and no GVHD, respectively. The molecules that provided the best discrimination between acute and chronic GVHD were: the activation marker CD9; adhesion molecules CD11c and CD18; chemokine receptor CCR3; and prostaglandin receptor CRTH2. Patients with acute or chronic GVHD who received systemic corticosteroid treatment showed down-regulation of the cell surface markers on their eosinophils, whereas corticosteroid treatment had no effect on the eosinophil phenotype in the patients without GVHD. In summary, eosinophils are activated in GVHD, display different activation profiles in acute and chronic GVHD, and are highly responsive to systemic corticosteroids.
doi:10.1002/iid3.25
PMCID: PMC4217552  PMID: 25400930
Corticosteroids; eosinophils; flow cytometry; graft-versus-host disease; hematopoietic stem cell transplantation
4.  Increasing use of radical prostatectomy for non-lethal prostate cancer in Sweden 
Purpose
The number of patients in Sweden treated with radical prostatectomy for localized prostate cancer has increased exponentially. The extent to which this increase reflects treatment of non-lethal disease detected through PSA screening is unknown.
Experimental design
We undertook a nationwide study of all 18,837 prostate cancer patients treated with radical prostatectomy in Sweden from 1988 to 2008 with complete follow-up through 2009. We compared cumulative incidence curves, fit Cox regression and cure models and performed a simulation study to determine changes in treatment of non-lethal cancer, in cancer-specific survival over time, and effect of lead-time due to PSA screening.
Results
The annual number of radical prostatectomies increased 25-fold during the study period. The five-year cancer-specific mortality decreased from 3.9% (95% CI 2.5 to 5.3) among patients diagnosed between 1988 and 1992 to 0.7% (95% CI 0.4–1.1) among those diagnosed between 1998 and 2002 (p for trend < 0.001). According to the cure model, the risk of not being cured declined by 13% (95% CI 12–14%) with each calendar year. The simulation study indicated that only about half of the improvement in disease-specific survival could be accounted for by lead-time.
Conclusion
Patients overdiagnosed with non-lethal prostate cancer appear to account for a substantial and growing part of the dramatic increase in radical prostatectomies in Sweden but increasing survival rates are likely also due to true reductions in the risk of disease-specific death over time. Because the magnitude of harm and costs due to overtreatment can be considerable, identification of men who likely benefit from radical prostatectomy is urgently needed.
doi:10.1158/1078-0432.CCR-12-1537
PMCID: PMC3711175  PMID: 22927485
Overdiagnosis; prostate cancer; PSA screening; radical prostatectomy
5.  Results From the Scandinavian Prostate Cancer Group Trial Number 4: A Randomized Controlled Trial of Radical Prostatectomy Versus Watchful Waiting 
In the Scandinavian Prostate Cancer Group Trial Number 4 (SPCG-4), 347 men were randomly assigned to radical prostatectomy and 348 to watchful waiting. In the most recent analysis (median follow-up time = 12.8 years), the cumulative mortality curves had been stable over the follow-up. At 15 years, the absolute risk reduction of dying from prostate cancer was 6.1% following randomization to radical prostatectomy, compared with watchful waiting. Hence, 17 need to be randomized to operation to avert one death. Data on self-reported symptoms, stress from symptoms, and quality of life were collected at 4 and 12.2 years of median follow-up. These questionnaire studies show an intricate pattern of symptoms evolving after surgery, hormonal treatments, signs of tumor progression, and also from natural aging. This article discusses some of the main findings of the SPCG-4 study.
doi:10.1093/jncimonographs/lgs025
PMCID: PMC3540876  PMID: 23271778
6.  Individualized Estimation of the Benefit of Radical Prostatectomy from the Scandinavian Prostate Cancer Group Randomized Trial 
European Urology  2012;62(2):204-209.
Background
Although there is randomized evidence that radical prostatectomy improves survival, there are few data on how benefit varies by baseline risk.
Objective
We aimed to create a statistical model to calculate the decrease in risk of death associated with surgery for an individual patient, using stage, grade, prostate-specific antigen, and age as predictors.
Design, setting, and participants
A total of 695 men with T1 or T2 prostate cancer participated in the Scandinavian Prostate Cancer Group 4 trial (SPCG-4).
Intervention
Patients in SPCG-4 were randomized to radical prostatectomy or conservative management.
Outcome measurements and statistical analysis
Competing risk models were created separately for the radical prostatectomy and the watchful waiting group, with the difference between model predictions constituting the estimated benefit for an individual patient.
Results and limitations
Individualized predictions of surgery benefit varied widely depending on age and tumor characteristics. At 65 yr of age, the absolute 10-yr risk reduction in prostate cancer mortality attributable to radical prostatectomy ranged from 4.5% to 17.2% for low- versus high-risk patients. Little expected benefit was associated with surgery much beyond age 70. Only about a quarter of men had an individualized benefit within even 50% of the mean. A limitation is that estimates from SPCG-4 have to be applied cautiously to contemporary patients.
Conclusions
Our model suggests that it is hard to justify surgery in patients with Gleason 6, T1 disease or in those patients much above 70 yr of age. Conversely, surgery seems unequivocally of benefit for patients who have Gleason 8, or Gleason 7, stage T2. For patients with Gleason 6 T2 and Gleason 7 T1, treatment is more of a judgment call, depending on patient preference and other clinical findings, such as the number of positive biopsy cores and comorbidities.
doi:10.1016/j.eururo.2012.04.024
PMCID: PMC3389180  PMID: 22541389
Prostatic neoplasms; Statistics and research design; Randomized controlled trial; Prostatectomy
7.  mRNA Expression Signature of Gleason Grade Predicts Lethal Prostate Cancer 
Journal of Clinical Oncology  2011;29(17):2391-2396.
Purpose
Prostate-specific antigen screening has led to enormous overtreatment of prostate cancer because of the inability to distinguish potentially lethal disease at diagnosis. We reasoned that by identifying an mRNA signature of Gleason grade, the best predictor of prognosis, we could improve prediction of lethal disease among men with moderate Gleason 7 tumors, the most common grade, and the most indeterminate in terms of prognosis.
Patients and Methods
Using the complementary DNA–mediated annealing, selection, extension, and ligation assay, we measured the mRNA expression of 6,100 genes in prostate tumor tissue in the Swedish Watchful Waiting cohort (n = 358) and Physicians' Health Study (PHS; n = 109). We developed an mRNA signature of Gleason grade comparing individuals with Gleason ≤ 6 to those with Gleason ≥ 8 tumors and applied the model among patients with Gleason 7 to discriminate lethal cases.
Results
We built a 157-gene signature using the Swedish data that predicted Gleason with low misclassification (area under the curve [AUC] = 0.91); when this signature was tested in the PHS, the discriminatory ability remained high (AUC = 0.94). In men with Gleason 7 tumors, who were excluded from the model building, the signature significantly improved the prediction of lethal disease beyond knowing whether the Gleason score was 4 + 3 or 3 + 4 (P = .006).
Conclusion
Our expression signature and the genes identified may improve our understanding of the de-differentiation process of prostate tumors. Additionally, the signature may have clinical applications among men with Gleason 7, by further estimating their risk of lethal prostate cancer and thereby guiding therapy decisions to improve outcomes and reduce overtreatment.
doi:10.1200/JCO.2010.32.6421
PMCID: PMC3107753  PMID: 21537050
8.  Evidence for two independent prostate cancer risk associated loci in the HNF1B gene at 17q12 
Nature genetics  2008;40(10):1153-1155.
A fine mapping study in the HNF1B gene at 17q12 among two study populations revealed a second prostate cancer locus, ~26 kb centromeric to the first known locus (rs4430796); these are separated by a recombination hotspot. A SNP in the second locus (rs11649743) was confirmed in five additional populations, and P=1.7×10−9 for an allelic test in the seven combined studies. The association at each SNP remains significant after adjusting for the other SNP.
doi:10.1038/ng.214
PMCID: PMC3188432  PMID: 18758462
9.  Genetic Variants and Family History predict Prostate Cancer similar to PSA 
Purpose
While PSA is the best biomarker for predicting prostate cancer, its predictive performance needs to be improved. Results from the Prostate Cancer Prevention Trial (PCPT) revealed the overall performance measured by the areas under curve (AUC) of the receiver operating characteristic (ROC) at 0.68. The goal of the present study is to assess the ability of genetic variants as a PSA independent method to predict prostate cancer risk.
Experimental Design
We systematically evaluated all prostate cancer risk variants that were identified from genome-wide association studies during the past year in a large population-based prostate cancer case-control study population in Sweden, including 2,893 prostate cancer patients and 1,781 men without prostate cancer.
Results
Twelve SNPs were independently associated with prostate cancer risk in this Swedish study population. Using a cutoff of any 11 risk alleles or family history, the sensitivity and specificity for predicting prostate cancer were 0.25 and 0.86, respectively. The overall predictive performance of prostate cancer using genetic variants, family history, and age, measured by AUC was 0.65 (95% CI: 0.63–0.66), significantly improved over that of family history and age (0.61%, 95% CI: 0.59–0.62), P = 2.3 × 10−10.
Conclusion
The predictive performance for prostate cancer using genetic variants and family history is similar to that of PSA. The utility of genetic testing, alone and in combination with PSA levels, should be evaluated in large studies such as the European Randomized Study for Prostate Cancer trial and PCPT.
doi:10.1158/1078-0432.CCR-08-1743
PMCID: PMC3187807  PMID: 19188186
prostate cancer; prediction; PSA; association
10.  Homogeneous Prostate Cancer Mortality in the Nordic Countries Over Four Decades 
European urology  2010;58(3):427-432.
Background
Incidence of prostate cancer (PCa) has greatly increased in the Nordic region over the past two decades, following the advent of prostate-specific antigen (PSA) screening. Consequently, interpreting temporal trends in PCa has become difficult, and the impact of changes in exposure to causal factors is uncertain.
Objective
To reveal geographic differences and temporal trends in PCa in the Nordic countries. Because the recorded incidence of PCa has been profoundly influenced by PSA screening, we focused our analyses primarily on PCa mortality.
Design, setting, and participants
We analyzed national PCa incidence and mortality data from Denmark, Finland, Norway, and Sweden from 1965 to 2006 using the PC-NORDCAN software program and the online NORDCAN database.
Measurements
Cumulative incidence and cumulative mortality from PCa were calculated for selected calendar years during four decades, along with age-standardized mortality rates. Incidence data in NORDCAN come from individual countries’ cancer registries, and mortality data come from national mortality registries.
Results and limitations
From 1965 to 2006, 172 613 deaths from PCa were reported in the four Nordic countries. A substantial rise in incidence was observed across the region, with some geographic variation, since the late 1980s. In contrast, both disease-specific mortality rates and cumulative risk of PCa mortality lacked consistent temporal trends over the same period. Cumulative risk of PCa mortality ranged between 3.5% and 7.5% in the region over four decades, whereas cumulative incidence jumped from about 9% to >20%. Mortality has remained fairly constant among the countries, with a minimally lower risk in Finland.
Conclusions
Unlike most malignancies, the occurrence of lethal PCa showed minimal geographic variation and lacked consistent temporal trends over four decades. These findings may guide our search for important causes of PCa, a malignancy with etiology that is still largely unknown.
doi:10.1016/j.eururo.2010.05.040
PMCID: PMC2936655  PMID: 20541313
Cancer trends; Mortality; Nordic region; Prostate cancer
11.  Estrogen-dependent signaling in a molecularly distinct subclass of aggressive prostate cancer 
Background
The majority of prostate cancers harbor gene fusions of the 5′-untranslated region of the androgen-regulated transmembrane protease, serine 2 (TMPRSS2) promoter with erythroblast transformation specific (ETS) transcription factor family members. The common v-ets erythroblastosis virus E26 oncogene homolog [avian] (TMPRSS2–ERG) fusion is associated with a more aggressive clinical phenotype, implying the existence of a distinct subclass of prostate cancer defined by this fusion.
Methods
We used cDNA-mediated annealing, selection, ligation, and extension to determine the expression profiles of 6144 transcriptionally informative genes in archived biopsy samples from 455 prostate cancer patients in the Swedish Watchful Waiting cohort (1987–1999) and the US-based Physicians Health Study cohort (1983–2003). A gene expression signature for prostate cancers with the TMPRSS2-ERG fusion was determined using partitioning and classification models and used in computational functional analysis. Cell proliferation and TMPRSS2-ERG expression in androgen receptor–negative (NCI-H660) and –positive (VCaP-ERβ) prostate cancer cells after treatment with vehicle or estrogenic compounds were assessed by viability assays and quantitative polymerase chain reaction, respectively. All statistical tests were two-sided.
Results
We identified an 87-gene expression signature that distinguishes TMPRSS2-ERG fusion prostate cancer as a discrete molecular entity (area under the curve = 0.80, 95% confidence interval [CI] = 0.792 to 0.81; P<.001). Computational analysis suggested that this fusion signature was associated with estrogen receptor (ER) signaling. Viability of NCI-H660 cells decreased after treatment with estrogen (viability normalized to day 0, estrogen vs vehicle at day 8, mean = 2.04 vs 3.40, difference = 1.36, 95% CI = 1.12 to 1.62) or ERβ agonist (ERβ agonist vs vehicle at day 8, mean = 1.86 vs 3.40, difference = 1.54, 95% CI = 1.39 to 1.69) but increased after ERα agonist treatment (ERα agonist vs vehicle at day 8, mean = 4.36 vs 3.40, difference = 0.96, 95% CI = 0.68 to 1.23). Similarly, expression of TMPRSS2-ERG decreased after ERβ agonist treatment (fold change over internal control, ERβ agonist vs vehicle at 24 hours, NCI H660, mean = 0.57-fold vs 1.0-fold, difference = 0.43, 95% CI = 0.29-fold to 0.57-fold) and increased after ERα agonist treatment (ERα agonist vs vehicle at 24 hours, mean = 5.63-fold vs 1.0-fold, difference = 4.63-fold, 95% CI = 4.34-fold to 4.92-fold).
Conclusions
TMPRSS2-ERG fusion prostate cancer is a distinct molecular subclass. TMPRSS2-ERG expression is regulated by a novel ER-dependent mechanism.
doi:10.1093/jnci/djn150
PMCID: PMC3073404  PMID: 18505969
12.  Estimation of Absolute Risk for Prostate Cancer using Genetic Markers and Family History 
The Prostate  2009;69(14):1565-1572.
Background
Multiple DNA sequence variants in the form of single nucleotide polymorphisms (SNPs) have been found to be reproducibly associated with prostate cancer (PCa) risk.
Methods
Absolute risk for PCa among men with various numbers of inherited risk alleles and family history of PCa was estimated in a population-based case-control study in Sweden (2,893 cases and 1,781 controls), and a nested case-control study from the Prostate, Lung, Colon and Ovarian (PLCO) Cancer Screening Trial in the U.S (1,172 cases and 1,157 controls).
Results
Increased number of risk alleles and positive family history were independently associated with PCa risk. Considering men with 11 risk alleles (mode) and negative family history as having baseline risk, men who had ≥ 14 risk alleles and positive family history had an Odds Ratio (OR) of 4.92 [95% confidence interval (CI): 3.64-6.64] in the Swedish study. These associations were confirmed in the U.S. population. Once a man's SNP genotypes and family history are known, his absolute risk for PCa can be readily calculated and easily interpreted. For example, 55 year old men with a family history and ≥ 14 risk alleles have a 52% and 41% risk of being diagnosed with PCa in the next 20 years in the Swedish and U.S. populations, respectively. In comparison, without knowledge of genotype and family history, these men had an average population absolute risk of 13%.
Conclusion
This risk prediction model may be used to identify men at considerably elevated PCa risk who may be selected for chemoprevention.
doi:10.1002/pros.21002
PMCID: PMC2793526  PMID: 19562736
SNPs; association; early detection; chemoprevention
13.  Outcomes in Localized Prostate Cancer: National Prostate Cancer Register of Sweden Follow-up Study 
Background
Treatment for localized prostate cancer remains controversial. To our knowledge, there are no outcome studies from contemporary population-based cohorts that include data on stage, Gleason score, and serum levels of prostate-specific antigen (PSA).
Methods
In the National Prostate Cancer Register of Sweden Follow-up Study, a nationwide cohort, we identified 6849 patients aged 70 years or younger. Inclusion criteria were diagnosis with local clinical stage T1–2 prostate cancer from January 1, 1997, through December 31, 2002, a Gleason score of 7 or less, a serum PSA level of less than 20 ng/mL, and treatment with surveillance (including active surveillance and watchful waiting, n = 2021) or curative intent (including radical prostatectomy, n = 3399, and radiation therapy, n = 1429). Among the 6849 patients, 2686 had low-risk prostate cancer (ie, clinical stage T1, Gleason score 2-6, and serum PSA level of <10 ng/mL). The study cohort was linked to the Cause of Death Register, and cumulative incidence of death from prostate cancer and competing causes was calculated.
Results
For the combination of low- and intermediate-risk prostate cancers, calculated cumulative 10-year prostate cancer–specific mortality was 3.6% (95% confidence interval [CI] = 2.7% to 4.8%) in the surveillance group and 2.7% (95% CI = 2.1% to 3.45) in the curative intent group. For those with low-risk disease, the corresponding values were 2.4% (95% CI = 1.2% to 4.1%) among the 1085 patients in the surveillance group and 0.7% (95% CI = 0.3% to 1.4%) among the 1601 patients in the curative intent group. The 10-year risk of dying from competing causes was 19.2% (95% CI = 17.2% to 21.3%) in the surveillance group and 10.2% (95% CI = 9.0% to 11.4%) in the curative intent group.
Conclusion
A 10-year prostate cancer–specific mortality of 2.4% among patients with low-risk prostate cancer in the surveillance group indicates that surveillance may be a suitable treatment option for many patients with low-risk disease.
doi:10.1093/jnci/djq154
PMCID: PMC2897875  PMID: 20562373
14.  Two independent prostate cancer risk associated loci at 11q13 
SNPs at 11q13 were recently implicated in prostate cancer risk by two genome-wide association studies and were consistently replicated in multiple study populations. To explore prostate cancer association in the regions flanking these SNPs, we genotyped 31 tagging SNPs in a ~110 kb region at 11q13 in a Swedish case-control study (CAPS), including 2,899 cases and 1,722 controls. We found evidence of prostate cancer association for the previously implicated SNPs including rs10896449, which we termed locus 1. In addition, multiple SNPs on the centromeric side of the region, including rs12418451, were also significantly associated with prostate cancer risk (termed locus 2). The two groups of SNPs were separated by a recombination hotspot. We then evaluated these two representative SNPs in an additional ~4,000 cases and ~3,000 controls from three study populations and confirmed both loci at 11q13. In the combined allelic test of all four populations, P = 4.0 × 10−11 for rs10896449 at locus 1, and P = 1.2 × 10−6 for rs12418451 at locus 2, and both remained significant after adjusting for the other locus and study population. The prostate cancer association at these two 11q13 loci was unlikely confounded by PSA detection bias because neither SNP was associated with PSA levels in controls. Unlike locus 1 where no known gene is located, several putative mRNAs are in close proximity to locus 2. Additional confirmation studies at locus 2 and functional studies for both loci are needed to advance our knowledge on the etiology of prostate cancer.
doi:10.1158/1055-9965.EPI-08-0983
PMCID: PMC2802212  PMID: 19505914
Prostate cancer; genetic; association; 11q13; fine mapping
15.  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
16.  Radical Prostatectomy Versus Watchful Waiting in Localized Prostate Cancer: the Scandinavian Prostate Cancer Group-4 Randomized Trial 
Background
The benefit of radical prostatectomy in patients with early prostate cancer has been assessed in only one randomized trial. In 2005, we reported that radical prostatectomy improved prostate cancer survival compared with watchful waiting after a median of 8.2 years of follow-up. We now report results after 3 more years of follow-up.
Methods
From October 1, 1989, through February 28, 1999, 695 men with clinically localized prostate cancer were randomly assigned to radical prostatectomy (n = 347) or watchful waiting (n = 348). Follow-up was complete through December 31, 2006, with histopathologic review and blinded evaluation of causes of death. Relative risks (RRs) were estimated using the Cox proportional hazards model. Statistical tests were two-sided.
Results
During a median of 10.8 years of follow-up (range = 3 weeks to 17.2 years), 137 men in the surgery group and 156 in the watchful waiting group died (P = .09). For 47 of the 347 men (13.5%) who were randomly assigned to surgery and 68 of the 348 men (19.5%) who were not, death was due to prostate cancer. The difference in cumulative incidence of death due to prostate cancer remained stable after about 10 years of follow-up. At 12 years, 12.5% of the surgery group and 17.9% of the watchful waiting group had died of prostate cancer (difference = 5.4%, 95% confidence interval [CI] = 0.2 to 11.1%), for a relative risk of 0.65 (95% CI = 0.45 to 0.94; P = .03). The difference in cumulative incidence of distant metastases did not increase beyond 10 years of follow-up. At 12 years, 19.3% of men in the surgery group and 26% of men in the watchful waiting group had been diagnosed with distant metastases (difference = 6.7%, 95% CI = 0.2 to 13.2%), for a relative risk of 0.65 (95% CI = 0.47 to 0.88; P = .006). Among men who underwent radical prostatectomy, those with extracapsular tumor growth had 14 times the risk of prostate cancer death as those without it (RR = 14.2, 95% CI = 3.3 to 61.8; P < .001).
Conclusion
Radical prostatectomy reduces prostate cancer mortality and risk of metastases with little or no further increase in benefit 10 or more years after surgery.
doi:10.1093/jnci/djn255
PMCID: PMC2518167  PMID: 18695132
17.  Testing a Multigene Signature of Prostate Cancer Death in the Swedish Watchful Waiting Cohort 
While prostate cancer is a leading cause of cancer death, most men die with and not from their disease, underscoring the urgency to distinguish potentially lethal from indolent prostate cancer. We tested the prognostic value of a previously identified multigene signature of prostate cancer progression to predict cancer-specific death. The Örebro Watchful Waiting Cohort included 172 men with localized prostate cancer of whom 40 died of prostate cancer. We quantified protein expression of the markers in tumor tissue by immunohistochemistry, and stratified the cohort by quintiles according to risk classification. We accounted for clinical parameters (age, Gleason, nuclear grade, tumor volume) using Cox regression, and calculated Receiver Operator Curves to compare discriminatory ability. The hazard ratio of prostate cancer death increased with increasing risk classification by the multigene model, with a 16-fold greater risk comparing highest versus lowest risk strata, and predicted outcome independent of clinical factors (p=0.002). The best discrimination came from combining information from the multigene markers and clinical data, which perfectly classified the lowest risk stratum where no one developed lethal disease; using the two lowest risk groups as referent, the hazard ratio (95% confidence interval) was 11.3 (4.0–32.8) for the highest risk group and difference in mortality at 15 years was 60% (50–70%). The combined model provided greater discriminatory ability (AUC 0.78) than the clinical model alone (AUC 0.71), p=0.04. Molecular tumor markers can add to clinical parameters to help distinguish lethal and indolent prostate cancer, and hold promise to guide treatment decisions.
doi:10.1158/1055-9965.EPI-08-0044
PMCID: PMC2536630  PMID: 18583469

Results 1-17 (17)