Genetic epidemiologic aspects of gastric cancer in Iceland

BACKGROUND: Association between gastric cancer and environmental factors (diet and infections) has been established, and genetic changes are well described in adenocarcinomas of the stomach. Less is known about clinical features of hereditary gastric cancer and whether the disease is associated with family clustering. STUDY DESIGN: Family trees of patients diagnosed with gastric cancer in Iceland between 1955 and 1999 were identified in the Genealogical Database of the University of Iceland. All probands with age of onset younger than 60 years were used in the study. Families of all probands (n = 455 men and 161 women) were traced to third degree. Through linkage of the genealogic data obtained by the Icelandic Cancer Registry (between 1955 and 1999), all reported cancers were identified in those families. The expected number of cases was calculated using age-specific population rates in Iceland. RESULTS: A relative risk (RR) of 2.2 (95% confidence interval [CI] = 1.6-3.0) and 1.3 (95% CI = 1.0-1.7) for the gastric cancer risk was observed among 2,846 first- and 8,658 second-degree relatives of male probands. For female probands the corresponding relative risks were 1.6 (95% CI = 1.1-2.6, n = 7,396) and 1.4 (95% CI = 0.9-2.0, n = 2,764). The increased risk was more pronounced for relatives of men and women diagnosed with gastric cancer before the age of 50 years. A minor difference in relative risk was found between relatives of probands who were diagnosed with intestinal type or diffuse type gastric cancer. Fifty-eight families with two or more relatives with cancer were identified. In 32 families 2 relatives with gastric cancer were identified and in 26 families 3 or more relatives had gastric cancer. CONCLUSIONS: Relatives of gastric cancer patients have two- to three-fold increased risk of developing gastric cancer. The risk is elevated for both genders.     

Familial prostate and breast cancer in men treated with prostatectomy for prostate cancer: a population based case-control study

PURPOSE: We assessed familial prostate and breast cancer in Quebec. MATERIALS AND METHODS: Using a self-administered mail survey we assessed the prevalence of prostate and breast cancer in first degree relatives of 1,633 men treated with prostatectomy for prostate cancer in the province of Quebec and in first degree relatives of 1,386 spouse controls. RESULTS: The OR of familial breast cancer was 1.1 (95% CI 0.9 to 1.4). The OR of 3.0 (95% CI 2.5 to 3.6) recorded for prostate cancer was modified by francophone versus anglophone linguistic preference (OR 3.2, 95% CI 2.6, 3.9 versus 1.5, 95% CI 0.8 to 2.7, p = 0.02). Male sibship size was a statistically significant parameter modifying this association (p = 0.02), namely no brothers (OR 1.7, 95% CI 1.0 to 2.8), 1 or 2 (OR 3.1, 95% CI 2.2 to 4.3) and 3 or more (OR 3.9, 95% CI 2.9 to 5.2). Geographic regions of the province including and neighboring greater Montreal showed a lower OR than more peripheral regions (2.5, 95% CI 2.0 to 3.2 versus 4.1, 95% CI 2.9 to 5.7, p = 0.02). CONCLUSIONS: Francophone men with large male sibships residing in remote areas may be at higher risk for familial prostate cancer and represent the ideal target for further efforts to determine the genetic component of prostate cancer in Quebec.     

Familiality of cardiovascular mortality in end-stage renal disease patients

A very high rate of cardiovascular (CV) death is well recognized in individuals with end-stage renal disease (ESRD). Besides many other factors, this excess risk may also be related to familiality. We tested this hypothesis by estimating the risk of CV death among both ESRD patients and their relatives. In this case-control study, we used the Utah Population Database (UPDB), which includes genealogy records, state-wide death certificates as well as other data sets. These have been linked to the University of Utah Health Sciences Enterprise Data Warehouse which provides multiple diagnosis data sources. Patients with ESRD either on dialysis or who received a kidney transplant were identified in the clinical databases at the University of Utah Dialysis Program and Kidney Transplant Program or from Utah death certificates. CV deaths were identified by the reporting on the death certificates. The relative risks for CV death, adjusted for several potential confounders in the ESRD patients (n = 516) and in their first-degree (n = 2,418) and second-degree (n = 7,720) relatives were estimated in relation to the general population. Using information from death certificates, ESRD patients were found to have disproportionately increased risk for CV mortality (relative risk or RR = 2.4; 95% CI 2.11-2.72), compared to the general population. First-degree relatives of ESRD patients were also found to have an increased CV mortality risk (RR = 1.10; 95% CI 1.01-1.20). When the specific categories of CVD were analyzed, the first-degree relatives also had higher risks for death from acute myocardial infarction (RR = 1.20; 95% CI 1.03-1.40) or heart failure (RR = 1.32; 95% CI 1.12-1.56). An increased risk for CV mortality was, however, not observed in second-degree relatives of ESRD patients, except for the subcategory of hypertensive heart disease (RR = 1.24, 95% CI 1.01-1.49). In conclusion, this study suggests that, in addition to many putative risk factors, the increased risk of CV death in ESRD patients may have a familial contribution.     

A systematic review and meta-analysis of familial prostate cancer risk

OBJECTIVE: To identify published studies quantifying familial prostate cancer risks in relatives of prostate cancer cases and, by meta-analysis, obtain more precise estimates of familial risk according to the family history. METHODS: Thirteen case-control and cohort studies were identified which have reported risks of prostate cancer in relatives of prostate cancer cases. Pooled estimates of risk for various categories of family history were obtained by calculating the weighted average of the log relative risk (RR) estimates from studies. RESULTS: The pooled RR (95% confidence interval) in first-degree relatives was 2.5 (2.2-2.8). There was evidence that this was highest in relatives of cases diagnosed before age 60 years and that RRs declined with age. The risk for the few men with two affected relatives was increased 3.5-fold (2.6-4.8). RRs to sons of cases appeared to be lower than in brothers; a complete explanation of this observation is uncertain. CONCLUSION: Men with a family history of prostate cancer have a significantly greater risk of developing prostate cancer than those with no such history. Risks are greatest for relatives of cases diagnosed when young and those with more than one relative affected.     

Body size, age at shaving initiation, and prostate cancer in a large, multiracial cohort

BACKGROUND: The purpose of this study was to examine the potential relationship between body size, self-reported age at initiation of shaving, and subsequent risk of prostate cancer in a large, racially diverse cohort of men followed for up to 32 years. METHODS: The study population included 70,712 male subscribers to the Kaiser Permanente Medical Care Program who had received a multiphasic health checkup between 1964-1973. This general health checkup consisted of a number of laboratory tests and physical measurements, as well as a self-completed health questionnaire that included a request for men to record the age when they began shaving. Subjects were followed for the development of prostate cancer, using the local tumor registry. Cox regression was used to estimate relative risks (RR) and 95% confidence intervals (CI). RESULTS: Altogether, 2, 079 men in the study cohort were diagnosed with prostate cancer. There was a very strong positive association between prostate cancer risk and birth cohort. After adjusting for race, age, and birth year, there was no association between height, weight, body mass index, or several other anthropometric measures and prostate cancer risk in the full cohort. There was a suggestion of a very weak positive association between height and prostate cancer risk among white men. There also was no overall association between age at shaving initiation and prostate cancer risk, although nonwhite men who started shaving at a young age (相似文献   

Effect of alpha1-adrenoceptor antagonist exposure on prostate cancer incidence: an observational cohort study

PURPOSE: The quinazoline based alpha1-adrenoceptor antagonists doxazosin and terazosin suppress prostate tumor growth via the induction of apoptosis and decrease in tissue vascularity. To assess the effect of alpha1-blocker exposure on the incidence of prostate cancer we performed an exploratory, observational cohort study. MATERIALS AND METHODS: The medical records of all male patients enrolled at Lexington Veterans Affairs Medical Center were searched to identify men treated with quinazoline based alpha1-adrenoreceptor antagonists between January 1, 1998 and December 31, 2002 for hypertension and/or benign prostatic enlargement. Medical records were subsequently linked to the Markey Cancer Center Kentucky Cancer Registry, a statewide population based central cancer registry that is part of the National Cancer Institute Surveillance, Epidemiology and End Results Program, to identify all incident prostate cancer cases diagnosed. All newly diagnosed prostate cancer cases unexposed to alpha1-adrenoreceptor antagonists in the total male Veterans Affairs population during this period were also identified from the Kentucky Cancer Registry database. Measures of disease incidence, relative risk and attributable risk were calculated to compare the risk of prostate cancer in alpha1-blocker exposed vs unexposed men. Kaplan-Meier curves and Cox regression models were used to compare overall survival between alpha1-blocker exposed and unexposed prostate cancer cases. RESULTS: Our analysis revealed a cumulative incidence of 1.65% in alpha1-blocker exposed men compared to 2.41% in the unexposed group. These data yielded an unadjusted RR of 0.683 (95% CI 0.532, 0.876) and a risk difference of -0.0076, indicating that 7.6 fewer prostate cancer cases developed per 1,000 exposed men. Thus, exposure to quinazoline alpha1-blockers may have prevented 32 prostate cancer cases among the 4,070 treated men during the study period. Therefore, men exposed to quinazoline alpha1-adrenoceptor antagonists were at 1.46 times lower RR and 31.7% lower attributable risk for prostate cancer than unexposed men. There was no association between alpha1-adrenoceptor antagonist exposure and overall survival. CONCLUSIONS: These data suggest that exposure to quinazoline based alpha1-adrenoceptor antagonists significantly decreases the incidence of prostate cancer. This evidence suggests that the apoptotic and anti-angiogenic effects of these drugs may prevent the development of prostate cancer.     

Breast cancer as a second primary in patients with prostate cancer--estrogen treatment or association with family history of cancer?

PURPOSE: In a large population based study we reported an increased risk of male breast cancer after prostate cancer. In the current study we performed a comprehensive investigation of whether treatment for prostate cancer and/or family history is responsible for the excess risk. MATERIALS AND METHODS: This study had 2 parts. 1) We performed a nested case-control study in 41 men who had previously been identified with first prostate cancer, followed by male breast cancer and in 81 matched controls with prostate cancer only. The medical records of these men were retrieved and clinical data such as stage, grade and treatment were extracted. 2) We also performed a family study including relatives of men with a diagnosis of prostate as well as breast cancer, irrespective of which was first. The 878 relatives were identified through parish offices and linked to the Swedish Cancer Registry to evaluate the occurrence of breast, prostate and other cancers and calculate if there were any excess risks for different cancers. RESULTS: Cases with prostate plus breast cancer received estrogen treatment more often than controls with prostate cancer only (p = 0.03). The period of estrogen treatment was longer in the cases, although it was not statistically significant. Mean time from prostate cancer diagnosis to breast cancer diagnosis was 47.6 months. Cases and controls did not differ in grade or stage. In the family study an increased risk of prostate cancer was found in relatives (SIR 2.14, 95% CI 1.09 to 3.18). For other cancers no significantly increased risks were found. In 2 families pedigree analysis using the BRCAPRO program (http://www3.utsouthwestern.edu/cancergene/) revealed an estimated 100% and 49% probability in families 1 and 2, respectively, that the proband was a BRCA2 carrier. CONCLUSIONS: Our data suggest that most of the increased risk of breast cancer following prostate cancer can be explained by estrogen treatment. However, in a small number of men with prostate as well as breast cancer pedigree analysis suggests that BRCA2 mutation might be the underlying cause.     

The effect of hypertension on the risk for kidney cancer in Korean men

BACKGROUND: The role of hypertension as a kidney cancer risk factor remains unclear. The objectives of this study were to prospectively examine the effects of hypertension on kidney cancer death, and to determine the synergistic effect of hypertension and smoking on kidney cancer risk. METHODS: The cohort was composed of 576,562 Korean men, aged 30 and older, who received health insurance from the National Health Insurance Corporation, and who underwent biennial medical evaluations in 1992 and 1994. At baseline, 343,132 men (59.5%) were identified as current cigarette smokers. Between 1995 and 2001, there were 92 deaths from kidney cancer (2.2/100,000 person years). Using deaths from kidney cancer as the main outcome variable, Cox proportional hazards models were tested while controlling for age and other covariates. RESULTS: An initial finding indicated that hypertension increased the mortality risk of kidney cancer [relative risk (RR) 2.43; 95% confidence interval (CI) 1.57-3.76]. After stratification of smoking status, RR for hypertension on kidney cancer was still increased for current smokers (RR 2.80; 95% CI 1.64-4.79). For current smokers, those with systolic blood pressure >/=160 mm Hg had a risk of kidney cancer that was 8.18 (95% CI, 3.13-21.36) times higher than those with a pressure less than 120 mm Hg. When the interaction term was included in the multivariate model, there was no significant synergistic effect of hypertension with current smoking on the risk of death from kidney cancer. CONCLUSION: This study supports the hypothesis that hypertension is an independent risk factor of kidney cancer mortality.     

Finasteride decreases the risk of prostatic intraepithelial neoplasia

PURPOSE: High grade prostatic intraepithelial neoplasia is likely a premalignant lesion of the prostate. Decreasing the frequency of high grade PIN may decrease the risk of prostate cancer. In the Prostate Cancer Prevention Trial we evaluated the impact of finasteride on the risk of a needle biopsy diagnosis of high grade prostatic intraepithelial neoplasia. MATERIALS AND METHODS: The Prostate Cancer Prevention Trial was a randomized, placebo controlled clinical trial that enrolled 18,882 men without evidence of prostate cancer, prostate specific antigen less than 3.0 ng/ml and normal digital rectal examination, and randomized them to 5 mg finasteride daily or placebo. Subjects were followed for 7 years with biopsy recommended for prostate specific antigen greater than 4.0 ng/ml, adjusted in the finasteride group to achieve an equal number of biopsy recommendations or for abnormal digital rectal examination. All cancer-free subjects were recommended to undergo biopsy after 7 years on study. We evaluated the diagnosis of high grade prostatic intraepithelial neoplasia with or without concomitant prostate cancer in these 2 study groups. RESULTS: The number of men evaluable for high grade prostatic intraepithelial neoplasia was 4,568 in the finasteride group and 4,886 in the placebo group. High grade prostatic intraepithelial neoplasia alone was diagnosed in 276 men (6.0%) in the finasteride group vs 347 (7.1%) in the placebo group (RR 0.85, 95% CI 0.73-0.99, p=0.04). High grade prostatic intraepithelial neoplasia accompanied by prostate cancer was diagnosed in 144 men (3.2%) in the finasteride group vs 223 (4.6%) in the placebo group (RR 0.69, 95% CI 0.56-0.85, p=0.0004). Finasteride significantly decreased the overall risk of high grade prostatic intraepithelial neoplasia (alone and with cancer) from 570 cases (11.7%) in the placebo group to 420 (9.2%) in the finasteride group (HR 0.79, 95% CI 0.70-0.89, p<0.001). CONCLUSIONS: Finasteride significantly decreased the risk of high grade PIN. This observation may explain how finasteride decreased prostate cancer in the Prostate Cancer Prevention Trial, supporting the notion that high grade prostatic intraepithelial neoplasia is a premalignant lesion of the prostate, and it provides new information relevant to the consideration of finasteride for prostate cancer prevention.     

Familial Transitional Cell Carcinoma Among the Population of Iceland

PurposeSeveral case reports have described familial aggregation of transitional cell carcinoma of the urinary tract but to our knowledge only 1 epidemiological study specifically addressed the issue of familial bladder cancer. We evaluated the extent of familial aggregation of transitional cell carcinoma among the population of Iceland.Materials and MethodsThe first to third degree relatives of 190 patients with bladder, ureter or renal pelvis transitional cell carcinoma diagnosed between 1983 and 1992 in Iceland were identified through the Icelandic Cancer Family Resource. The records of these 12,328 relatives were subsequently linked to the 1965 to 1994 cancer registry. The observed occurrence of transitional cell carcinoma of the urinary tract was compared to the expected occurrence based on age, gender and calendar specific incidence rates. Observed-to-expected ratios and 95% confidence intervals were calculated.ResultsIn 41 of the 190 pedigrees at least 1 relative had transitional cell carcinoma of the urinary tract. Of the probands 38 had only 1 and 3 had 2 affected relatives. The prevalence of family history of transitional cell carcinoma was 3% in first degree and 10% in first or second degree relatives. The risk of transitional cell carcinoma among all relatives was slightly elevated (observed-to-expected ratio 1.24, 95% confidence interval 0.90 to 1.67). The observed-to-expected ratio was greater among second and third degree relatives than among first degree relatives.ConclusionsThe risk of transitional cell carcinoma among relatives of patients is somewhat increased. However, the greater risk for more distant relatives argues against the existence of a hereditary subtype of bladder transitional cell carcinoma, at least in the founder population of Iceland.     

Late fetal death in offspring and subsequent incidence of prostate cancer in fathers: the Jerusalem Perinatal Study cohort

BACKGROUND: Little is known of the causes of prostate cancer and few previous studies have investigated men's reproductive histories in relation to this disease. We sought to determine whether risk of prostate cancer was altered in men who had fathered stillborn offspring. METHODS: We studied the incidence of prostate cancer (N = 252) in a cohort of 15,268 fathers followed for 28-41 years from the birth of a live offspring, whose wives participated in one of two separate surveys of outcomes of previous births. Proportional hazards models were used to estimate relative risks (RR) associated with previous stillbirths, controlling for changes in incidence over time, social and occupational factors. RESULTS: The 543 men with one or more stillborn offspring experienced an increased risk of prostate cancer (adjusted RR = 1.87, 95% confidence interval = 1.17-3.00, P = 0.0095), compared to men without stillbirths. With one reported stillbirth, the RR was 1.68 (0.99-2.84); with two or more, the RR was 3.29 (1.22-8.88). Results were consistent in men whose wives were interviewed in 1965-1968 and 1974-1976. In 100 fathers with no male offspring and at least one stillbirth the RR was 4.04 (1.87-8.71, P = 0.0004). CONCLUSIONS: These findings should be considered hypothesis-generating and require confirmation in other studies. They suggest that stillbirth and prostate cancer may have shared environmental causes; alternatively, genetic susceptibility to prostate cancer might increase the risk of a stillbirth in offspring.     

N-acetyltransferase-2 gene polymorphism as a possible biomarker for prostate cancer in Japanese men

BACKGROUND: The purpose of this study was to determine the frequency of a polymorphism of the candidate metabolic enzyme N-acetyltransferase-2 (NAT2) in Japanese prostate cancer patients and Japanese non-cancer controls, in order to determine if an association exists between NAT2 genotype and the occurrence, clinical stage and grade of prostate cancer. METHODS: In the present case-control study, 111 patients with prostate cancer and 152 controls were genotyped for the NAT2 polymorphism using the polymerase chain reaction-based restriction fragment length polymorphism method. The NAT2 genotypes (slow or rapid acetylator genotype) were determined by the combination of three known NAT2 mutant alleles (M1, M2, M3) and the wild-type allele. RESULTS: The NAT2 slow acetylator genotype was statistically higher among prostate cancer patients (17.1%) compared with controls (8.6%) (Odds ration (OR) = 2.21; 95% confidence interval (CI), 1.04-4.69; P = 0.0289). In addition, there was a statistically increased risk of prostate cancer among smokers with the NAT2 slow genotype (OR = 3.78: 95% CI, 1.48-9.66; P = 0.0041). Furthermore, the NAT2 slow acetylator genotype was significantly higher among prostate cancer patients with locally advanced and metastatic disease (22.7%) compared with controls (8.6%) (OR = 3.14; 95% CI, 1.40-7.06; P = 0.0051). Lastly, the NAT2 slow acetylator genotype was significantly higher among prostate cancer patients with high-grade tumors (31.4%) compared with controls (8.6%) (OR = 4.90; 95% CI, 1.97-12.20; P = 0.0010). CONCLUSION: These data demonstrate that the NAT2 slow acetylator genotype plays an important role in determining the risk of developing prostate cancer in Japanese men and is also associated with more clinically advanced and pathologically aggressive disease. Furthermore, a possible interaction between the NAT2 slow acetylator genotype and smoking status was suggested.     

Bladder cancer incidence and risk factors in men with prostate cancer: results from Cancer of the Prostate Strategic Urologic Research Endeavor

PURPOSE: We evaluated a large disease registry to determine the incidence of bladder cancer in patients with prostate cancer and investigate whether the type of treatment for prostate cancer increased the risk of bladder cancer. MATERIALS AND METHODS: We analyzed the CaPSURE disease registry for men diagnosed with prostate cancer plus bladder cancer between 1989 and 2003. Demographics, comorbidities and prostate cancer treatment modalities were compared in patients with and without bladder cancer. A backward stepwise Cox proportional hazards regression model was used to predict bladder cancer onset after treatment for prostate cancer in patients who had bladder cancer 30 days or greater after prostate cancer treatment. RESULTS: Of 9,780 patients from CaPSURE 143 (1.46%) also had bladder cancer. Patients with bladder cancer and prostate cancer were older (p<0.01) and more likely to be white (p=0.03), and they had lower levels of income (p<0.01) and education (p=0.04) than patients with prostate cancer only. Comorbidities did not differ between patients with and without bladder cancer. Patients treated with radical prostatectomy were approximately half as likely to have posttreatment bladder cancer as patients who underwent radiation therapy (HR 0.51, 95% CI 0.29-0.89). Patients who smoked had an independent increase in the risk of bladder cancer (HR 2.08, 95% CI 1.09-3.97), while smokers treated with radiation therapy were at almost 4-fold risk for bladder cancer (HR 3.65, 95% CI 1.45-9.16). CONCLUSIONS: The incidence of bladder cancer in patients with prostate cancer was 1.5%. Radiation therapy and smoking increased the risk of bladder cancer.     

A prospective study of risk factors for erectile dysfunction

PURPOSE: We examined the impact of obesity, physical activity, alcohol use and smoking on the development of erectile dysfunction. MATERIALS AND METHODS: Subjects included 22,086 United States men 40 to 75 years old in the Health Professionals Followup Study cohort who were asked to rate their erectile function for multiple periods on a questionnaire mailed in 2000. Men who reported good or very good erectile function and no major chronic disease before 1986 were included in the analyses. RESULTS: Of men who were healthy and had good or very good erectile function before 1986, 17.7% reported incident erectile dysfunction during the 14-year followup. Obesity (multivariate relative risk 1.9, 95% CI 1.6-2.2 compared to men of ideal weight in 1986) and smoking (RR 1.5, 95% CI 1.3-1.7) in 1986 were associated with an increased risk of erectile dysfunction, while physical activity (RR 0.7, 95% CI 0.7-0.8 comparing highest to lowest quintile of physical activity) was associated with a decreased risk of erectile dysfunction. For men in whom prostate cancer developed during followup, smoking (RR 1.4, 95% CI 1.0-1.9) was the only lifestyle factor associated with erectile dysfunction. CONCLUSIONS: Reducing the risk of erectile dysfunction may be a useful and to this point unexploited motivation for men to engage in health promoting behaviors. We found that obesity and smoking were positively associated, and physical activity was inversely associated with the risk of erectile dysfunction developing.     

Association between attributed cause of end-stage renal disease and risk of death in Brazilian patients receiving renal replacement therapy

BACKGROUND: Studies conducted in several countries have indicated that the survival of patients undergoing renal replacement therapy (RRT) depends on the attributed cause of end-stage renal disease (ESRD). OBJECTIVES: This study was conducted to evaluate the association between attributed cause of ESRD and mortality risk in RRT patients in Brazil. METHODS: We analyzed 88,881 patients from the Brazilian Ministry of Health Registry who were undergoing RRT between April 1997 and July 2000. Cox proportional hazards models were used to estimate the relative risk (RR) of death in patients with ESRD secondary to diabetes mellitus (DM), polycystic kidney disease (PKD), and primary glomerulopathies (GN) compared with a reference group comprised of patients with ESRD caused by hypertensive nephropathy. Patient's age, gender, and length of time (years) in RRT before inclusion in the registry (vintage) were included in the adjusted Cox model. RESULTS: Compared with the reference group, the mortality risk was 27% lower in patients with PKD (RR=0.73, 95% CI: 0.65-0.83, p<0.0001); 29% lower in patients with GN (RR=0.71, 95% CI: 0.68-0.74, p<0.0001); and 100% greater in DM patients (RR=2.00, 95% CI: 1.92-2.10, p<0.0001). These relative risks remained statistically significant after adjustment for age, gender, and length of time in RRT before inclusion in the registry. CONCLUSIONS: Our data indicate that compared with the patients with hypertensive nephrosclerosis as attributed cause of ESRD, patients undergoing RRT in Brazil with idiopathic glomerulopathy and polycystic kidney disease have a lower risk of mortality, and patients with diabetes mellitus have a greater risk of mortality.     

Prostate cancer at the peripheral end of a prostate biopsy specimen as assessed by a novel marking technique may indicate increased risk of locally advanced disease

The objective of this study was to test a novel technique of processing a prostate biopsy (PB) specimen by marking its peripheral end (PE) as a predictive tool for locally advanced prostate cancer (PC) or margin-positive resection (R1) after radical prostatectomy (RP). Prospective evaluation of a consecutive cohort of men who underwent PB and subsequent RP was carried out. Transrectal ultrasound-guided 10-20 core PB was performed according to a standardized protocol. Each biopsy core was inked at the PE and classified as PE positive or negative. The study cohort comprised 100 men with a mean age of 62.3 years (41-75 years). Overall, PE-positive cores were found in 71 men, postoperative tumour (pT)3/pT4 stages were diagnosed in 33 men and R1 status in 45 men after RP. In univariate analysis, the presence of at least one PE-positive core was correlated to an increased risk for pT3/pT4 stage (relative risk (RR): 3.15; 95% confidence interval (95% CI): 1.1-9.9; P = 0.03) and R1 status (RR: 2.9; 95% CI: 1.1-7.5; P = 0.03). In multivariate analysis including Gleason score, total number of positive cores, PE positivity and PSA, PE positivity was correlated to pT3/pT4 stage (P = 0.04). In conclusion, PC at the PE of a PB specimen predicts non-organ-confined tumour stage in subsequent prostatectomy. This simple, new technique may contribute to increasing the accuracy of risk stratification for curative treatment of PC.     

Low-activity V89L variant in SRD5A2 is associated with aggressive prostate cancer risk: an explanation for the adverse effects observed in chemoprevention trials using 5-alpha-reductase inhibitors

OBJECTIVE: The 5-alpha-reductase type 2 (5A2) enzyme catalyses the irreversible conversion of testosterone to dihydrotestosterone, the most active androgen in the prostate. This key enzyme in prostate gland physiopathology has recently been targeted by using inhibitors for chemoprevention of prostate cancer. However, some controversies have arisen by the observation of greater than expected high-grade tumours in men diagnosed with prostate cancer in the finasteride chemoprevention trial. To help understand the impact of prolonged exposure to low 5A2 activity on prostate cancer risk, we analysed the rather common genetic V89L polymorphism, which has previously been well characterised functionally for determining low enzymatic activities. METHODS: The study was performed on 1605 white Caucasian French men categorised in 803 patients with prostate adenocarcinoma and 802 matched healthy male controls. The different alleles and genotypes were analysed according to case-control status and the aggressiveness pattern of the tumours. RESULTS: The V89L amino acid substitution leading to the homozygous genotype LL increased the risk of clinically significant disease (odds ratio [OR]=1.89, 95% confidence interval (%95 CI), 1.07-2.74; p=0.0017) and was also associated with the most aggressive patterns of the disease (OR=2.56, 95%CI, 1.41-4.63; p=0.002). CONCLUSIONS: Our data confirm in a large and homogeneous Caucasian French population that the low-activity V89L variant is associated with an increased risk of aggressive prostate cancer. These results corroborate that long-term exposure to 5A2 inhibitors (chemoprevention) must be evaluated in terms of risk of prostate cancer adverse effects.     

High dose zinc increases hospital admissions due to genitourinary complications

PURPOSE: Zinc is a common dietary supplement that is widely believed to have beneficial health effects. To assess the impact of high dose supplemental zinc on genitourinary diseases we analyzed a recent randomized trial comparing zinc, antioxidants and their combination to placebo for complications related to the genitourinary tract. MATERIALS AND METHODS: In a further analysis of the recent Age-related Eye Disease Study we examined the data pool for primary International Classification of Diseases, 9th revision codes given for hospital admissions related to urological problems. The Age-Related Eye Disease Study randomized 3,640 patients with age related macular degeneration to 1 of 4 study arms, including placebo, antioxidants (500 mg vitamin C, 400 IU vitamin E and 15 mg beta-carotene), 80 mg zinc and antioxidant plus zinc. Statistical analyses using Fisher's exact test were performed. RESULTS: We found a significant increase in hospital admissions due to genitourinary causes in patients on zinc vs nonzinc formulations (11.1% vs 7.6%, p = 0.0003). The risk was greatest in male patients (RR 1.26, 95% CI 1.07-1.50, p = 0.008). In the study group of 343 patients requiring hospital admission the most common primary International Classification of Diseases, 9th revision codes included benign prostatic hyperplasia/urinary retention (benign prostatic hyperplasia), urinary tract infection, urinary lithiasis and renal failure. When comparing zinc to placebo, significant increases in urinary tract infections were found (p = 0.004), especially in females (2.3% vs 0.4%, RR 5.77, 95% CI 1.30-25.66, p = 0.013). Admissions for urinary lithiasis approached significance in men on zinc compared to placebo (2.0% vs 0.5%, RR = 4.08, 95% CI 0.87-19.10). There was no increase in prostate or other cancers with zinc supplementation. A significant decrease in prostate cancer diagnoses was seen in patients receiving antioxidants vs placebo (RR = 0.6, 95% CI 0.49-0.86, p = 0.049). Subgroup analysis revealed that this finding was significant in men who smoked but not in nonsmokers. CONCLUSIONS: Zinc supplementation at high levels results in increased hospitalizations for urinary complications compared to placebo. These data support the hypothesis that high dose zinc supplementation has a negative effect on select aspects of urinary physiology.     

Variants in circadian genes and prostate cancer risk: a population-based study in China

Circadian genes influence a variety of biological processes that are important in prostate tumorigenesis including metabolism. To determine if variants in circadian genes alter prostate cancer risk, we genotyped five variants in five circadian genes in a population-based case-control study conducted in China (187 cases and 242 controls). These variants included CRY2 rs1401417:G>C, CSNK1E rs1005473:A>C, NPAS2 rs2305160:G>A, PER1 rs2585405:G>C and PER3 54-bp repeat length variant. Men with the cryptochrome 2 (CRY2)-variant C allele had a significant 1.7-fold increased prostate cancer risk (95% confidence interval (CI), 1.1-2.7) relative to those with the GG genotype. This risk increased to 4.1-fold (95% CI, 2.2-8.0) in men who also had greater insulin resistance (IR) as compared to men with the GG genotype and less IR. In contrast, among men with less IR, the NPAS2-variant A allele was associated with decreased prostate cancer risk (odds ratio=0.5, 95% CI, 0.3-1.0) as compared to the GG genotype. Our findings, although in need of confirmation, suggest that variations in circadian genes may alter prostate cancer risk and some biological processes may modify this effect.