Components of the metabolic syndrome-risk factors for the development of benign prostatic hyperplasia

The purpose of the present study was to perform a BPH risk factor analysis in men, relating the prostate gland volume to components of the metabolic syndrome and to identify clues to the etiology of BPH. Our material comprised a consecutive series of 158 patients with lower urinary tract symptoms with or without manifestations of the metabolic syndrome. In this group, the measured volume of the prostate was related consecutively to potential risk factors. The diagnoses atherosclerosis, non-insulin-dependent diabetes mellitus (NIDDM) and treated hypertension were obtained from the patient's medical history. Data on blood pressure, waist and hip measure, body height and weight were collected and body mass index (BMI) and waist/hip ratio (WHR) were calculated. Blood samples were drawn from fasting patients to determine insulin, cholesterol, triglycerides, HDL and LDL-cholesterol, uric acid and ALAT. The prostate gland volume was determined using ultrasound. Our results show that there was a larger prostate gland in men with NIDDM (P=0.0058), treated hypertension (P=0.0317), obesity (P<0.0001), low HDL-cholesterol levels (P=0.0132) and high insulin levels (P<0.0001) than in men without these conditions. The prostate gland volume correlated positively with the systolic blood pressure (r(s)=0.17; P=0.03), obesity (r(s)=0.34; P<0.0001) and fasting insulin (r(s)=0.38; P<0.0001) and negatively with HDL-cholesterol (r(s)=-0.22; P=0.009). On the basis of our findings, we concluded that NIDDM, treated hypertension, obesity, low HDL-cholesterol levels and high insulin levels constitute risk factors for the development of BPH. The results suggest that BPH is a facet of the metabolic syndrome and that BPH patients may share the same metabolic abnormality of a defective insulin-mediated glucose uptake and secondary hyperinsulinemia as patients with the metabolic syndrome. The findings generate a hypothesis of a causal relationship between high insulin levels and the development of BPH. In a clinical setting, the findings of the present report suggest that, in any patient presenting with BPH, the possible presence of NIDDM, hypertension, obesity, high insulin and low HDL-cholesterol levels should be considered. Conversely, in patients suffering from these conditions, the possibility of a clinically important BPH should be kept in mind.     

Hyperinsulinaemia as a risk factor for developing benign prostatic hyperplasia

OBJECTIVE: To determine the validity coefficient of the total prostate gland volume as an expression of the transition zone (TZ) volume. To test the hypothesis of hyperinsulinaemia as a causal factor for the development of benign prostatic hyperplasia (BPH). PATIENTS AND METHODS: Three hundred and seven consecutive patients with lower urinary tract symptoms were studied. A subgroup of 114 patients were tested with regard to the validity coefficient between the total prostate gland volume and the TZ volume. In the total material of 307 men, a BPH risk factor analysis was performed in which groups of men with the following conditions were related to the annual BPH growth rate: men without or with metabolic disease; men with different components of the metabolic syndrome, and men with low or high fasting plasma insulin values. The prostate gland volume and the TZ volume were determined using ultrasound. The presence of non-insulin-dependent diabetes mellitus (NIDDM) and treated hypertension was obtained from the patients' medical records. Data on blood pressure, waist and hip measurement, body height and weight were collected and body mass index and waist/hip ratio were calculated. Blood samples were drawn from fasting patients to determine the insulin and HDL-cholesterol values. RESULTS: In the subgroup of men subjected to measurement of both the total prostate gland volume and the TZ volume, the correlation coefficient between total prostate gland volume and the TZ volume was r.s. = 0.97 (p < 0.0001) which, thus, constituted the validity coefficient. The median annual BPH growth rate in the total group was 1.03 ml/year. The median annual BPH growth rate was faster in men with metabolic disease (p < 0.0001), NIDDM (p < 0.0001), treated hypertension (p < 0.0001), obesity (p < 0.0001) and dyslipidaemia (p < 0.0001) than in men without metabolic disease. Moreover, the annual BPH growth rate correlated positively with the diastolic blood pressure (r.s. = 0.27; p < 0.001), the BMI (r.s. = 0.22; p < 0.001) and four other expressions of obesity, and negatively with the HDL-cholesterol level (r.s. = -0.15; p < 0.001). The median annual BPH growth rate was faster in men with a high than in men with a low fasting plasma insulin level (p = 0.019). When the patients were divided into quartiles, the median annual BPH growth rate increased statistically significantly with increasing fasting plasma insulin levels. The fasting plasma insulin values correlated with the annual BPH growth rates (p = 0.009). When performing a multivariate analysis using the total prostate gland volume as dependent variable, fasting plasma insulin (p = 0.001) and age (p < 0.001) became statistically significant. CONCLUSION: The results of the present report suggest that the total prostate gland volume constitutes a valid expression of BPH. The findings support the hypothesis that hyperinsulinaemia is causally related to the development of BPH and generate the hypothesis of an increased sympathetic nerve activity in men with BPH.     

High serum prostate-specific antigen levels in the absence of prostate cancer in Middle-Eastern men: the clinician's dilemma

OBJECTIVE: To investigate the common causes of total serum prostate-specific antigen (PSA) values of> 10 ng/mL in an Arab population, as in the USA and Europe the risk of prostate cancer is considered high in men with such PSA levels. PATIENTS AND METHODS: Serum total PSA was measured in men presenting to our hospital as part of the investigation for prostate cancer screening and/or in elderly men with prostatism. Men with a serum PSA level of> 10 ng/mL were further investigated by transrectal ultrasonography (TRUS) of the prostate and biopsy of suspicious lesions for histological diagnosis. In addition, the percentage of free PSA, PSA velocity and PSA density were determined. All the patients included in this study were men of Arab origin residing in Kuwait. RESULTS: In all, 1700 men (mean age 55.6 years, range 35-94) were assessed; of these, 161 had a serum PSA of> 10 ng/mL, attributable to benign prostatic hyperplasia (BPH) in 110 (68%), BPH with histological features of prostatitis in 33 (21%) and prostate cancer in 18 (11%). TRUS of the prostate in 143 of the 161 men with either BPH or BPH with prostatitis showed varying grades of intraprostatic calcifications in 22 (15%). Both PSA density and percentage free PSA did not contribute to determining the causes of total PSA levels of> 10 ng/mL. There was a progressive decline in PSA in all patients with BPH and prostatitis, except one who at re-biopsy had prostate cancer (T1N0M0, G1). CONCLUSION: Total PSA values of> 10 ng/mL in Arab men may be a result of BPH, BPH with prostatitis or prostate cancer, in that order. A gradual decline in total PSA (decreased PSA velocity) with time to < 4 ng/mL often confirms the diagnosis of BPH with prostatitis. The percentage of free PSA and PSA density may not be helpful in diagnosing prostate cancer with certainty in these patients. Compared with Caucasians in the USA and Europe, BPH and BPH with prostatitis appear to be more frequent causes of serum PSA levels of> 10 ng/mL in Arab men.     

Serum keratinocyte growth factor measurement in patients with prostate cancer

PURPOSE: Keratinocyte growth factor (KGF) is a stromally derived growth factor important in mediating androgen induced activities in benign prostatic hyperplasia (BPH) and prostate cancer. We assessed whether serum KGF could be used as a molecular marker in patients with prostate cancer. MATERIALS AND METHODS: Using a modified double sandwich enzyme-linked immunosorbent assay, we measured serum KGF in 56 men with prostate cancer and 81 men with BPH. Comparative analyses were made with total serum prostate specific antigen (PSA), disease stage and clinical grade. RESULTS: Following optimization, a sensitive and reproducible assay for serum KGF measurement was developed. Serum KGF levels tend to be higher in men with BPH compared to those with prostate cancer (1,242 and 828 pg./ml., respectively). A weak but significant linear relationship between PSA and KGF (p = 0.034) was found in patients with BPH. There was no association between KGF and tumor grade or stage but there was a strong positive linear relationship between PSA and KGF (p = 0.006, R(2) = 68.3%) in low grade tumors. In those men with serum PSA less than 10 ng./ml. KGF levels were significantly higher in BPH compared to prostate cancer cases (965 +/- 245 and 133 +/- 61.3 pg./ml., respectively, p = 0.0058). Using a KGF threshold range of 500 to 900 pg./ml., specificity for detecting BPH was 88% to 100% and the positive predictive value was 92% to 100%. CONCLUSIONS: We have optimized a reproducible and sensitive enzyme-linked immunosorbent assay system for the measurement of serum KGF. Overall KGF levels tend to be lower in patients with prostate cancer than with BPH. In patients with serum PSA less than 10 ng./ml. serum KGF levels were significantly higher in the BPH compared to the prostate cancer group. A large prospective study is indicated to assess the role of serum KGF measurement in patients with prostate cancer.     

Urinary PSA: a potential useful marker when serum PSA is between 2.5 ng/mL and 10 ng/mL

Introduction

Our objective was to evaluate the usefulness of urinary prostate specific antigen (PSA) in the differential diagnosis of benign prostatic hyperplasia (BPH) and prostate cancer.

Methods

We undertook a prospective study and obtained informed consent from 170 men. They provided blood samples to measure serum PSA and 50 mL of first-voided urine to measure urinary PSA. Seventy-seven men were diagnosed with BPH; 42 patients had newly diagnosed prostate cancer; and 51 were selected as age-matched control subjects. Data were analyzed using Wilcoxon signed rank tests, receiver operating characteristic (ROC) curves and logistic regression.

Results

Prostate volume was 35 cm³ and 45 cm³ (p < 0.05), serum PSA was 9.7 ng/mL and 4.5 ng/mL (p < 0.001) and PSA density was 0.28 and 0.11 (p < 0.01) for prostate cancer and BPH patients, respectively. Overall, urinary PSA was not significantly different, but PSA ratio (urinary:serum) was significantly different at 6.7 and 30.6 (p < 0.001) for prostate cancer and BPH patients, respectively. A subgroup with serum PSA between 2.5 ng/mL and 10.0 ng/mL was selected and urinary PSA was significant: 52.6 ng/mL (n = 29) and 123.2 ng/mL (n = 35) (p < 0.05) for prostate cancer and BPH patients, respectively. PSA ratios were also significant (p = 0.007). ROC curves identified a cutoff for urinary PSA at > 150 ng/mL, with a sensitivity of 92.5%. When comparing prostate cancer patients with age-matched control subjects, serum PSA, urinary PSA and PSA ratio were different (p = 0.004).

Conclusion

Our study supports urinary PSA as a useful marker in the differential diagnosis of prostate cancer and BPH, especially when serum PSA is between 2.5 ng/mL and 10 ng/mL. Low urinary PSA and PSA ratios point toward prostate cancer. A urinary PSA threshold of > 150 ng/mL may be used to decrease the number of prostatic biopsies.     

Discrimination of men with prostate cancer from those with benign disease by measurements of human glandular kallikrein 2 (HK2) in serum

PURPOSE: To investigate the clinical value of measuring human glandular kallikrein 2 (hK2) compared with free and total prostate specific antigen (PSA-F and PSA-T) in serum from patients with prostate disease. MATERIALS AND METHODS: Serum from healthy controls, from men with benign prostate hyperplasia (BPH), clinically localized prostate cancer (PCa), and advanced PCa were analyzed for hK2 (using an in-house-research assay with detection limit of 0.05 ng./mL and <0.1% cross-reaction with PSA) and for PSA-F and PSA-T (using the Dual Prostatus assay from EG&G Wallac). RESULTS: HK2 concentrations were <0.05 ng./mL in 50/50 healthy volunteers but significantly higher (p <0.0001) and > or =0.05 ng./mL in 28/54 (52%) patients with BPH. In comparison to these men, the hK2 levels were significantly higher (p <0.0001, median 0.085 ng./mL) and > or =0.05 ng./mL in 100/136 (74%) men with clinically localized PCa. Compared with localized PCa, the hK2 levels were significantly higher (p <0.0001, median 0.57 ng./mL) and > or =0.05 ng./mL in 55/57 (96%) patients with advanced PCa. The median hK2 levels ranged from 1.3 to 1.6% of those of PSA-T in all three patient groups, whereas percent hK2/PSA-F and hK2 x PSA-T/PSA-F levels were significantly higher in cancer patients compared with those with BPH. In the discrimination of clinically localized PCa from BPH, hK2 x PSA-T/PSA-F gave the largest area under the receiver operating curve (AUC = 0.81) and significantly (p = 0.025) larger AUC than PSA-T alone (0.70). Further, at 95% sensitivity there was significant gain in specificity, and at specificity levels of 90 to 95% there was significant gain in sensitivity using the measurements of PSA-T+PSA-F+hK2 compared with analysis of PSA-T and/or percent free PSA. CONCLUSIONS: Discrimination of patients with benign prostate disease from those with prostate cancer was significantly enhanced using measurements of hK2 in addition to those of PSA-T and PSA-F. Percent hK2/PSA-F was higher in PCa than in BPH, a phenomena not yet understood.     

Circulating tumour-associated plasma DNA represents an independent and informative predictor of prostate cancer

OBJECTIVE: To investigate whether preoperative plasma levels of free DNA can discriminate between men with localized prostate cancer and benign prostatic hyperplasia (BPH). PATIENTS AND METHODS: In all, 161 referred patients suspicious for prostate cancer either by an elevated prostate-specific antigen (PSA) level and/or abnormal digital rectal examination (DRE) were included in this prospective study. Peripheral plasma was taken before prostate biopsy and genomic DNA was extracted from the plasma using the a commercial kit and a vacuum chamber. After controlling for age, PSA level, the percentage free/total (f/t) PSA and prostate volume, the median prostate cancer plasma DNA concentration served as diagnostic threshold in uni- and multivariate logistic regression models. Multivariate models were subjected to 200 bootstraps for internal validation and to reduce over-fit bias. RESULTS: Subgroups consisted of 142 men with clinically localized prostate cancer and 19 with BPH. The median plasma concentration of cell-free DNA was 267 ng/mL in men with BPH vs 709 ng/mL in men with prostate cancer. In univariate analyses, plasma DNA concentration was a statistically significant and informative predictor (P = 0.032 and predictive accuracy 0.643). In multivariate analyses, it remained statistically significant after controlling for age, tPSA, f/tPSA and prostate volume, increasing the predictive accuracy by 5.6%. CONCLUSIONS: Our data suggest that plasma DNA level is a highly accurate and informative predictor in uni- and multivariate models for the presence of prostate cancer on needle biopsy. The predictive accuracy was substantially increased by adding plasma DNA level. However, larger-scale studies are needed to further confirm its clinical impact on prostate cancer detection.     

Serum prostate-specific antigen as a predictor of prostate volume in men with benign prostatic hyperplasia

OBJECTIVES: To assess the utility of prostate-specific antigen (PSA) as a predictor of prostate volume by characterizing the relationship between prostate volume and serum PSA in men with symptomatic benign prostatic hyperplasia (BPH) and no evidence of prostate cancer, stratified by decade of life. METHODS: Placebo-controlled multicenter trials in patients with BPH and a safety study in normal young men provided baseline measurements of serum PSA and prostate volume. The analyses included patients with a baseline prostate volume measured by either transrectal ultrasound (TRUS) or magnetic resonance imaging and baseline serum PSA. A common central laboratory was used for all but one of the individual studies; both laboratories used the Hybritech method. Patients 80 years of age or older were excluded. Patients with a baseline serum PSA greater than 10 ng/mL were excluded to reduce the likelihood of including occult prostate cancer cases. The patients in the BPH trials were screened at baseline by digital rectal examination (DRE) and serum PSA. Those with suspicious findings underwent TRUS-guided biopsy; only patients with negative biopsies are included in these analyses. RESULTS: The analyses included 4627 patients, 4448 from the BPH trials and 179 from the safety study. The men in the BPH trials were older (mean age+SE, 63.7+0.10 years) than the men in the safety study (mean age + SE, 30.8+/-0.43), had larger prostates (mean volume+/-SE, 43.7+/-0.38 mL versus 26.3+/-0.49 mL in the safety study), and had higher serum PSA values (mean+/-SE, 2.6+/-0.03 ng/mL versus 0.7+/-0.39 ng/mL in the safety study). The relationship between prostate volume and serum PSA was evaluated using only the BPH trial data. Prostate volume and serum PSA have an age-dependent log-linear relationship (ie, their logarithms are linearly related, and the parameters of the relationship depend on age). Older men tend to have a steeper rate of increase in prostate volume with increasing serum PSA (P < 0.00 for differences between slopes), and there was a slight tendency for PSA density to increase with age. Receiver operating characteristic (ROC) curves were constructed to evaluate the ability of serum PSA to predict threshold prostate sizes in men with BPH. The ROC curve analyses revealed that PSA had good predictive value for assessing prostate volume, with areas under the curve ranging from 0.76 to 0.78 for various prostate volume cutoff points (30, 40, and 50 mL). Conclusions. Prostate volume is strongly related to serum PSA in men with BPH and no evidence of prostate cancer, and the relationship depends on age. Since treatment outcome or risk of long-term complications depend on baseline prostate volume, serum PSA can estimate the degree of prostate enlargement sufficiently accurately to be useful for therapeutic decision making. To achieve a specificity of 70% while maintaining a sensitivity between 65% and 70%, approximate age-specific criteria for detecting men with prostate glands exceeding 40 mL are PSA > 1.6 ng/mL, >2.0 ng/mL, and >2.3 ng/mL for men with BPH in their 50s, 60s, and 70s, respectively.     

Diagnostic value of prostate-specific antigen-related parameters in discriminating prostate cancer.

BACKGROUND: Using the percentage (of total) of free prostate-specific antigen (PSA) in discriminating prostate cancer (CaP) from benign prostate hyperplasia (BPH) has not been fully delineated in Japanese men. To clarify the clinical significance of percent free PSA, various parameters, including total prostate volume, percent free PSA, PSA density (PSAD) and PSA density of transition zone volume (PSAT), were compared. METHODS: Ninety-seven patients who had visited one of three community-based hospitals, and whose total PSA value ranged from 4 to 20 ng/mL were prospectively enrolled in this study. Fresh sera were applied to measure the percent free PSA. RESULTS: Of the 97 patients, CaP and BPH were diagnosed in 24 (25%) and 73 patients, respectively. In discriminating CaP patients, the cutoff values of 17% for percent free PSA, 0.3 ng/mL per cm3 for PSAT, and 0.19 ng/mL per cm3 for PSAD yielded specificity levels of 56, 40 and 58% at sensitivity levels of 92, 92 and 79%, respectively. As for the 65 patients with intermediate PSA, range 410 ng/mL, and normal digital rectal examination, the percent free PSA and total prostate volume statistically discriminated CaP patients from BPH patients. A multiple logistic regression model proved percent free PSA to be the only significant discriminating factor (P=0.045; odds ratio, 9.06). CONCLUSIONS: This prospective study revealed percent free PSA to be a significant useful predictor in discriminating CaP from BPH in Japanese men.     

Relationship between serum prostate-specific antigen and prostate volume in Korean men with benign prostatic hyperplasia: a multicentre study

OBJECTIVES: To evaluate the relationship between prostate specific antigen (PSA) and prostate volume (PV) in Korean men, as PV is a key predictor of both disease progression and response to medical therapy in patients with benign prostatic hyperplasia (BPH), and PSA has been suggested as a proxy marker to estimate the total PV, mainly in Caucasians. PATIENTS AND METHODS: From 1999 to 2004, men aged 50-79 years with lower urinary tract symptoms (LUTS) and BPH were enrolled into this multicentre study. The analyses included 5716 patients presenting to 11 medical centres with LUTS (International Prostate Symptom Score >8, peak urinary flow rate <15 mL/s); they had a mean age of 64.3 years, mean baseline PV of 36.9 mL, and mean baseline PSA level of 2.2 ng/mL. Men with a baseline PSA of >10 ng/mL were excluded, to reduce the likelihood of including occult prostate cancer. A biopsy was taken in those with suspicious findings on a digital rectal examination or serum PSA level of >4 ng/mL, to exclude prostate cancer. Receiver operating characteristic (ROC) curves were constructed to evaluate the ability of serum PSA to predict threshold PV in men with BPH. RESULTS: The PV and serum PSA level had an age-dependent log-linear relationship, the strength of which increased with age. The ROC curve analysis showed that PSA had good predictive value for various prostate volume thresholds (30, 40 and 50 mL). CONCLUSIONS: The PSA-PV relationship in Korean men is similar to that in Caucasians, but Korean men have a slightly lower PSA level and a smaller PV than Caucasians. The approximate age-specific criteria for detecting Korean men with a PV of >40 mL were a PSA level of >1.3 ng/mL, >1.7 ng/mL and >2.0 ng/mL for men with BPH in their sixth, seventh and eighth decade, respectively.     

Prostate specific antigen density for discriminating prostate cancer from benign prostatic hyperplasia in the gray zone of prostate-specific antigen.

Serum prostate specific antigen (PSA) is currently the best blood marker for prostate cancer. However, low specificity for detection of prostate cancer, especially in the gray zone of PSA, is a problem. We evaluated the clinical significance of PSA density (PSAD) in gray zone PSA cases with conversion of serum PSA to a Stanford reference value. In a series of histologically confirmed 63 benign prostatic hyperplasia (BPH) patients and 234 prostate cancer patients, 36 BPH patients and 25 prostate cancer patients had gray zone PSA levels. Serum PSA was measured with the Markit-F or Markit-M PA assay. All data were converted to Stanford reference values. We used transabdominal ultrasound to determine prostate volume. PSAD was determined as the serum PSA/prostate volume ratio. The mean PSA values for BPH and prostate cancer were 6.42 +/- 1.80 and 7.80 +/- 2.15 ng/ml (p = 0.0116), respectively, and prostate volume was 33.4 +/- 14.1 ml and 17.1 +/- 8.2 ml, respectively (p < 0.0001). The mean PSAD for prostate cancer was 0.572 +/- 0.363 while that for BPH was 0.218 +/- 0.085 (p = 0.0001). Cut-off values with sensitivity > 90% were 0.218 for PSAD and 30 ml for prostate volume. At these cut-off values, specificity reached 56% for each marker. In discriminating prostate cancer from BPH in the gray zone of PSA, PSAD demonstrated better performance than PSA.     

Validity of prostate-specific antigen as a tumour marker in men with prostate cancer managed by watchful-waiting: correlation with findings at serial endorectal magnetic resonance imaging and spectroscopic imaging

OBJECTIVE: To investigate the validity of prostate-specific antigen (PSA) as a tumour marker in men with clinically localized prostate cancer who have selected watchful waiting, by determining if serial PSA level measurements are correlated with findings of malignancy or benign prostatic hyperplasia (BPH) at serial endorectal magnetic resonance imaging (MRI) and magnetic resonance spectroscopic imaging (MRSI). PATIENTS AND METHODS: We retrospectively identified 69 men with biopsy-proven prostate cancer being managed by watchful waiting, who underwent serial endorectal MRI/MRSI and who had contemporaneous serial PSA measurements. The mean (range) follow-up was 392 (294-571) days. A panel of three experienced readers reviewed the initial and follow-up MRI/MRSI studies, and classified findings of prostate cancer as stable or progressive. Another reader assessed BPH by calculating total gland and central gland volumes on all studies. RESULTS: At the follow-up MRI/MRSI, 51, 17 and one patient had stable, progressive, or unevaluable prostate cancer, respectively. The mean PSA velocity was significantly greater in patients with radiologically progressive disease (1.42 vs 0.42 ng/mL/year, P = 0.04). A PSA velocity of >0.75 ng/mL/year identified those with radiologically progressive disease with a true-positive fraction of 0.71 and a false-positive fraction of 0.39. PSA levels were not correlated with changes in total or central gland volumes (P > 0.05). CONCLUSIONS: In men with clinically localized prostate cancer who select watchful waiting, serial PSA levels are correlated with findings of malignancy but not BPH at serial endorectal MRI/MRSI, suggesting that PSA is a useful longitudinal tumour marker in this population.     

Prostate tissue and leukocyte levels of n-3 polyunsaturated fatty acids in men with benign prostate hyperplasia or prostate cancer

OBJECTIVE: To compare the levels of n-3 polyunsaturated fatty acids (PUFAs) in leukocytes and prostate tissue in men with prostate cancer or benign prostatic hyperplasia (BPH), as dietary intake of n-3 PUFAs has been linked to the risk of prostate cancer; the prostate-specific antigen (PSA) level was also compared to prostate tissue levels of n-3 PUFAs. PATIENTS AND METHODS: Prostate tissue was obtained and leukocytes isolated from 20 men with prostate cancer and 35 with BPH. The n-3 PUFAs alpha-linolenic acid (ALA), eicosapentanoic acid (EPA) and docosahexaenoic acid (DHA) were measured in prostate tissue and in peripheral blood leukocytes using gas chromatography. PSA levels were measured in all of the men. RESULTS: There was a strong positive correlation between EPA and DHA in leukocytes and in prostate tissue (EPA: r = 0.80, DHA: r = 0.53, both P < 0.001) in all the men, whereas there was no association between the content of ALA in leukocytes and in prostate tissue (r = -0.15). Men with BPH had similar levels of ALA in leukocytes and in prostate tissue, but men with prostate cancer had more ALA in prostate tissue than in leukocytes. The PSA level was significantly positively correlated with ALA level in prostate tissue (r = 0.42, P < 0.01) but there was no significant correlation between PSA level and EPA and DHA levels. There were no significant correlations between PSA level and n-3 PUFA levels in leukocytes. CONCLUSION: Dietary intake of the marine n-3 PUFAs reflected in EPA and DHA levels in leukocytes are also reflected in EPA and DHA levels in prostate tissue in men with and without prostate cancer. However, there is a discrepancy between the levels of ALA in leukocytes and in prostate tissue, with higher levels in men with prostate cancer. This is in accordance with the strong positive association between PSA and ALA levels in prostate tissue. This study therefore does not support the hypothesis that intake of marine n-3 PUFAs might protect against prostate cancer, but lends support to the deleterious role of ALA in the development of prostate cancer.     

Study of free to total prostate specific antigen ratio in the detection of patients with prostate cancer

BACKGROUND: We investigated the clinical usefulness of free to total serum prostate specific antigen (PSA) ratio (F/T ratio) in order to improve the specificity of total PSA measurement for detecting prostate cancer. METHOD: In this study 129 patients with total PSA level 4-20 ng/ml underwent transrectal ultrasound guided sextant biopsy. Serum samples were assessed for total PSA, free PSA and the F/T ratio calculated. All patients were pathologically diagnosed as benign prostatic hyperplasia or prostate cancer. RESULTS: Of 129 patients 21 had prostate carcinoma (PCa) and 108 had benign prostatic hyperplasia (BPH) from the results of prostate biopsies. The mean of total PSA were not significantly different between men with PCa and with BPH. The mean of free PSA for PCa was significantly lower than that for BPH (p = 0.043). Furthermore, the mean of F/T ratio was significantly different between PCa and BPH group (p = 0.0014). The F/T ratio had a higher specificity than total PSA at all levels of sensitivity in detecting prostate cancers. Sensitivity, specificity and accuracy for cancer detection at a cut off 0.12 was 90.4%, 51.8% and 58.1%, respectively. Also, free PSA was as useful as F/T ratio for cancer detection when analyzed in receiver operating characteristic curves analysis. When determined the cut off number of free PSA at 0.78 ng/ml, the sensitivity, specificity and accuracy for cancer detection were 61.9%, 66.7% and 65.9%, respectively. CONCLUSION: This study indicated that the F/T ratio and free PSA could improve the specificity without impairing the sensitivity for detecting PCa in patients with 4-20 ng/ml of total PSA.     

Predictive value of prostate specific antigen density in the detection of prostate cancer in patients with elevated prostate specific antigen levels and normal digital rectal findings or stage A prostate cancer

We compared the usefulness of PSA and PSA density (PSAD) in diagnosing prostate cancer in 102 men who had a PSA value higher than 4.0 ng/ml and normal digital rectal examination and who had undergone transrectal ultrasonography-guided systematic sextant biopsies of the prostate between August 1996 and October 1999. In addition, for a group of 53 patients who underwent retropubic simple prostatectomy, PSA, PSAD and PSA transition zone (PSA-TZ) examination results for those with stage A prostate cancer were compared with the results for those with benign prostatic hyperplasia (BPH). Of the former 102 men, 20 (19.6%) had prostate cancer. There was no significant difference in mean PSA level between patients with negative and those with positive biopsy results (mean 9.3 and 11.8, respectively, p = 0.295), but the mean PSAD of patients with positive biopsy results was significantly higher than that of those with negative results (mean 0.55 and 0.29, respectively, p = 0.0007). Of the 53 men who underwent retropubic simple prostatectomy, 10 (18.9%) were diagnosed with stage A prostate cancer. There was no significant difference in mean PSA, PSAD and PSA-TZ examination results between patients with BPH and those with stage A prostate cancer. For all 102 patients and for 71 patients with PSA levels of 4.1-10.0 ng/ml, a PSAD cutoff value of 0.1 reduced the number of biopsies 15.7% (16 of 102 cases), and 22.5% (16 of 71 cases), respectively. These results suggest that by measurement of PSAD some patients with benign disease could be spared a biopsy which would have been performed based on PSA results alone.     

Hormonal predictors of prostate cancer

INTRODUCTION: Androgens are necessary for the development and functioning of the prostate gland. The association of serum testosterone and pituitary hormone levels with prostate cancer development is not completely understood. In this clinical study, we evaluated the role of serum testosterone, free testosterone, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels in predicting prostate cancer risk in patients who had transrectal ultrasonography-guided prostate biopsy with the suspicion of prostate cancer. MATERIAL AND METHODS: A total of 211 patients who were selected to undergo prostatic biopsy due to abnormal digital rectal examination and/or a serum prostate-specific antigen (PSA) level >2.5 ng/ml were included in the study. The patient characteristics of total PSA, free/total PSA ratio, serum total testosterone, free testosterone, free/total testosterone ratio, FSH and LH levels were compared according to the pathological diagnosis. RESULTS: The mean age was 63.91 years (range 44-83) and the mean PSA level was 9.23 ng/ml (range 0.13-50.41) in the whole group. Of 211 patients, 69 (32.7%) were positive for prostate cancer. The patients who were positive for prostate cancer had statistically lower levels of serum total testosterone compared with the patients who were diagnosed as having benign prostatic hyperplasia (BPH; 405 vs. 450.5 ng/dl, respectively; p = 0.013). The serum FSH level was significantly higher in men with prostatic cancer than in men with BPH (7.56 vs. 6.06 mIU/ml, respectively; p = 0.029). No significant differences between men with prostatic cancer and those with BPH were found for serum LH levels. When normal ranges for serum free and total testosterone levels were defined as 9 pg/ml and 300 ng/dl, respectively, patients who had low free testosterone and total testosterone levels had significantly higher cancer detection rates than patients with high serum androgen levels: 40.8% (40/98) versus 25.6% (29/113) (p = 0.021), and 48.6% (18/37) versus 29.3% (51/174), respectively (p = 0.023). After logistic regression analysis, none of the hormones showed a significant difference in predicting the risk of prostate cancer in patients undergoing prostate biopsy with suspicion of the disease. CONCLUSION: Our data suggest that patients diagnosed with prostate cancer have low levels of serum testosterone and high levels of serum FSH compared with the patients with BPH. No support was found for the theory that high levels of testosterone increase prostate cancer risk. Further studies are needed to clarify the relationship between hormones and prostate cancer etiology.     

Comparison of the clinical value of complexed PSA and total PSA in the discrimination between benign prostatic hyperplasia and prostate cancer

BACKGROUND: To compare the clinical value of the measurement of complex and total PSA in the discrimination between benign prostatic hyperplasia (BPH) and prostate cancer. METHODS: In serum samples collected from 166 men with histopathologically proven clinically localized prostate cancer and of 97 men with BPH, total prostate-specific antigen (PSA), complexed PSA and the free to total PSA ratio were determined. The statistical analysis was done by the comparison of the receiver operator characteristic (ROC) curves. RESULTS: The areas under the ROC curves were 0.776 for total PSA, 0.799 for complexed PSA (total PSA vs. cPSA: p < 0.0001) and 0.812 for the free to total PSA ratio. With a cut-off of 3.0 ng/ml for complexed PSA, the sensitivity was 90%, the specificity 58%, the positive and the negative predictive values 79 and 78%, respectively. With a cut-off of 4.0 ng/ml for total PSA, the sensitivity was 87%, the specificity 59%, the positive and the negative predictive values were 78 and 72%, respectively. CONCLUSIONS: There was a statistically significant advantage for complexed PSA compared to total PSA in the discrimination between BPH and prostate cancer. The difference was, however, small and its clinical relevance is questionable.     

Prostate-specific antigen 1.5-4.0 ng/mL: a diagnostic challenge and danger zone

Study Type – Prognosis (inception cohort) Level of Evidence 1b What’s known on the subject? and What does the study add? Large population screening trials like the ERSPC, PCPT and PLCO have noted that men with seemingly low PSA (even as low as 0.5 ng/dL) still can have prostate cancer. Despite these findings, PSA is still predominantly used as a current indicator for possible presence of prostate cancer rather than also serving as a prognostic marker. This study examines a larger number of men in a diverse US population to determine the prognostic value of a man’s baseline or first PSA.

OBJECTIVES

? To assess the value of a PSA threshold of 1.5 ng/mL as a predictor of increased prostate cancer risk over a four‐year period based on a man’s first PSA test, including racial differences. ? To review the risk of progression of benign prostatic hyperplasia (BPH) based on a similar PSA threshold.

PATIENTS AND METHODS

? A retrospective review involving 21 502 men from a large Midwestern health system was performed. ? Men at least 40 years old with baseline PSA values between 0 and 4.0 ng/mL and at least four years of follow‐up after initial PSA test were included. ? Optimal PSA threshold and predictive value of PSA for development of prostate cancer were calculated.

RESULTS

? Prostate cancer rates were 15‐fold higher in patients with PSA ≥1.5 ng/mL vs patients with PSA <1.5 ng/mL (7.85% vs 0.51%). ? African American patients with baseline PSA <1.5 ng/mL faced prostate cancer rates similar to the whole study population (0.54% vs 0.51%, respectively), while African American patients with PSA 1.5–4.0 ng/mL faced a 19‐fold increase in prostate cancer.

CONCLUSION

? Both Caucasian and African American men with baseline PSA values between 1.5 and 4.0 ng/mL are at increased risk for future prostate cancer compared with those who have an initial PSA value below the 1.5 ng/mL threshold. ? Based on a growing body of literature and this analysis, it is recommended that a first PSA test threshold of 1.5 ng/mL and above, or somewhere between 1.5 and 4.0 ng/mL, represent the Early‐Warning PSA Zone (EWP Zone). ? This should serve to inform patients and clinicians alike to future clinical activities with respect to prostate cancer and BPH.     

THE EFFECT OF HIGH GRADE PROSTATIC INTRAEPITHELIAL NEOPLASIA ON SERUM TOTAL AND PERCENTAGE OF FREE PROSTATE SPECIFIC ANTIGEN LEVELS

PURPOSE: It is established that the percentage of free prostate specific antigen (PSA) in serum is low in patients with prostate cancer. An unanswered question is whether a low percentage of free PSA can be explained by high grade prostatic intraepithelial neoplasia alone. We compared the percentage of free PSA in men with high grade prostatic intraepithelial neoplasia alone, prostate cancer, benign prostatic hyperplasia (BPH) and a normal prostate (that is normal digital rectal examination and PSA less than or equal to 2.5 ng./ml.). MATERIALS AND METHODS: From October 1994 through December 1997, 48 men were diagnosed with high grade prostatic intraepithelial neoplasia without concomitant prostate cancer. Of these men 43 with a mean age plus or minus standard deviation of 67.4 +/- 7.8 years comprised our study group. To date none has been diagnosed with cancer during followup. Serum free and total PSA levels were measured, and the percentage of free PSA was calculated. The percentage of free PSA in the 43 men was compared to that in 50 with prostate cancer (mean age 65.4 +/- 7.8 years), 50 with biopsy proved BPH (67 +/- 7) and 43 with a normal prostate (61 +/- 8). RESULTS: There was no significant difference in mean total serum PSA in patients with high grade prostatic intraepithelial neoplasia, prostate cancer or BPH. The percentage of free PSA was significantly lower in patients with prostate cancer (14.9 +/- 6.5%) than those with high grade prostatic intraepithelial neoplasia (20.8 +/- 7.1%), BPH (20.1 +/- 7.3%) or a normal prostate (27.7 +/- 12.2%). There was also no significant difference in the percentage of free PSA between men with high grade prostatic intraepithelial neoplasia (20.8 +/- 7.1%) and those with BPH (20.1 +/- 7.3%). Additionally, men with a normal prostate had a higher percentage of free PSA (27.7%) than those with BPH (20.1%), high grade prostatic intraepithelial neoplasia (20.8%) or prostate cancer (14.9%). CONCLUSIONS: The percentages of free PSA in men with high grade prostatic intraepithelial neoplasia and BPH are similar, and significantly higher than those found in men with prostate cancer.     

Prostate-specific antigen adjusted for the transition zone volume versus free-to-total prostate-specific antigen ratio in predicting prostate cancer

BACKGROUND: We performed this study to assess the efficacy of prostate-specific antigen adjusted for the transition zone volume (PSATZ) and free-to-total prostate-specific antigen (PSA) ratio (F/T ratio) in predicting prostate cancer in men with intermediate PSA levels of 4.1-10.0 ng/mL. METHODS: Between March 1997 and September 1998, PSATZ was obtained from 67 patients who underwent ultrasonography guided systemic sextant biopsies and had a PSA of 4.1-10.0 ng/mL. PSATZ was compared with F/T ratio via receiver operating characteristic (ROC) curves. RESULTS: Of 67 patients, 22 (32.8%) had prostate cancer and 45 (67.2%) had benign prostatic hyperplasia (BPH) on pathologic examination. Mean PSA, PSA density, F/T ratio and PSATZ were 7.96+/-2.01ng/mL, 0.28+/-0.14 ng/mL/cc, 0.10+/-0.06 and 0.70+/-0.28 ng/mL/cc in patients with prostate cancer and 6.39+/-1.68 ng/mL, 0.16+/-0.06 ng/mL/cc, 0.15+/-0.05 and 0.29+/-0.10 ng/mL/cc in patients with BPH, respectively. The ROC curve analysis demonstrated that PSATZ predicted the biopsy outcome significantly better than F/T ratio in all 67 patients (P<0.01) and in a subset of 53 men with normal digital rectal examination (P<0.01). With a cut-off value of 0.35 ng/mL/cc, PSATZ had a sensitivity of 86% and a specificity of 89% for predicting prostate cancer. CONCLUSIONS: These results suggest that PSATZ and F/T ratio may be useful in diagnosing prostate cancer with intermediate levels of PSA. Prostate-specific antigen adjusted for the transition zone volume is more accurate than F/T ratio in distinguishing benign prostatic disease from prostate cancer. But large prospective studies are required to assess the precise role of PSATZ and F/T ratio in early prostate cancer detection.