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Abstracts

Prostate Cancer
Updated: 08/26/2004

ABSTRACTS

Arachidonic acid to eicosapentaenoic acid ratio in blood correlates positively with clinical symptoms of depression.

Adams PB, Lawson S, Sanigorski A, et al.

Lipids. 1996 Mar; 31 Suppl:S157-S161.

In this study of 20 moderately to severely depressed patients, diagnosed using current research diagnostic criteria and excluding known bipolar affective disorder and reactive depression, we investigated relationships between severity of depression and levels and ratios of n-3 and n-6 long-chain polyunsaturated fatty acids (PUFA) in plasma and erythrocyte phospholipids (PL). Severity of depression was measured using the 21-item Hamilton depression rating scale (HRS) and a second linear rating scale (LRS) of severity of depressive symptoms that omitted anxiety symptoms. There was a significant correlation between the ratio of erythrocyte PL arachidonic acid (AA) to eicosapentaenoic acid (EPA) and severity of depression as rated by the HRS (P < 0.05) and the LRS for depression (P < 0.01). There was also a significant negative correlation between erythrocyte EPA and the LRS (P < 0.05). The AA/EPA ratio in plasma PL and the ratio of erythrocyte long-chain (C20 and C22 carbon) n-6 to long-chain n-3 PUFA were also significantly correlated with the LRS (P < 0.05). These findings do not appear to be simply explained by differences in dietary intake of EPA. We cannot determine whether the high ratios of AA/EPA in both plasma and erythrocyte PL are the result of depression or whether tissue PUFA change predate the depressive symptoms. We suggest, however, that our findings provide a basis for studying the effect of the nutritional supplementation of depressed subjects, aimed at reducing the AA/EPA ratio in tissues and severity of depression

Tomato lycopene and its role in human health and chronic diseases.

Agarwal S, Rao AV.

CMAJ. 2000 Sep 19; 163(6):739-44.

Lycopene is a carotenoid that is present in tomatoes, processed tomato products and other fruits. It is one of the most potent antioxidants among dietary carotenoids. Dietary intake of tomatoes and tomato products containing lycopene has been shown to be associated with a decreased risk of chronic diseases, such as cancer and cardiovascular disease. Serum and tissue lycopene levels have been found to be inversely related to the incidence of several types of cancer, including breast cancer and prostate cancer. Although the antioxidant properties of lycopene are thought to be primarily responsible for its beneficial effects, evidence is accumulating to suggest that other mechanisms may also be involved. In this article we outline the possible mechanisms of action of lycopene and review the current understanding of its role in human health and disease prevention

Prostate specific antigen and gleason grade: an immunohistochemical study of prostate cancer.

Aihara M, Lebovitz RM, Wheeler TM, et al.

J Urol. 1994 Jun; 151(6):1558-64.

Prostate cancer is histologically heterogeneous as reflected in the 5 patterns of the Gleason grading system. Gleason grade correlates with volume, extent and prognosis. Serum prostate specific antigen (PSA) levels also correlate with tumor volume but the degree to which grade correlates with PSA has not been precisely defined. To quantify this relationship further, we prepared maps of each grade of cancer in 86 radical prostatectomy specimens from patients with clinical stage T2 cancer. The median per cent of the volume of cancer per prostate composed of grade 1 was 0%, while it was 1% for grade 2, 84% for grade 3, 5% for grade 4 and 0% for grade 5. We stained 95 cancer foci (grades 1 to 5) in 40 of these specimens for PSA. The presence and intensity (0 to 3+) of staining in more than 33,000 acini (or cells) correlated inversely with grade (p < 0.0001). Nearly all acini in grade 1 and most in grade 2 stained positive (2 to 3+) for PSA; 87% were positive but with less intensity in grade 3. While many grade 4 (79%) and grade 5 (49%) cells were positive, the intensity of staining was weak. Serum PSA levels correlated with total tumor volume (r = "0.67)" but serum PSA levels per cm.3 of cancer decreased with increasing grade (r = "-0.24" and p < 0.02). These studies confirm the strong inverse correlation between Gleason grade and the PSA content of prostate cancer. Since more than 85% of grade 3 acini stained for PSA and grade 3 made up the largest portion (84%) of cancer, the predominant contributor to serum PSA levels from prostate cancer was Gleason grade 3. The other grades contribute relatively little to the serum PSA levels either because of the small volume (grades 1 and 2) or the diminished PSA content (grades 4 and 5)

Local anesthesia for ultrasound guided prostate biopsy: a prospective randomized trial comparing 2 methods.

Alavi AS, Soloway MS, Vaidya A, et al.

J Urol. 2001 Oct; 166(4):1343-5.

PURPOSE: Since the introduction of prostate specific antigen (PSA) screening, asymptomatic men often undergo transrectal ultrasound guided prostate biopsy. This procedure may cause significant discomfort, which may limit the number of biopsies. We performed a randomized prospective study to compare periprostatic infiltration with 1% lidocaine with intrarectal instillation of 2% lidocaine gel before prostate biopsy. MATERIALS AND METHODS: From October 1999 to July 2000, 150 men underwent prostate biopsy at the Miami Veterans Administration and Jackson Memorial Hospital. Experienced senior residents performed all biopsies. Patients were randomized into 2 groups depending on the method of anesthetic delivery. A visual analog scale was used to assess the pain score. Statistical analysis of pain scores was performed using the Student t test. RESULTS: Ultrasound guided prostate biopsy was done in 150 cases. There was a statistical difference in the mean pain score after periprostatic infiltration and intrarectal instillation (2.4 versus 3.7, p = 0.00002) with patients receiving periprostatic infiltration reporting significantly less pain. CONCLUSIONS: Men should have the opportunity to receive local anesthesia before ultrasound guided prostate biopsy with the goal of decreasing the discomfort associated with this procedure. Our prospective randomized study indicates that ultrasound guided periprostatic nerve block with 1% lidocaine provides anesthesia superior to the intrarectal placement of lidocaine gel

Prospective study of C-reactive protein, homocysteine, and plasma lipid levels as predictors of sudden cardiac death.

Albert CM, Ma J, Rifai N, et al.

Circulation. 2002 Jun 4; 105(22):2595-9.

BACKGROUND: Sudden cardiac death (SCD) is an important cause of mortality even among apparently healthy populations. However, our ability to identify those at risk for SCD in the general population is poor, and more specific markers are needed. METHODS AND RESULTS: To compare and contrast the relative importance of C-reactive protein (CRP), homocysteine, and lipids as long-term predictors of SCD, we performed a prospective, nested, case-control analysis involving 97 cases of SCD among apparently healthy men enrolled in the Physician's Health Study. Of these plasma markers measured, only baseline CRP levels were significantly associated with the risk of SCD over the ensuing 17 years of follow-up (P for trend=0.001). The increase in risk associated with CRP levels was primarily seen among men in the highest quartile, who were at a 2.78-fold increased risk of SCD (95% CI 1.35 to 5.72) compared with men in the lowest quartile. These results were not significantly altered in analyses that (in addition to the matching variables of age and smoking status) controlled for lipid parameters, homocysteine, and multiple cardiac risk factors (relative risk for highest versus lowest quartile 2.65, 95% CI 0.79 to 8.83; P for trend=0.03). In contrast to the positive relationship observed for CRP, neither homocysteine nor lipid levels were significantly associated with risk of SCD. CONCLUSIONS: These prospective data suggest that CRP levels may be useful in identifying apparently healthy men who are at an increased long-term risk of SCD

The impact of co-morbidity on life expectancy among men with localized prostate cancer.

Albertsen PC, Fryback DG, Storer BE, et al.

J Urol. 1996 Jul; 156(1):127-32.

PURPOSE: We evaluated 3 indexes used to assess patient co-morbidities to determine whether they could predict mortality among men with clinically localized prostate cancer. MATERIALS AND METHODS: We measured the impact of co-morbidity classifications on all cause mortality using a parametric proportional hazards model based on a retrospective cohort analysis. RESULTS: Each index tested is a highly significant predictor of mortality for patients dying of nonprostate cancer related causes after adjusting for age and Gleason score. CONCLUSIONS: Each co-morbidity index provides significant, independent predictive information concerning patient mortality beyond that provided by age, Gleason score and clinical stage alone

Lycopene and cardiovascular disease.

Arab L, Steck S.

Am J Clin Nutr. 2000 Jun; 71(6 Suppl):1691S-5S.

Considerable evidence suggests that lycopene, a carotenoid without provitamin A activity found in high concentrations in a small set of plant foods, has significant antioxidant potential in vitro and may play a role in preventing prostate cancer and cardiovascular disease in humans. Tomato products, including ketchup, tomato juice, and pizza sauce, are the richest sources of lycopene in the US diet, accounting for >80% of the total lycopene intake of Americans. Unlike other carotenoids, lycopene is not consistently lower among smokers than among nonsmokers, suggesting that any possible preventive activity is not as an antioxidant. Instead, lycopene may have a cholesterol synthesis-inhibiting effect and may enhance LDL degradation. Available evidence suggests that intimal wall thickness and risk of myocardial infarction are reduced in persons with higher adipose tissue concentrations of lycopene. The question of whether lycopene helps to prevent cardiovascular disease can only be answered by a trial specifically evaluating its effectiveness in this area

The role of volume-weighted mean nuclear volume in predicting tumour biology and clinical behaviour in patients with prostate cancer undergoing watchful waiting.

Arai Y, Egawa S, Kuwao S, et al.

BJU Int. 2001 Dec; 88(9):909-14.

OBJECTIVE: To investigate whether the volume-weighted mean nuclear volume (MNV, the only means by which unbiased estimates of three-dimensional variables can be obtained from a two-dimensional section by stereological methods) at diagnosis correlates with tumour biology and clinical behaviour in patients with prostate cancer treated by watchful waiting. PATIENTS AND METHODS: In a prognostic study, 64 patients with clinically localized prostate cancer were followed prospectively with initial expectant management. The median (mean, range) follow-up was 22 (27, 6.0-68) months. The prostate specific antigen (PSA) doubling time (PSADT) was calculated by linear regression. The MNV was estimated using biopsy specimens, based on a stereological method, and compared with PSADT and traditional clinicopathological variables. RESULTS: PSADT was significantly associated with MNV, but not with other clinicopathological variables. The PSA 'rapid-riser' subset (PSADTor=median value) and PSA-stable subsets (P = 0.0017 and 0.004, respectively). On multivariate analysis using a stepwise Cox proportional hazards regression, only MNV remained independently significant as a predictor of clinical progression among the clinicopathological variables (P < 0.001). CONCLUSIONS: These findings suggest that cancer cell nuclear volume is significantly associated with tumour biology and behaviour in patients with prostate cancer. Although further study with a larger patient population is needed to confirm the findings, estimates of MNV may be an important prognostic indicator in men treated with watchful waiting

Antibiotic prophylaxis for transrectal needle biopsy of the prostate: a randomized controlled study.

Aron M, Rajeev TP, Gupta NP.

BJU Int. 2000 Apr; 85(6):682-5.

OBJECTIVES: To determine the effect of antibiotic prophylaxis on infective complications after transrectal needle biopsy of the prostate. PATIENTS AND METHODS: Between June 1996 and September 1998, 231 patients who satisfied the inclusion and exclusion criteria entered the study; the patients were randomized into three groups. Each patient underwent transrectal needle biopsy of the prostate after a cleansing enema at 06:00 hours. Patients in group 1 (75) then received a placebo tablet twice a day for 3 days; those in group 2 (79) were given a single dose of ciprofloxacin (500 mg) and tinidazole (600 mg), while those in group 3 (77) were given the same combination twice a day for 3 days. Urine cultures were obtained 48 h after the biopsy and blood cultures only from patients who developed fever. The complications (categorized as infective or noninfective) occurring in the three groups were compared using the chi-square test. RESULTS: Noninfective complications included were lower urinary tract symptoms, rectal bleeding, haematuria and perineal pain. The infective complications included urinary tract infection and fever. There was no significant difference among the three groups in noninfective complications (27, 29 and 31 in groups 1-3, respectively) but the incidence of infective complications (19, six and eight, respectively) was significantly higher in group 1 (P = 0.003). However, the difference was significant only for urinary tract infection (P = 0.01) and not for fever. CONCLUSIONS: In selected patients a single dose of ciprofloxacin-tinidazole is adequate prophylaxis for transrectal needle biopsy of the prostate. The present urinary infection rate was higher if no antibiotics were used. Continuing the antibiotic prophylaxis for 3 days offered no benefit over single-dose prophylaxis

Inhibitors of prostaglandin synthesis inhibit human prostate tumor cell invasiveness and reduce the release of matrix metalloproteinases.

Attiga FA, Fernandez PM, Weeraratna AT, et al.

Cancer Res. 2000 Aug 15; 60(16):4629-37.

Eicosanoids modulate the interaction of tumor cells with various host components in cancer metastasis. Their synthesis involves the release of arachidonic acid (AA) from cellular phospholipids by phospholipase A2 (PLA2), followed by metabolism by cyclooxygenases (COXs) and lipooxygenases (LOXs). This study aimed to identify the pathway(s) of AA metabolism that are required for the invasion of prostate tumor cells. DU-145 and PC-3 human prostate cancer cell lines were used to test the effect of inhibitors of PLA2, COX, or LOX on the invasion of prostate tumor cells through Matrigel in vitro using the Boyden chamber assay and fibroblast-conditioned medium as the chemoattractant. We used nontoxic doses that did not inhibit simple cell motility and did not decrease clonogenic survival. All of the inhibitors caused a significant reduction in AA release from treated cells compared with control cells, which indicated that the treatments were biochemically active. Invasion through Matrigel was inhibited by the PLA2 inhibitor 4-bromophenacyl bromide (4-BPB), the general COX inhibitor ibuprofen (IB), and the highly selective COX-2 inhibitor NS398. Inhibition of cell invasiveness by 4-BPB (1.0 microM), IB (10.0 microM), and NS398 (10.0 microM) was reversed by the addition of prostaglandin E2 (PGE2). PGE2 alone, however, did not stimulate invasiveness, which suggests that its production is necessary for rendering the cells invasive-permissive but not sufficient for inducing invasiveness. In contrast, we found no significant inhibition of invasion of prostate tumor cells treated with esculetin (1.0 microM) or nordihydroguiaretic acid (1.0 microM), which are specific inhibitors of LOX. We also tested the effect of 4-BPB, IB, NS398, and esculetin on the secretion of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs), as key enzymes in the proteolysis of Matrigel during invasion, using gelatin zymograms and Western blots. Cells that received 4-BPB, IB, or NS398, but not esculetin showed a significant reduction in the levels of proMMP-2, MMP-9, and proMMP-9 in the culture medium. DU-145 cells did not secrete TIMP-1, and the drugs did not alter the secretion of TIMP-2. This work highlights the role played by COX in disturbing the balance between MMPs and TIMPs in prostate cancer cells, and it points to the potential use of COX inibitors, especially COX-2 selective inhibitors, in the prevention and therapy of prostate cancer invasion

Performance of a neural network in detecting prostate cancer in the prostate-specific antigen reflex range of 2.5 to 4.0 ng/mL.

Babaian RJ, Fritsche H, Ayala A, et al.

Urology. 2000 Dec 20; 56(6):1000-6.

OBJECTIVES: To explore the potential role of a neural network-derived algorithm in enhancing the specificity of prostate cancer detection compared with the determination of prostate-specific antigen (PSA) and free PSA (fPSA) while maintaining a 90% detection rate. Recent information suggests that the incidence of detectable prostate cancer is similar in men whose PSA values range from 2.5 to 4.0 ng/mL and from 4.0 to 10.0 ng/mL. If the PSA threshold triggering a prostate biopsy is lowered to 2.5 ng/mL, approximately 13% of men older than 50 would be added to the patient biopsy pool. METHODS: One hundred fifty-one men were enrolled in a prospective, Institutional Review Board-approved protocol to evaluate the incidence of cancer in a population of men who participated in an early-detection program and whose PSA level was between 2.5 and 4.0 ng/mL. All the men underwent biopsy using an 11-core multisite-directed biopsy scheme, and all biopsy specimens were examined by one pathologist. All men had a second blood specimen drawn before the biopsy for a determination of serum PSA, creatinine kinase, prostatic acid phosphatase, and fPSA. A new neural network algorithm was developed with PSA, creatinine kinase, prostatic acid phosphatase, fPSA, and age as input variables to produce a single-valued prostate cancer detection index (PCD-I). This new algorithm was then prospectively tested in the 151 men. Performance parameters (including sensitivity, specificity, positive and negative predictive values, and biopsies saved) were calculated, and a comparative analysis was performed to evaluate the differences among the new algorithm, percent fPSA, PSA density, and PSA density-transition zone. RESULTS: Cancer was histologically confirmed in 24.5% (37 of 151) of the men. The median age of the men was 62 years (range 43 to 74). At a sensitivity of 92%, the specificity for percent fPSA was 11%. The new algorithm (PCD-I) demonstrated an additional enhancement of specificity to 62% at 92% sensitivity. Clinically, the PCD-I would result in a savings of 49% (74 of 151) of all biopsies or 63.6% (71 of 114) of all unnecessary biopsies. CONCLUSIONS: A new generation algorithm, derived from a neural network (PCD-I) incorporating the parameters of age, creatinine kinase, PSA, prostatic acid phosphatase, and fPSA can significantly enhance the specificity and reduce the number of biopsies while maintaining a 92% sensitivity rate

An algorithm for predicting nonorgan confined prostate cancer using the results obtained from sextant core biopsies with prostate specific antigen level.

Badalament RA, Miller MC, Peller PA, et al.

J Urol. 1996 Oct; 156(4):1375-80.

PURPOSE: We determined the enhanced ability to predict nonorgan confined prostate cancer using several histopathological and quantitative nuclear imaging parameters combined with serum prostate specific antigen (PSA). MATERIALS AND METHODS: Several independent pathological and quantitative image analysis variables obtained from sextant biopsy specimens, as well as preoperative PSA were used. The study population included 210 patients with pathologically staged disease (192 with PSA). All variables were examined by univariate and multivariate logistic regression analyses to assess ability to predict disease organ confinement status. RESULTS: Univariate logistic regression analysis demonstrated that, in decreasing order, quantitative nuclear grade, preoperative PSA, total percent tumor involvement, number of positive sextant cores, preoperative Gleason score and involvement of more than 5% of a base and/or apex biopsy were significant (p < or = "0.006)" for prediction of disease organ confinement status. Backward stepwise logistic regression was applied to these univariately significant variables, including deoxyribonucleic acid ploidy, to calculate a multivariate model for prediction of disease organ confinement status. This algorithm had a sensitivity of 85.7%, specificity 71.3%, positive predictive value 72.9%, negative predictive value 84.7% and area under the receiver operating characteristic curve 85.9%. CONCLUSIONS: Information from pathological study of sextant prostate biopsies, preoperative PSA blood test and a new image analysis variable termed quantitative nuclear grade can be combined to create a multivariate algorithm that can predict more accurately nonorgan confined prostate cancer compared to previously reported methods

Vesicular stomatitis virus (VSV) therapy of tumors.

Balachandran S, Barber GN.

IUBMB Life. 2000 Aug; 50(2):135-8.

Vesicular stomatitis virus (VSV) is an essentially nonpathogenic negative-stranded RNA virus, the replication of which is extremely sensitive to the antiviral effects of interferon (IFN). We demonstrate here that VSV selectively induces the cytolysis of numerous transformed human cell lines in vitro, with all the morphological characteristics of apoptotic cell death. Importantly, VSV can also potently inhibit the growth of p53-null C6 glioblastoma tumors in vivo without infecting and replicating in normal tissue. With our previous findings demonstrating that primary cells containing the double-stranded RNA-activated protein kinase PKR and a functional IFN system are not permissive to VSV replication, these results suggest that signaling by IFN may be defective in many malignancies. Thus VSV might be useful in novel therapeutic strategies for targeting neoplastic disease

Oncolytic activity of vesicular stomatitis virus is effective against tumors exhibiting aberrant p53, Ras, or myc function and involves the induction of apoptosis.

Balachandran S, Porosnicu M, Barber GN.

J Virol. 2001 Apr; 75(7):3474-9.

We have recently shown that vesicular stomatitis virus (VSV) exhibits potent oncolytic activity both in vitro and in vivo (S. Balachandran and G. N. Barber, IUBMB Life 50:135-138, 2000). In this study, we further demonstrated, in vivo, the efficacy of VSV antitumor action by showing that tumors that are defective in p53 function or transformed with myc or activated ras are also susceptible to viral cytolysis. The mechanism of viral oncolytic activity involved the induction of multiple caspase-dependent apoptotic pathways was effective in the absence of any significant cytotoxic T-lymphocyte response, and occurred despite normal PKR activity and eIF2alpha phosphorylation. In addition, VSV caused significant inhibition of tumor growth when administered intravenously in immunocompetent hosts. Our data indicate that VSV shows significant promise as an effective oncolytic agent against a wide variety of malignant diseases that harbor a diversity of genetic defects

The additional value of free prostate specific antigen to the battery of age-dependent prostate-specific antigen, prostate-specific antigen density and velocity.

Barak M, Cohen M, Mecz Y, et al.

Eur J Clin Chem Clin Biochem. 1997 Jun; 35(6):475-81.

This study describes the value of using the fraction of free prostate-specific antigen as a further marker in the early detection of prostate cancer. This newly introduced marker is compared to the usual battery of age-dependent total prostate-specific antigen, prostate-specific antigen density (microg/l x g tissue) and prostate-specific antigen velocity (microg/l x year). Determination of total prostate-specific antigen and free prostate-specific antigen was performed on fresh serum samples obtained from 3470 symptomatic patients aged 45-80 attending the Urology Clinics, or their General Practitioners. Among them, 310 patients had total prostate-specific antigen above the age-dependent cut-off, and/or free/total prostate-specific antigen under 11%, with different prostate-specific antigen densities and velocities. Only 147 patients complied to undergo biopsy: in 72 of those patients, benign prostatic disease was histologically confirmed, while in 75 patients primary prostate cancer was histologically confirmed. Total and free prostate-specific antigen levels were determined using the third generation DPCs prostate-specific antigen assay performed on the Immulite automated immunoassay instrument. Total prostate-specific antigen age reference values were adopted from Oesterling et al. (J Am Med Ass 1993; 270:860-4); the prostate-specific antigen density was considered suspicious of prostate cancer if it was greater than 0.15 microg/l prostate-specific antigen per gram tissue (Seaman et al. Urol Clin N Am 1993; 20:653); prostate-specific antigen velocity greater than 0.75 microg/l x year (Carter et al., J Am Med Ass 1992; 267:215) was considered suspicious for prostate cancer. Of the 147 patients, 75 had prostate cancer and 72 had benign prostatic hypertrophy. The difference between prostate cancer and benign prostatic hypertrophy was significantly reflected only by free/total prostate-specific antigen and prostate-specific antigen velocity. These parameters also provided the best sensitivity and specificity. Only these parameters proved to be significant when using a backwards logistic regression model (prostate-specific antigen velocity, p = 0.007 odds ratio 2.782; free/total prostate-specific antigen %, p = 0.016 odds ratio 2.678). Combinations of various parameters became significant when including free/total prostate-specific antigen, increasing prostate cancer detection to 88%. We conclude that free/total prostate-specific antigen is the most significant among prostate-specific antigen quantities (total age-dependent prostate-specific antigen, prostate-specific antigen density and prostate-specific antigen velocity). Adding this parameter to other prostate-specific antigen parameters improves the discrimination between prostate cancer and benign prostatic hypertrophy for the population at risk

Addition of eicosapentaenoic acid to gamma-linolenic acid-supplemented diets prevents serum arachidonic acid accumulation in humans.

Barham JB, Edens MB, Fonteh AN, et al.

J Nutr. 2000 Aug; 130(8):1925-31.

Previous studies reveal that supplementation of human diets with gamma-linolenic acid (GLA) reduces the generation of lipid mediators of inflammation and attenuates clinical symptoms of chronic inflammatory disorders such as rheumatoid arthritis. However, we have shown that supplementation with this same fatty acid also causes a marked increase in serum arachidonate (AA) levels, a potentially harmful side effect. The objective of this study was to design a supplementation strategy that maintained the capacity of GLA to reduce lipid mediators without causing elevations in serum AA levels. Initial in vitro studies utilizing HEP-G2 liver cells revealed that addition of eicosapentaenoic acid (EPA) blocked Delta-5-desaturase activity, the terminal enzymatic step in AA synthesis. To test the in vivo effects of a GLA and EPA combination in humans, adult volunteers consuming controlled diets supplemented these diets with 3.0 g/d of GLA and EPA. This supplementation strategy significantly increased serum levels of EPA, but did not increase AA levels. EPA and the elongation product of GLA, dihomo-gamma-linolenic acid (DGLA) levels in neutrophil glycerolipids increased significantly during the 3-wk supplementation period. Neutrophils isolated from volunteers fed diets supplemented with GLA and EPA released similar quantities of AA, but synthesized significantly lower quantities of leukotrienes compared with their neutrophils before supplementation. This study revealed that a GLA and EPA supplement combination may be utilized to reduce the synthesis of proinflammatory AA metabolites, and importantly, not induce potentially harmful increases in serum AA levels

The American Urological Association symptom index for benign prostatic hyperplasia. The Measurement Committee of the American Urological Association.

Barry MJ, Fowler FJ, Jr., O'Leary MP, et al.

J Urol. 1992 Nov; 148(5):1549-57.

A symptom index for benign prostatic hyperplasia (BPH) was developed and validated by a multidisciplinary measurement committee of the American Urological Association (AUA). Validation studies were conducted involving a total of 210 BPH patients and 108 control subjects. The final AUA symptom index includes 7 questions covering frequency, nocturia, weak urinary stream, hesitancy, intermittence, incomplete emptying and urgency. On revalidation, the index was internally consistent (Cronbach's alpha = 0.86) and the score generated had excellent test-retest reliability (r = 0.92). Scores were highly correlated with subjects' global ratings of the magnitude of their urinary problem (r = 0.65 to 0.72) and powerfully discriminated between BPH and control subjects (receiver operating characteristic area 0.85). Finally, the index was sensitive to change, with preoperative scores decreasing from a mean of 17.6 to 7.1 by 4 weeks after prostatectomy (p < 0.001). The AUA symptom index is clinically sensible, reliable, valid and responsive. It is practical for use in practice and for inclusion in research protocols

Pathological features of hereditary prostate cancer.

Bastacky SI, Wojno KJ, Walsh PC, et al.

J Urol. 1995 Mar; 153(3 Pt 2):987-92.

The aim of this study was to characterize the pathological features of hereditary prostate cancer, a recently recognized variant of prostate cancer with an autosomal dominant inheritance of a rare highly penetrant gene associated with early onset of disease. We compared the histology at radical prostatectomy of clinical stage T2 prostate cancer, including its relationship to prostatic intraepithelial neoplasia, in men with a family history of prostate cancer to those without a family history of prostate cancer. Three cohorts (hereditary, familial and sporadic) were identified based on pedigree analysis. A hereditary subgroup (28 patients) met 1 of the following 3 criteria: 1) cluster of greater than 3 affected relatives within the nuclear family, 2) occurrence of prostate cancer in each of 3 generations in either the proband paternal or maternal lineage, or 3) a cluster of 2 relatives affected at an early age of less than 55 years. This subgroup was compared to an age-matched subgroup with family history of prostate cancer (26 patients) yet the aforementioned conditions for inclusion within the hereditary subgroup were not met and to a sporadic subgroup without a family history of prostate cancer (27 patients). All parameters were statistically similar among the groups except that hereditary and familial group multifocal tumors were of lower grade (p = 0.0001), sporadic cases had a greater proportion of small multifocal cancers associated with prostatic intraepithelial neoplasia (p = 0.02) and the familial group had a weaker correlation between total tumor volume and grade. In conclusion, our analysis failed to demonstrate substantial pathological differences among hereditary, familial and sporadic forms of prostate cancer. Rather, our data are remarkable for the wide range of all parameters studied in each group. Even the sporadic cases had features, such as increased numbers of precursor lesions and tumor multifocality, which in other organs are commonly associated with either hereditary cancer or cancer arising in a field effect due to diffuse exposure to a carcinogen

Artificial neural network model for the assessment of lymph node spread in patients with clinically localized prostate cancer.

Batuello JT, Gamito EJ, Crawford ED, et al.

Urology. 2001 Mar; 57(3):481-5.

OBJECTIVES: To develop an artificial neural network (ANN) model to predict lymph node (LN) spread in men with clinically localized prostate cancer and to describe a clinically useful method for interpreting the ANN's output scores. METHODS: A simple, feed-forward ANN was trained and validated using clinical and pathologic data from two institutions (n = 6135 and n = 319). The clinical stage, biopsy Gleason sum, and prostate-specific antigen level were the input parameters and the presence or absence of LN spread was the output parameter. Patients with similar ANN outputs were grouped and assumed to be part of a cohort. The prevalence of LN spread for each of these patient cohorts was plotted against the range of ANN outputs to create a risk curve. RESULTS: The area under the receiver operating characteristic curve for the first and second validation data sets was 0.81 and 0.77, respectively. At an ANN output cutoff of 0.3, the sensitivity achieved for each validation set was 63.8% and 44.4%; the specificity was 81.5% and 81.3%; the positive predictive value was 13.6% and 6.5%; and the negative predictive value was 98.0% and 98.1%, respectively. The risk curve showed a nearly linear increase (best fit R(2) = 0.972) in the prevalence of LN spread with increases in raw ANN output. CONCLUSIONS: The ANN's performance on the two validation data sets suggests a role for ANNs in the accurate clinical staging of patients with prostate cancer. The risk curve provides a clinically useful tool that can be used to give patients a realistic assessment of their risk of LN spread

A Phase I trial of pulse calcitriol in patients with refractory malignancies: pulse dosing permits substantial dose escalation.

Beer TM, Munar M, Henner WD.

Cancer. 2001 Jun 15; 91(12):2431-9.

BACKGROUND: Calcitriol is the principal biologically active metabolite of vitamin D. Calcitriol's activity against many neoplasms is well documented, but calcitriol's therapeutic application has been hampered by predictable hypercalcemia when it is given daily. Because laboratory data has suggested that intermittent exposure to high levels of calcitriol may be sufficient to produce antiproliferative effects, the authors developed a Phase I trial to determine the maximal tolerated dose, dose-limiting toxicity, and the pharmacokinetic profile of calcitriol given weekly by mouth. METHODS: Patients with refractory malignancies were enrolled for 4 weeks of treatment followed by 4 weeks of observation. Reenrollment at a higher dose level was permitted for patients who had evidence of response or stable disease and no Grade 3 or greater toxicity. The starting dose was 0.06 microg/kg. RESULTS: Fifteen patients received 20 cycles of therapy. Doses up to 2.8 microg/kg of calcitriol weekly produced no dose-limiting toxicity. While peak levels and the area under the serum concentration-time curve of calcitriol increased in a linear fashion at lower doses, saturable absorption was observed at doses above 0.48 microg/kg. Doses of 0.48 microg/kg and above produced mean peak calcitriol levels of 1625 pg/mL, approximately 25-fold greater than top normal levels and well within the therapeutic range suggested by in vitro experiments. Eight patients experienced self-limiting Grade 1 hypercalcemia. CONCLUSIONS: Weekly dosing of oral calcitriol permitted substantial dose escalation with minimal toxicity. Peak serum calcitriol levels were in the predicted therapeutic range. A dose of 0.5 microg/kg was selected for evaluation in Phase II studies

Variations in morbidity after radical prostatectomy.

Begg CB, Riedel ER, Bach PB, et al.

N Engl J Med. 2002 Apr 11; 346(15):1138-44.

BACKGROUND: Recent studies of surgery for cancer have demonstrated variations in outcomes among hospitals and among surgeons. We sought to examine variations in morbidity after radical prostatectomy for prostate cancer. METHODS: We used the Surveillance, Epidemiology, and End Results-Medicare linked data base to evaluate health-related outcomes after radical prostatectomy. The rates of postoperative complications, late urinary complications (strictures or fistulas 31 to 365 days after the procedure), and long-term incontinence (more than 1 year after the procedure) were inferred from the Medicare claims records of 11,522 patients who underwent prostatectomy between 1992 and 1996. These rates were analyzed in relation to hospital volume and surgeon volume (the number of procedures performed at individual hospitals and by individual surgeons, respectively). RESULTS: Neither hospital volume nor surgeon volume was significantly associated with surgery-related death. Significant trends in the relation between volume and outcome were observed with respect to postoperative complications and late urinary complications. Postoperative morbidity was lower in very-high-volume hospitals than in low-volume hospitals (27 percent vs. 32 percent, P=0.03) and was also lower when the prostatectomy was performed by very-high-volume surgeons than when it was performed by low-volume surgeons (26 percent vs. 32 percent, P

Quinazoline-derived alpha1-adrenoceptor antagonists induce prostate cancer cell apoptosis via an alpha1-adrenoceptor-independent action.

Benning CM, Kyprianou N.

Cancer Res. 2002 Jan 15; 62(2):597-602.

Recent evidence suggests that the quinazoline-based alpha1-adrenoceptor antagonists, doxazosin and terazosin, exhibit a potent apoptotic effect against prostate tumor epithelial cells, whereas tamsulosin, a sulfonamide-based alpha1-adrenoceptor antagonist, was ineffective in inducing a similar apoptotic effect against prostate cells (Cancer Res., 60: 4550-4555, 2000). In this study, to identify the precise molecular mechanism underlying this apoptosis induction, we examined whether doxazosin and terazosin (both piperazinyl quinazolines) affect prostate growth via an alpha1-adrenoceptor-independent action. Transfection-mediated overexpression of alpha1-adrenoceptor in human prostate cancer cells, DU-145 (that lack alpha1-adrenoceptor), did not alter the ability of prostate cancer cells to undergo apoptosis in response to quinazolines. Significantly enough, there was no modification of the apoptotic threshold of the androgen-sensitive prostate cancer cells, LNCaP, to either quinazoline-based alpha1-agonist by androgens. Furthermore, human normal prostate epithelial cells exhibited a very low sensitivity to the apoptotic effects of doxazosin compared with that observed for the malignant prostate cells. These findings provide the first evidence that the apoptotic activity of the quinazoline-based alpha1-adrenoceptor antagonists (doxazosin and terazosin) against prostate cancer cells is independent of: (a) their capacity to antagonize alpha1-adrenoceptors; and (b) the hormone sensitivity status of the cells. This may have potential therapeutic significance in the use of quinazoline-based alpha1-adrenoceptor antagonists (already in clinical use for the treatment of hypertension and benign prostate hyperplasia) for the treatment of androgen-independent human prostate cancer

Lipid profile in obesity.

Bhatti MS, Akbri MZ, Shakoor M.

J Ayub Med Coll Abbottabad. 2001 Jan; 13(1):31-3.

BACKGROUND: Obesity is associated with social and medical risks that especially make it a problem. The importance of obesity in the prediction of cardiovascular disease has been the subject of long standing debate. Direct correlation between plasma triglycerides and body weight have been noticed. We report the results of a study in our center. METHODS: Fifty adult subjects who were obese (body mass index > 25 Kg/m) and non smokers were selected along with thirty non obese non smokers as controls. Lipid profile was studied including total lipids, total cholesterol, HDL, LDL, VLDL and chylomicrons. Various ratios like LDL/HDL, VLDL/HDL, TG/HDL and TC/HDL ratios were calculated to find the risk of atherosclerosis and coronary heart disease. RESULTS: All the parameters except serum HDL level showed significant increase in obese persons while HDL level was significantly decreased

Kinetics of serum tumor marker concentrations and usefulness in clinical monitoring.

Bidart JM, Thuillier F, Augereau C, et al.

Clin Chem. 1999 Oct; 45(10):1695-707.

Only a few markers have been instrumental in the diagnosis of cancer. In contrast, tumor markers play a critical role in the monitoring of patients. The patient's clinical status and response to treatment can be evaluated rapidly using the tumor marker half-life (t(1/2)) and the tumor marker doubling time (DT). This report reviews the interest of determining these kinetic parameters for prostate-specific antigen, human chorionic gonadotropin, alpha-fetoprotein, carcinoembryonic antigen, cancer antigen (CA) 125, and CA 15-3. A rise in tumor markers (DT) is a yardstick with which benign diseases can be distinguished from metastatic disease, and the DT can be used to assess the efficacy of treatments. A decline in the tumor marker concentration (t(1/2)) is a predictor of possible residual disease if the timing of blood sampling is soon after therapy. The discrepancies in results obtained by different groups may be attributable to the multiplicity of immunoassays, the intrinsic characteristics of each marker (e.g., antigen specificity, molecular heterogeneity, and associated forms), individual factors (e.g., nonspecific increases and renal and hepatic diseases) and methods used to calculate kinetics (e.g., exponential models and timing of blood sampling). This kinetic approach could be of interest to optimize patient management

Palladium-103 brachytherapy for prostate carcinoma.

Blasko JC, Grimm PD, Sylvester JE, et al.

Int J Radiat Oncol Biol Phys. 2000 Mar 1; 46(4):839-50.

PURPOSE: A report of biochemical outcomes for patients treated with palladium-103 (Pd-103) brachytherapy over a fixed time interval. METHODS AND MATERIALS: Two hundred thirty patients with clinical stage T1-T2 prostate cancer were treated with Pd-103 brachytherapy and followed with prostate-specific antigen (PSA) determinations. Kaplan-Meier estimates of biochemical failure on the basis of two consecutive elevations of PSA were utilized. Multivariate risk groups were constructed. Aggregate PSA response by time interval was assessed. RESULTS: The overall biochemical control rate achieved at 9 years was 83.5%. Failures were local 3.0%; distant 6.1%; PSA progression only 4.3%. Significant risk factors contributing to failure were serum PSA greater than 10 ng/ml and Gleason sum of 7 or greater. Five-year biochemical control for those exhibiting neither risk factor was 94%; one risk factor, 82%; both risk factors, 65%. When all 1354 PSA determinations obtained for this cohort were considered, the patients with a proportion of PSAs < or = "0.5" ng/ml continued to increase until at least 48 months post-therapy. These data conformed to a median PSA half-life of 96.2 days. CONCLUSIONS: Prostate brachytherapy with Pd-103 achieves a high rate of biochemical and clinical control in patients with clinically organ-confined disease. PSA response following brachytherapy with low-dose-rate isotopes is protracted

Eliminating the need for bilateral pelvic lymphadenectomy in select patients with prostate cancer.

Bluestein DL, Bostwick DG, Bergstralh EJ, et al.

J Urol. 1994 May; 151(5):1315-20.

To determine if the preoperative variables of serum prostate specific antigen (PSA), primary Gleason grade from the biopsy specimen and local clinical stage as determined from digital rectal examination can accurately predict the pelvic lymph node status in patients with clinically localized prostate cancer, we reviewed the medical records of 1,632 patients who underwent bilateral pelvic lymphadenectomy at our institution between January 1988 and December 1991. Using logistic regression analysis, serum PSA was found to be the best predictor of pelvic lymph node metastases (p < 0.0001). The predictive power of serum PSA could be enhanced considerably by taking into account the Gleason grade (p < 0.001) and local clinical stage (p < 0.001). A statistical model using all 3 variables was developed that allows the practicing urologist to estimate on an individual basis the probability of pelvic lymph node involvement. Using a conservative cutoff point of less than 3% as an acceptable false-negative rate, 61% of the patients with clinical stages T1a to T2b (A1 to B1) disease and 29% of those with clinical stages T1a to T2c (A1 to B2) prostate cancer may be spared an open or laparoscopic staging bilateral pelvic lymphadenectomy. As a result, patient morbidity can be decreased and a significant economic savings to the health care system can be realized. This observation has particular importance for prostate cancer patients being managed with radical perineal prostatectomy or definitive radiation therapy

Nutritional aspects of prostate cancer: a review.

Blumenfeld AJ, Fleshner N, Casselman B, et al.

Can J Urol. 2000 Feb; 7(1):927-35.

OBJECTIVES: The primary prevention of prostate cancer through nutritional modification is becoming a focus of attention as important relationships between diet and cancer are becoming evident. Relevant research is reviewed, along with recent data implicating various vitamin supplements and food products in the prevention and treatment of prostate cancer. METHODS: The epidemiology of prostate cancer, and current knowledge of prevention, screening, and progression of neoplasia is discussed. The current understanding of diet and its importance in primary and secondary prevention is explored. Literature searches were performed on MedLine using relevant keywords to find studies relating to prevention and treatment of prostate cancer using dietary methods. Of these, 104 published manuscripts were used. The search was limited from the year 1975 to the present. RESULTS: Incidence rates for prostate cancer vary according to diet and lifestyle. Several double-blind placebo-controlled clinical trials have shown that supplementation with selenium reduces cancer incidence. Inhibitory effects on the growth of in vitro prostate cancer cell lines have been observed with the administration of soy isoflavones, lycopenes from tomatoes, and vitamin D. Other compounds, such as calcium and fatty acids, have been linked to higher incidences of prostate cancer. CONCLUSIONS: Evidence exists that diet may play an important role in the primary prevention of prostate cancer. Further research is necessary to define the role that nutrition plays in the prevention or promotion of prostate cancer

The effect of calcium supplementation on the circadian rhythm of bone resorption.

Blumsohn A, Herrington K, Hannon RA, et al.

J Clin Endocrinol Metab. 1994 Sep; 79(3):730-5.

Bone resorption shows a circadian rhythm in human subjects, but the physiological mechanisms underlying this rhythm are unknown. We compared the circadian rhythm of bone collagen degradation in 18 premenopausal women before and after oral calcium supplementation (1000 mg calcium for 14 days). Subjects were randomized to receive calcium at either 0800 h or 2300 h. Continuous 48-h urine collections and 1 day of 4-h urine collections were obtained before and after the 14-day supplementation period. We measured urinary deoxypyridinoline (Dpd) and the cross-linked N-telopeptide of type I collagen (NTx) as biochemical markers of bone resorption. There was a significant effect of time of day on excretion of Dpd and NTx (analysis of variance, P < 0.001) with peak excretion between 0300-0700 h and a nadir between 1500-1900 h. The mean amplitude (peak to trough) was similar for Dpd and NTx (70.3% and 63.3%, respectively). Evening calcium supplementation resulted in marked suppression of the nocturnal increase in Dpd and NTx and reversed the usual nocturnal increase in the level of parathyroid hormone. In contrast, morning calcium supplementation had no significant effect on the circadian rhythm of Dpd or NTx. Evening calcium supplementation suppressed overall daily excretion of Dpd by 20.1% (P = "0.03)" and NTx by 18.1% (P = "0.03)." Morning calcium supplementation had no significant effect on overall daily excretion of either Dpd or NTx. We conclude that evening calcium supplementation suppresses the circadian rhythm of bone resorption. The daily rhythm of PTH secretion or calcium intake is likely to be an important determinant of this rhythm. Experimental protocols designed to investigate the effect of calcium supplementation on bone mineral density should take the timing of supplementation into account

Use of Gleason score, prostate specific antigen, seminal vesicle and margin status to predict biochemical failure after radical prostatectomy.

Blute ML, Bergstralh EJ, Iocca A, et al.

J Urol. 2001 Jan; 165(1):119-25.

PURPOSE: We determine the importance of clinical and pathological variables for predicting biochemical progression in patients after surgery for specimen confined prostate cancer. We developed a simple scoring algorithm for biochemical progression in node negative cases and tested the algorithm performance on an independent group. MATERIALS AND METHODS: Our study included 2,518 patients with pT2N0 or pT3N0 disease treated between 1990 and 1993. Gleason score, preoperative prostate specific antigen (PSA), margin status, extraprostatic extension, seminal vesicle involvement, DNA ploidy and adjuvant treatment were primary variables analyzed univariately. The Cox proportional hazards model was used on 2,000 randomly selected patients to develop a multivariate scoring algorithm for the aforementioned factors to predict biochemical progression-free survival. The final model included Gleason score, preoperative PSA, margin status, seminal vesicle involvement and adjuvant treatment. The prognostic score derived from this model was validated by applying it to the remaining 518 patients. Harrell's measure of concordance (C) was used to compare competing models. RESULTS: For patients who did not receive adjuvant therapy the derived score based on the Cox model coefficient was Gleason +1 (PSA 4 to 10), +2 (PSA 10.1 to 20), +3 (PSA greater than 20), +2 (positive seminal vesicle) and +2 (positive margin). The score was reduced by 4 if adjuvant hormonal therapy was given and by 2 for only adjuvant radiotherapy. The 5-year progression-free survival was 94% for scores less than 5, 60% for 10 and 32% for greater than 12 (C = 0. 718). Applying the score to the independent validation data set (518) resulted in 5-year progression-free survival of 96% for scores less than 5, 53% for 10 and 30% for greater than 12 (C = 0.759). CONCLUSIONS: Progression-free survival determined by the model score group identified a wide range of risk levels for patients with specimen confined prostate cancer. This simple predictive model allows identification of patients at high risk for cancer progression with specimen confined disease who may be targeted for closer surveillance and adjuvant therapy, while those at lower risk may be simply observed

Inaccuracies inherent in dual-energy X-ray absorptiometry in vivo bone mineral densitometry may flaw osteopenic/osteoporotic interpretations and mislead assessment of antiresorptive therapy effectiveness.

Bolotin HH.

Bone. 2001 May; 28(5):548-55.

New, anatomically realistic simulation studies based on a cadaveric lumbar vertebra and a broad range of soft tissue anthropometric representations have quantitatively delineated inaccuracies inherent in dual-energy X-ray absorptiometry (DXA) in vivo bone mineral density (BMD) methodology. It is found that systematic inaccuracies in DXA BMD measurements may readily exceed +/-20% at typical in vivo lumbar vertebral sites, especially for osteopenic/osteoporotic, postmenopausal, and elderly patients. These findings are quantitatively compared with extensive clinical evidence of strong, positive correlations between soft tissue anthropometrics and DXA in vivo BMD upon which prior significant bone biology interpretations and implications have been based. The agreement is found to be both qualitatively and quantitatively excellent. Moreover, recent extensive multicenter clinical studies have also exposed new facets of strong linkages between body mass/percent body fat/body mass index (BMI) and DXA-measured BMD that are particularly relevant to osteopenia/osteoporosis and remedial effectiveness of antiresorptive drug therapy. These seemingly disparate and unrelated diagnostic and prognostic aspects of clinically observed associations between soft tissue anthropometrics and measured vertebral BMD are, in this study, self-consistently shown to share the common origin of being manifestations of systematic inherent inaccuracies in DXA in vivo BMD methodology, without the need to invoke any underlying biologically causal mechanism(s). These inaccuracies arise principally from absorptiometric disparities between the intra- and extraosseous soft tissues within the DXA scan region of interest. The present evaluative comparisons are based exclusively on an incisive and diverse body of clinical data that appears difficult to dismiss or discount. Previous invocations of biologically causal mechanisms responsible for this broad range of observations linking body mass, percent body fat, and/or BMI to measured BMD now appear questionable. This doubtful status has also been extended in the present work to previously reported relationships between antiresorptive therapies and observed changes in DXA-derived BMD. These findings strongly indicate that critical and insightful reassessments of diagnostic/prognostic imputations underpinned by DXA in vivo BMD measurements are warranted. It is suggested that a good deal of what is known of bone fragility, bone densitometry, antiresorptive drug efficacy, and/or other therapeutic regimens, if based on patient-specific in vivo DXA methodology, may prove to be equivocal and tenuous

Microvessel density predicts survival in prostate cancer patients subjected to watchful waiting.

Borre M, Offersen BV, Nerstrom B, et al.

Br J Cancer. 1998 Oct; 78(7):940-4.

The biological potential of prostate cancer is highly variable and cannot be satisfactorily predicted by histopathological criteria alone. Angiogenesis, the formation of new blood vessels, has been suggested to provide important prognostic information in prostate cancer. The aim of this study was to investigate whether microvessel density (MVD) at diagnosis was correlated with disease-specific survival in a non-curative treated population of prostate cancer patients. MVD was immunohistochemically (factor VIII-related antigen) quantified in archival tumours obtained at diagnosis in 221 prostate cancer patients. Median length of follow-up was 15 years. The maximal MVD was quantified inside a 0.25 mm2 area of the tumour and the median MVD was 43 (range 16-151) mm2. MVD was statistically significantly correlated with clinical stage (P < 0.0001) and histopathological grade (P < 0.0001). When dichotomized by the median counts, MVD was shown to be significantly associated (P = "0.0001)" with disease-specific survival in the entire population as well as in the theoretically curable clinically localized subpopulation. A multivariate analysis demonstrated that MVD was a significant predictor of disease-specific survival in the entire cancer population (P = "0.0004)," as well as in the clinically localized cancer population (P < 0.0001). These findings suggest that quantitation of angiogenesis reflects the spontaneous clinical outcome of prostate cancer

p53 accumulation associated with bcl-2, the proliferation marker MIB-1 and survival in patients with prostate cancer subjected to watchful waiting.

Borre M, Stausbol-Gron B, Overgaard J.

J Urol. 2000 Sep; 164(3 Pt 1):716-21.

PURPOSE: We describe the association of p53 nuclear protein accumulation with bcl-2 expression, tumor cell proliferation and clinical outcome in a prostate cancer population undergoing watchful waiting. MATERIALS AND METHODS: Immunohistochemical staining for p53 was semiquantitatively scored in archival formalin fixed, paraffin embedded tumor tissue obtained at diagnosis in 221 patients with prostate cancer. At a median of 15 years followup was nearly complete. Eventually 57% of the patients died of prostate cancer. RESULTS: p53 Immunohistochemical staining was heterogeneous but in all cases at least clusters of tumor cells had nuclear staining for p53. The percent of p53 immunoreactive tumor cells was scored as 0 to 4+ in p53 positive hot spots. p53 immunoreactivity correlated with clinical stage and histopathological grade (p = 0.003 and 0.009, respectively). When dichotomized into low (0% to 50%) and high (51% to 100%) immunoreactivity groups of 40 and 181 patients, respectively, p53 accumulation was significantly associated with disease specific survival in the study population overall (p

Association between immunohistochemical expression of vascular endothelial growth factor (VEGF), VEGF-expressing neuroendocrine-differentiated tumor cells, and outcome in prostate cancer patients subjected to watchful waiting.

Borre M, Nerstrom B, Overgaard J.

Clin Cancer Res. 2000 May; 6(5):1882-90.

Tumor growth is dependent on angiogenesis, which is thought to be controlled by angiogenic factors. Therefore, the immunoreactivity of the angiogenic cytokine vascular endothelial growth factor (VEGF) was semiquantitatively scored in archival prostate tumors obtained at diagnosis in 221 patients followed expectantly. At diagnosis, 125 patients suffered from clinically localized disease. Median length of follow-up was 15 years, and 57% of the patients eventually died of prostate cancer. All of the tumors exhibited cytoplasmic staining for VEGF. The staining intensity was weak in 47 tumors and moderate and strong in 107 and 67, respectively. VEGF expression was significantly correlated with microvessel density (MVD; median, 43; range, 16-151; P = 0.014), increasing T-classification (P = 0.001), dedifferentiation (P < 0.001), and disease-specific survival (P = "0.013)." Strongly VEGF-immunoreactive, neuroendocrine-differentiated (NE) tumor cells were observed in 125 tumors. NE expression was significantly correlated with increasing MVD, increasing T-classification, dedifferentiation, and survival (all, P < 0.001). MVD and NE tumor cell expressions were significant variables in a multivariate analysis that included patients with clinically localized prostate cancer only. VEGF and NE expression were significantly correlated with MVD, clinical characteristics, and disease-specific survival. NE expression was a significant prognostic marker in localized prostate cancer patients, whereas the applied semiquantitatively scoring of VEGF expression was inadequate to make this growth factor provide any additional prognostic information. Moreover, the significant VEGF expression of NE tumor cells suggests an additional important character of these cells in the involvement in disease progression

Endogenous interleukin 6 is a resistance factor for cis-diamminedichloroplatinum and etoposide-mediated cytotoxicity of human prostate carcinoma cell lines.

Borsellino N, Belldegrun A, Bonavida B.

Cancer Res. 1995 Oct 15; 55(20):4633-9.

Hormonal treatment of advanced prostatic cancer patients generally results in an initially beneficial response, but the treated patients develop hormonally resistant disease in which no curative therapy is currently available. Recent studies have revealed that interleukin 6 (IL-6) is a growth factor for myeloma, renal cell carcinoma, and certain T-cell lymphomas. Further, IL-6 has been shown to block apoptosis induced by p53, transforming growth factor beta, and certain cancer chemotherapeutic compounds. The objective of the present study was to determine whether IL-6 is a growth factor for two human prostate cancer lines and whether it protects the tumor cells from drug-induced cell death. Two hormone-independent prostate cell lines were used in this study, namely PC-3 and DU145, and these have been shown to be relatively resistant to cis-diamminedichloroplatinum (CDDP), etoposide (VP-16), and adriamycin (ADR). Both cell lines express IL-6 mRNA and secrete IL-6 constitutively. The addition of anti-IL-6 antiserum to the cell lines resulted in a significant inhibition of cell growth up to day 2, and when additional antibody was added at day 2 the inhibition persisted for 4 days. The coaddition of anti-IL-6 antiserum and CDDP or VP-16 resulted in synergy in cytotoxicity in both cell lines, whereas the combination of antibody and ADR or suramin resulted only in additive effects. Sequential treatment revealed that anti-IL-6 antibody was required to achieve synergy, whereas either sequence of pretreatment resulted in synergy with anti-IL-6 and CDDP but not with VP-16. CDDP treatment of tumor cells down-regulated IL-6 mRNA expression and IL-6 secretion. The present findings demonstrate that IL-6 is an autocrine/paracrine growth factor for DU145 and PC-3 prostate lines. Additionally, the secretion of this cytokine protects the tumor cells against the cytotoxic effect of CDDP and VP-16 and its neutralization sensitizes the cells to cytotoxicity. Overall, the studies suggest that agents that can down-regulate or inhibit protective factors in tumors may overcome drug resistance

Fraction of prostate cancer incidence attributed to diet in Athens, Greece.

Bosetti C, Tzonou A, Lagiou P, et al.

Eur J Cancer Prev. 2000 Apr; 9(2):119-23.

Diet appears to be a major determinant in the incidence of prostate cancer. In a case-control study conducted in Athens, Greece, we found that dairy products, butter and seed oils were positively associated with risk of prostate cancer, whereas cooked and raw tomatoes were inversely associated. We utilized the data from this study to calculate the population attributable fractions under alternative assumptions of feasible dietary changes. For each subject, a dietary score was calculated and categorized into approximately quintiles, representing increasing levels of prostate cancer risk as a function of the intake of the five discriminatory food groups or items. Population attributable fractions in terms of this dietary score were calculated taking into account multivariate adjustment. We observed that, if all individuals were shifted to the baseline category, the incidence of prostate cancer in this study population would be reduced by 41% (95% confidence interval 23-59%). However, if all individuals were shifted to the adjacent lower risk quintile, the expected incidence reduction would be a more modest 19%. The incidence of prostate cancer in Greece could be reduced by about two-fifths if the population increased the consumption of tomatoes and reduced the intake of dairy products, and substituted olive oil for other added lipids

Plasma selenium level before diagnosis and the risk of prostate cancer development.

Brooks JD, Metter EJ, Chan DW, et al.

J Urol. 2001 Dec; 166(6):2034-8.

PURPOSE: Epidemiological studies and a randomized intervention trial suggest that the risk of prostate cancer may be reduced by selenium intake. We investigated whether plasma selenium level before diagnosis correlated with the risk of later developing prostate cancer. MATERIALS AND METHODS: A case control study was performed on men from the Baltimore Longitudinal Study of Aging registry, including 52 with known prostate cancer and 96 age matched controls with no detectable prostatic disease. Plasma selenium was measured at an average time plus or minus standard deviation of 3.83 +/- 1.85 years before the diagnosis of prostate cancer by graphite furnace atomic absorption spectrophotometry. Adjusted odds ratio and 95% confidence interval were computed with logistic regression. RESULTS: After correcting for years before diagnosis, body mass index, and smoking and alcohol use history, higher selenium was associated with a lower risk of prostate cancer. Compared with the lowest quartile of selenium (range 8.2 to 10.7 microg./dl.), the odds ratios of the second (10.8 to 11.8), third (11.9 to 13.2) and fourth (13.3 to 18.2) quartiles were 0.15 (95% confidence interval 0.05 to 0.50), 0.21 (0.07 to 0.68) and 0.24 (0.08 to 0.77, respectively, p =0.01). Furthermore, plasma selenium decreased significantly with patient age (p

Unravelling the links between calcium excretion, salt intake, hypertension, kidney stones and bone metabolism.

Cappuccio FP, Kalaitzidis R, Duneclift S, et al.

J Nephrol. 2000 May; 13(3):169-77.

Evidence from animal, clinical and epidemiological studies suggests that high blood pressure is associated with abnormalities of calcium metabolism, leading to increased calcium loss, secondary activation of the parathyroid gland, increased movement of calcium from bone and increased risk of urinary tract stones. Some of these abnormalities are detectable in children and young people and continue throughout adult life. The cluster of abnormalities may be due either to a primary renal tubular defect ('renal calcium leak' hypothesis) or to the effect of central volume expansion seen in hypertension ('central blood volume' hypothesis). A high salt intake is known to aggravate these abnormalities and their consequences. If substantial calcium loss related to high blood pressure is sustained over many decades, increased excretion of calcium in the urine may result in an increased risk of urinary tract stones, and the increased movement of calcium from bone may result in higher rates of bone mineral loss, thereby increasing the risk of osteoporosis. The present review summarises the evidence, suggests a unifying hypothesis and discusses clinical and public health implications

An algorithm combining age, total prostate-specific antigen (PSA), and percent free PSA to predict prostate cancer: results on 4298 cases.

Carlson GD, Calvanese CB, Partin AW.

Urology. 1998 Sep; 52(3):455-61.

OBJECTIVES: To (1) determine if patient age and total prostate-specific antigen (PSA) levels could enhance the ability of percent free PSA to distinguish prostate cancer from benign prostate disease within the 4.0 to 20 ng/mL total PSA range; (2) define the probability of prostate cancer based on patient age, total PSA, and percent free PSA; and (3) define a probability cutoff that distinguishes benign from malignant prostate disease. METHODS: The 3773 urologically referred patients with serum PSA values between 4.0 and 20 ng/mL had a sextant biopsy diagnosed as either prostatic carcinoma (1234) or benign prostatic disease (2539) within 60 days of serum specimen collection. We created a logistic regression model, using patient age, total PSA, and percent free PSA, to assign a probability of prostate cancer, and tested the model on an additional data set (525 patients) to calculate sensitivity and specificity. RESULTS: An 18% probability cutoff detected 95% of malignant biopsies and identified 34% of negative biopsies in the validation set. This approach yielded an 11% percentage point increase in specificity over percent free PSA alone. A 20% probability cutoff detected 90% of malignant cases and identified 42% of negative biopsies. CONCLUSIONS: A prostate cancer probability based on age, total PSA, and percent free PSA is more effective than percent free PSA alone in differentiating benign prostate disease from prostate cancer. This model may assist physicians and patients regarding the need for biopsy

Dexamethasone-induced cytotoxic activity and drug resistance effects in androgen-independent prostate tumor PC-3 cells are mediated by lipocortin 1.

Carollo M, Parente L, D'Alessandro N.

Oncol Res. 1998; 10(5):245-54.

We have examined the effects that dexamethasone (DEX), alone or in combination with doxorubicin (DOX), cisplatin (CDDP), or etoposide (VP-16), exerts on the growth of the androgen-independent prostate cancer PC-3 cells. DEX exhibited only a limited cytotoxicity (growth inhibition of about 28% or 20% after 24 or 72 h of exposure, respectively, in the range of DEX 10-100 nM) and did not induce apoptosis in the cells. This cytotoxicity of DEX was mimicked by an active peptide (peptide Ac2-26) drawn from the human lipocortin 1 N-terminus region and abrogated by an antibody to human lipocortin 1. Two inhibitors of arachidonic acid metabolism, tenidap and indomethacin, also caused cytotoxicity. The cytotoxic effects of DEX in combination with DOX, CDDP, or VP-16 were antagonistic when the steroid was administered 3 h before or simultaneously with the drugs. Other schedule-dependency experiments further clarified that, at least in the case of the combination with DOX, it is the steroid that desensitizes the cells to the drug. When peptide Ac2-26, tenidap, or indomethacin were tested in combination with DOX, antagonism was also observed. DEX treatment neither modified the ability of the cells to accumulate DOX nor changed their weak expression of P-glycoprotein. PC-3 cells also produce IL-6, which autocrinally stimulates their growth, and whose gene expression may be reduced by glucocorticoids. In the present experiments DEX only slightly decreased the production and secretion of IL-6 by the cells. The present findings suggest that the slight cytotoxic activity and the drug resistance effects of DEX on PC-3 cells are mediated by induction of lipocortin 1 and inhibition of arachidonic acid metabolism, with no relationship to downregulation of IL-6 levels. These findings indicate also that the combination of DEX with conventional chemotherapeutic agents may result in antagonistic antitumor effects

Familial risk factors for prostate cancer.

Carter BS, Steinberg GD, Beaty TH, et al.

Cancer Surv. 1991; 11:5-13.

This chapter describes the application of the genetic epidemiological approach to the study of human prostate cancer. We review the evidence for the familial clustering of prostate cancer and the Mendelian nature of this aggregation. The nature of this clustering is such that the closer genetically a man is to an affected relative and the greater number of relatives affected in a man's family, the greater his risk of prostate cancer. A complex segregation analysis of the 691 prostate cancer families showed that prostate cancer clustering can be explained by Mendelian inheritance of a rare autosomal gene producing prostate cancer at an early age. A model of inherited prostate cancer in the setting of multistep carcinogenesis is presented. The implications of these data for clinicians who diagnose and treat prostate cancer are also discussed

Mendelian inheritance of familial prostate cancer.

Carter BS, Beaty TH, Steinberg GD, et al.

Proc Natl Acad Sci U S A. 1992 Apr 15; 89(8):3367-71.

Previous studies have demonstrated familial clustering of prostate cancer. To define the nature of this familial aggregation and to assess whether Mendelian inheritance can explain prostate cancer clustering, proportional hazards and segregation analyses were performed on 691 families ascertained through a single prostate cancer proband. The proportional hazards analyses revealed that two factors, early age at onset of disease in the proband and multiple affected family members, were important determinants of risk of prostate cancer in these families. Furthermore, segregation analyses revealed that this clustering can be best explained by autosomal dominant inheritance of a rare (q = 0.0030) high-risk allele leading to an early onset of prostate cancer. The estimated cumulative risk of prostate cancer for carriers revealed that the allele was highly penetrant: by age 85, 88% of carriers compared to only 5% of noncarriers are projected to be affected with prostate cancer. The best fitting autosomal dominant model further suggested that this inherited form of prostate cancer accounts for a significant proportion of early onset disease but overall is responsible for a small proportion of prostate cancer occurrence (9% by age 85). These data provide evidence that prostate cancer is inherited in Mendelian fashion in a subset of families and provide a foundation for gene mapping studies of heritable prostate cancer. Characterization of genes involved in inherited prostate cancer could provide important insight into the development of this disease in general

Hereditary prostate cancer: epidemiologic and clinical features.

Carter BS, Bova GS, Beaty TH, et al.

J Urol. 1993 Sep; 150(3):797-802.

Estimation of prostatic growth using serial prostate-specific antigen measurements in men with and without prostate disease.

Carter HB, Morrell CH, Pearson JD, et al.

Cancer Res. 1992 Jun 15; 52(12):3323-8.

Prostate growth curves were estimated from serial prostate-specific antigen (PSA) measurements on frozen sera in three groups of men: (a) 16 men with no prostatic disease by urological history and examination; (b) 20 men with a histological diagnosis of benign prostatic hyperplasia (BPH) who had undergone simple prostatectomy; and (c) 18 men with a histological diagnosis of prostate cancer. The median number of repeated PSA measurements over an 8- to 26-yr period prior to histological diagnosis or exclusion of prostate disease was eight and 11 for noncancer and cancer subjects, respectively. Predicted rates of change in PSA (PSA velocity) were linear and curvilinear for control and BPH subjects, respectively. Subjects with cancer demonstrated both a linear and an exponential phase of PSA velocity. Based on time to double PSA, we estimated the epithelial doubling time for men without prostate disease to range from 54 +/- 13 yr at age 40 to 84 +/- 13 yr at age 70. For men with BPH, doubling times ranged from 2 +/- 13 yr at age 40 to 17 +/- 5 yr at age 85. Subjects with local/regional and advanced/metastatic cancer had similar PSA doubling times of 2.4 +/- 0.6 yr and 1.8 +/- 0.2 yr, respectively. These data are consistent with what is known about prostatic growth with age in men without prostate disease and BPH, and the kinetics of prostate cancer growth. Estimates of prostatic growth rate from changes in PSA may be useful clinically in management of men with prostate disease

PSA velocity for the diagnosis of early prostate cancer. A new concept.

Carter HB, Pearson JD.

Urol Clin North Am. 1993 Nov; 20(4):665-70.

An evaluation of longitudinal changes in PSA in men with and without prostate disease revealed that with age, the development of prostate disease is the most important factor influencing changes in PSA. Furthermore, the PSA changes with age are significantly different in men with and without prostate disease. The PSA velocity is greater in men with prostate cancer than in men with BPH and greater in men with prostate cancer and BPH than in men without any prostate disease. Thus, evaluation of PSA changes may help distinguish between men with prostate cancer and those without the disease. This idea will need to be confirmed prospectively. Finally, estimation of PSA doubling time from changes in PSA suggests that changes reflect prostatic growth. Therefore, PSA velocity could be of benefit in identifying men with prostate cancer that is destined to progress

Prostate-specific antigen variability in men without prostate cancer: effect of sampling interval on prostate-specific antigen velocity.

Carter HB, Pearson JD, Waclawiw Z, et al.

Urology. 1995 Apr; 45(4):591-6.

OBJECTIVES. To evaluate short-term and long-term variability between prostate-specific antigen (PSA) measurements to determine the most appropriate PSA sampling interval and rate of PSA change (PSA velocity) to distinguish between men with and without prostate cancer. METHODS. Retrospective study of PSA variability and PSA velocity in three groups of men without a diagnosis of prostate cancer and PSA levels less than 10 ng/mL: 56 men with a histologic diagnosis of benign prostatic hyperplasia (BPH; histologic BPH group) and 527 men with no history of cancer (noncancer group) who were part of the Baltimore Longitudinal Study of Aging and had PSA sampled at 2-year intervals (long-term), and 223 men with a clinical diagnosis of BPH (clinical BPH group) who had PSA sampled at 3-month intervals (short-term). PSA variability (deviation between consecutive measurements) and PSA velocity based on both two consecutive measurements and three consecutive measurements (average velocity) were calculated for each study group. RESULTS. PSA velocity is the deviation in PSA measurements relative to the elapsed time between the measurements. Because the variability in PSA between measurements was similar for the groups, the major factors that influenced PSA velocity were the sampling interval between PSA measurements, and to a lesser extent, the number of repeat PSA measurements. The 99th percentile for PSA velocity was 0.7 (histologic BPH group) and 0.75 ng/mL per year for the noncancer group when three measurements with a 24-month PSA sampling interval were used. However, the 99th percentile for PSA velocity was 5.8 and 2.4 ng/mL per year when three measurements with 3-month and 6-month PSA sampling intervals were used. Using three measurements, the percentage of subjects with a PSA velocity more than 0.75 ng/mL per year was 1% for the groups with a 24-month PSA sampling interval and 28% and 17% for 3-month and 6-month PSA sampling intervals, respectively. The 99th percentile for PSA velocity and the percentage of subjects with a PSA velocity more than 0.75 ng/mL per year was higher using two measurements compared to three measurements regardless of PSA sampling interval. CONCLUSIONS. PSA velocity is inversely related to the interval between PSA measurements. A PSA velocity more than 0.75 ng/mL per year is useful in distinguishing between men with and without prostate cancer when: (1) velocity is based on three consecutive measurements; and (2) PSA is sampled long-term (2 years) but not short-term (3 to 6 months)

Prostate-specific antigen velocity and repeated measures of prostate-specific antigen.

Carter HB, Pearson JD.

Urol Clin North Am. 1997 May; 24(2):333-8.

Numerous studies evaluating different populations have shown similar findings with respect to repeated PSA measurements and PSAV. First, there is substantial within-individual variability between repeated PSA measures. Second, this variability between PSA measurements precludes the use of a simple change in PSA as a marker for prostate cancer. Third, when one adjusts the changes that occur in PSA over an elapsed time of 1.5 to 2 years (PSAV), less than 5% of men without prostate cancer will have a PSAV of 0.75 ng/mL/ y or greater, and approximately 70% of men with prostate cancer will have a PSAV of 0.75 ng/mL/ y or greater. These data strongly suggest that PSAV is a specific marker for the presence of prostate cancer

Use of percentage of free prostate-specific antigen to identify men at high risk of prostate cancer when PSA levels are 2.51 to 4 ng/mL and digital rectal examination is not suspicious for prostate cancer: an alternative model.

Catalona WJ, Partin AW, Finlay JA, et al.

Urology. 1999 Aug; 54(2):220-4.

OBJECTIVES: Currently, many clinicians do not recommend prostate biopsy for men with digital rectal examination (DRE) results that are not suspicious for cancer and prostate-specific antigen (PSA) values between 2.51 and 4 ng/mL. We propose a new model for the detection of prostate cancer using the percentage of free PSA (%FPSA) in the limited range of PSA values between 2.51 and 4 ng/mL that maximizes clinical specificity (ie, minimizes false-positive results). This model identifies higher risk patients in this relatively low-risk population. METHODS: Three hundred sixty-eight archived serum samples from men evaluated and treated at two academic institutions were reviewed. All men had a histologic diagnosis, findings not suspicious for cancer on DRE, and PSA levels between 2.51 and 4 ng/mL. Samples were tested in Hybritech's Tandem-R PSA and Tandem-R free PSA (FPSA) assays in the same laboratory at each institution. RESULTS: Various models for cancer detection using %FPSA when PSA is 2.51 to 4 ng/mL and DRE is not suspicious for cancer are proposed. These models recommend biopsy for only 10% to 36% of the men in this population and would identify as many as 30% to 54% of the detectable cancers. There is evidence that the cancers that would be detected are the most aggressive cancers in this population. CONCLUSIONS: Our models identified men with a higher risk of prostate cancer in a relatively low-risk population that currently does not routinely undergo biopsy. This may allow for a more cost-effective way to increase cancer detection when PSA values are between 2.51 and 4 ng/mL and DRE is not suspicious for cancer. This model has the potential to detect a greater number of clinically important and potentially curable cancers than would be detected with current practice

Anti-p53 antibodies in patients with Barrett's esophagus or esophageal carcinoma can predate cancer diagnosis.

Cawley HM, Meltzer SJ, De Benedetti VM, et al.

Gastroenterology. 1998 Jul; 115(1):19-27.

BACKGROUND & AIMS: We previously discovered anti-p53 antibodies predating a cancer diagnosis in subjects at increased risk for liver, lung, breast, and prostate cancer. Recently, we reported a significant correlation (P < 0.017) between p53 antibodies and p53 mutations in patients with late-stage esophageal carcinoma. Because others have reported p53 mutations and overexpression of p53 protein in Barrett's esophagus, we studied p53 antibodies in plasma of 88 serially endoscoped patients: 36 with Barrett's metaplasia, 23 with esophageal squamous cell carcinoma, 10 with esophageal adenocarcinoma, and 19 with esophagitis or normal esophagus. METHODS: We used enzyme immunoassay, immunoblotting, and immunoprecipitation assays for p53 antibodies; polymerase chain reaction, denaturant gradient gel electrophoresis, and sequencing for p53 mutations; and immunohistochemistry for p53 protein. RESULTS: p53 antibodies were detected in 4 patients with Barrett's esophagus, including 1 with dysplasia that later progressed to adenocarcinoma, and in 10 cancer patients (P = "0.002)" (8 squamous and 2 adenocarcinoma), 2 of whom (1 squamous, 1 adenocarcinoma) had antibodies before cancer was diagnosed. Other patient groups were too small for informative statistical analysis. Six antibody-positive cancer patients had p53 mutations, whereas 2 patients with cancer and 1 with Barrett's esophagus with antibodies had p53 protein overexpressed in esophageal tissues. CONCLUSIONS: Patients with Barrett's esophagus and esophageal cancer can develop p53 antibodies that may predate the clinical diagnosis of malignancy

The usefulness of prostate specific antigen density as a screening method for prostatic carcinoma.

Chakrabarti S, Raha K, Bhunia CL, et al.

J Indian Med Assoc. 2001 Nov; 99(11):627-8, 630.

Prostate specific antigen (PSA) has been used extensively for monitoring the progression of prostatic cancer since its discovery in 1979. Unfortunately the measurement of PSA in serum is not sufficiently specific for early detection of prostatic carcinoma (CaP) as it is secreted by normal as well as hyperplastic or cancerous prostatic tissue. As serum PSA is the reflection of the number of prostatic epithelial cells, a small cancerous prostate gland having increased number of cells per unit volume leaks more PSA in serum than a benign, large gland. Thus the concept of PSA density (PSAD) has been proposed (the quotient of serum PSA divided by the volume of prostate in cubic centimeter) as an indicator for prostatic malignancy. In the present study pre-operative PSAD values of 65 cases of prostatic diseases were calculated [54 cases of benign prostatic hyperplasia (BPH) and 11 cases of C3P]. Serum PSA was measured by enzyme linked immunosorbent assay (ELISA) method and the prostatic volume was measured by transrectal ultrasonography (TRUS). Although 8 cases of BPH (14.8%) had raised PSA level, abnormal PSAD (0.1 or above) was noted in only 3 cases. All cases having PSAD value above 0.2 had carcinoma. The PSAD value above 0.1 in cases of CaP was found to be significant (p

Plasma insulin-like growth factor-I and prostate cancer risk: a prospective study.

Chan JM, Stampfer MJ, Giovannucci E, et al.

Science. 1998 Jan 23; 279(5350):563-6.

Insulin-like growth factor-I (IGF-I) is a mitogen for prostate epithelial cells. To investigate associations between plasma IGF levels and prostate cancer risk, a nested case-control study within the Physicians' Health Study was conducted on prospectively collected plasma from 152 cases and 152 controls. A strong positive association was observed between IGF-I levels and prostate cancer risk. Men in the highest quartile of IGF-I levels had a relative risk of 4.3 (95 percent confidence interval 1.8 to 10.6) compared with men in the lowest quartile. This association was independent of baseline prostate-specific antigen levels. Identification of plasma IGF-I as a predictor of prostate cancer risk may have implications for risk reduction and treatment

Dairy products, calcium, phosphorous, vitamin D, and risk of prostate cancer (Sweden).

Chan JM, Giovannucci E, Andersson SO, et al.

Cancer Causes Control. 1998 Dec; 9(6):559-66.

OBJECTIVES: Dairy products consistently have been associated with an increased risk of prostate cancer, yet the mechanism of this relationship remains unknown. Recent hypotheses propose that 1,25 dihydroxyvitamin D (1,25 D) is protective for prostate cancer. One study in the United States found that calcium consumption, which can lower circulating 1,25 D, was associated with higher risk of advanced prostate cancer, and we sought to address this hypothesis in a distinct population. METHODS: We analyzed data from a population-based case-control study of prostate cancer conducted in Orebro, Sweden, with 526 cases and 536 controls. Using unconditional logistic regression models, we examined the relationship of dairy products, dietary calcium, phosphorous, and vitamin D with risk of total, extraprostatic, and metastatic prostate cancer. RESULTS: Calcium intake was an independent predictor of prostate cancer (relative risk (RR) = 1.91, 95 percent confidence interval (CI) 1.23-2.97 for intake > or = 1183 vs. < 825 mg/day), especially for metastatic tumors (RR = "2.64," 95 percent CI 1.24-5.61), controlling for age, family history of prostate cancer, smoking, and total energy and phosphorous intakes. High consumption of dairy products was associated with a 50 percent increased risk of prostate cancer. CONCLUSIONS: Our results support the hypothesis that high calcium intake may increase risk of prostate cancer, and this relation may underlie previously observed associations between dairy products and prostate cancer

Supplemental vitamin E intake and prostate cancer risk in a large cohort of men in the United States.

Chan JM, Stampfer MJ, Ma J, et al.

Cancer Epidemiol Biomarkers Prev. 1999 Oct; 8(10):893-9.

A clinical trial of vitamin E and beta-carotene supplementation for lung cancer prevention among male smokers in Finland recently reported an unexpected, strong protective effect of vitamin E against prostate cancer incidence and mortality. Our objective was to prospectively examine supplemental vitamin E intake and prostate cancer risk in a distinct U.S. population. In 1986, we identified 47,780 U.S. male health professionals, free from diagnosed cancer, who completed a dietary and lifestyle questionnaire; supplemental vitamin E and prostate cancer incidence were updated biennially through 1996. We estimated relative risks (RRs) from multivariate pooled logistic regression models. There were 1896 total (non-stage A1), 522 extraprostatic, and 232 metastatic or fatal incident prostate cancer cases diagnosed between 1986-1996. Men consuming at least 100 IU of supplemental vitamin E daily had multivariate RRs of 1.07 (95% confidence interval [CI], 0.95-1.20) for total and 1.14 (95% CI, 0.82-1.59) for metastatic or fatal prostate cancer compared with those consuming none. Current use, dosage, and total duration of use of specific vitamin E supplements or multivitamins were not associated with risk. However, among current smokers and recent quitters, those who consumed at least 100 IU of supplemental vitamin E per day had a RR of 0.44 (95% CI, 0.18-1.07) for metastatic or fatal prostate cancer compared with nonusers. Thus, supplemental vitamin E was not associated with prostate cancer risk generally, but a suggestive inverse association between supplemental vitamin E and risk of metastatic or fatal prostate cancer among current smokers and recent quitters was consistent with the Finnish trial among smokers and warrants further investigation

Dairy products, calcium, and prostate cancer risk in the Physicians' Health Study.

Chan JM, Stampfer MJ, Ma J, et al.

Am J Clin Nutr. 2001 Oct; 74(4):549-54.

BACKGROUND: A high calcium intake, mainly from dairy products, may increase prostate cancer risk by lowering concentrations of 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], a hormone thought to protect against prostate cancer. The results of epidemiologic studies of this hypothesis are inconclusive. OBJECTIVE: We investigated the association between dairy product and calcium intakes and prostate cancer risk in the Physicians' Health Study, a cohort of male US physicians. DESIGN: At baseline, the men answered abbreviated dietary questionnaires. During 11 y of follow-up, we documented 1012 incident cases of prostate cancer among 20885 men. We estimated dairy calcium intake on the basis of consumption of 5 major dairy products and used logistic regression to estimate relative risk. RESULTS: At baseline, men who consumed >600 mg Ca/d from skim milk had lower plasma 1,25(OH)(2)D(3) concentrations than did those consuming < or ="150" mg Ca/d [71 compared with 85 pmol/L (30.06 compared with 35.64 pg/mL); P = "0.005]." Compared with men consuming 2.5 servings had a multivariate relative risk of prostate cancer of 1.34 (95% CI: 1.04, 1.71) after adjustment for baseline age, body mass index, smoking, exercise, and randomized treatment assignment in the original placebo-controlled trial. Compared with men consuming 600 mg/d had a 32% higher risk of prostate cancer (95% CI: 1.08, 1.63). CONCLUSIONS: These results support the hypothesis that dairy products and calcium are associated with a greater risk of prostate cancer

Prognostic significance of Gleason score 3+4 versus Gleason score 4+3 tumor at radical prostatectomy.

Chan TY, Partin AW, Walsh PC, et al.

Urology. 2000 Nov 1; 56(5):823-7.

OBJECTIVES: To determine the clinical significance of Gleason score 3+4 versus 4+3 on radical prostatectomy. METHODS: Of 2390 men who underwent radical prostatectomy by a single surgeon, 570 had Gleason score 7 tumors without lymph node metastasis, seminal vesicle invasion, or tertiary Gleason pattern 5. Patients were evaluated for biochemical recurrence (prostate-specific antigen progression) and distant metastases. RESULTS: Eighty percent of patients had Gleason score 3+4, 20% had 4+3. The rate of established extraprostatic extension at radical prostatectomy for Gleason score 3+4 and 4+3 tumors was 38.2% and 52.7%, respectively (P = 0.008). With a mean follow-up of 4.6 years for men without progression, Gleason score 4+3 tumors had an increased risk of progression independent of stage and margin status (P

Using proportions of free to total prostate-specific antigen, age, and total prostate-specific antigen to predict the probability of prostate cancer.

Chen YT, Luderer AA, Thiel RP, et al.

Urology. 1996 Apr; 47(4):518-24.

OBJECTIVES: This study was undertaken to define the probability of prostate cancer as a function of the proportion of free to total prostate-specific antigen (FTPSA), total PSA, and age for those patients with total PSA levels between 2.5 and 20.0 ng/mL. METHODS: Prebiopsy serums were obtained from 428 untreated patients (165 malignant, 263 benign) who had undergone sextant six-core biopsy. Each patient had no prior history of prostate cancer and a prebiopsy total PSA value between 2.5 and 20.0 ng/mL. Total PSA levels were determined using the PA immunoassay performed on the TOSOH AIA-1200 automated immunoassay instrument. Free PSA levels were determined using a monoclonal-polyclonal antibody sandwich radioimmunoassay. RESULTS: In men with total PSA values between 2.5 and 20.0 ng/mL, the FTPSA significantly differentiated between patients with benign and malignant histologic states. Log linear modeling indicated distinct differences in the risk for cancer as a function of FTPSA, total PSA, and age. The highest probability for cancer was observed in men greater than 70 years of age who had a FTPSA less than 7% and total PSA more than 10.0 ng/mL. Conversely, the lowest probability for cancer was observed in patients less than 60 years of age who had a FTPSA more than 25% and a total PSA less than 4 ng/mL. CONCLUSIONS: The probability that prostate cancer will be found on biopsy has a marked gradient that is associated with age, total PSA, and FTPSA. The extreme ends of FTPSA of less than 7% and more than 25% are diagnostic for prostate cancer and benign prostatic disease, respectively

Alpha 1-adrenoceptor antagonists terazosin and doxazosin induce prostate apoptosis without affecting cell proliferation in patients with benign prostatic hyperplasia.

Chon JK, Borkowski A, Partin AW, et al.

J Urol. 1999 Jun; 161(6):2002-8.

PURPOSE: Recent evidence indicated that an alpha 1 blocker, doxazosin, induces prostate apoptosis in patients with benign prostatic hyperplasia (BPH). In this study, to determine whether this apoptotic response was mediated by alpha 1 adrenoceptor-dependent mechanism or was specific to doxazosin, we examined the effect of another alpha 1 blocker, terazosin, in addition to doxazosin, on the dynamics of prostate cell growth. MATERIALS AND METHODS: Cell proliferation and apoptosis were evaluated in BPH patients, an untreated (control) group (n = 31), and men treated with terazosin (n = 42) and doxazosin (n = 61) for the relief of the obstructive symptoms. Terazosin (1 to 10 mg./day) and doxazosin (2 to 8 mg./day) treatment varied from 1 week to 3 years. Ki-67 immunostaining and the TUNEL assay were used to evaluate the proliferative and apoptotic indices, respectively, in both the epithelial and stromal components of prostate (biopsy and prostatectomy) specimens. The smooth muscle cell content of the prostatic stroma was identified on the basis of smooth muscle alpha-actin immunoreactivity. RESULTS: A significant induction of apoptosis was observed in both the prostatic epithelial and stromal cells within the first month of terazosin and doxazosin therapy, as compared with untreated controls (p < 0.05). Furthermore, the marked induction of prostatic stroma apoptosis in response to both alpha 1 adrenoceptor antagonists was paralleled by a significant decrease in the smooth muscle alpha-actin expression. This loss of prostatic smooth muscle cells correlated with morphological stromal regression (as detected by trichrome staining) and BPH symptom improvement. Neither terazosin nor doxazosin therapy resulted in significant changes in prostate cell proliferation. CONCLUSIONS: These findings demonstrate that alpha-blockers as a class may regulate prostate growth by inducing apoptosis in both the epithelial and stromal cells, with little effect on cell proliferation. Apoptosis-mediated prostate stromal regression appears as a molecular mechanism underlying the therapeutic response to alpha 1 blockade in the treatment of BPH

Feasibility study: watchful waiting for localized low to intermediate grade prostate carcinoma with selective delayed intervention based on prostate specific antigen, histological and/or clinical progression.

Choo R, Klotz L, Danjoux C, et al.

J Urol. 2002 Apr; 167(4):1664-9.

PURPOSE: We assessed the feasibility of a watchful waiting protocol with selective delayed intervention using clinical, prostate specific antigen (PSA) or histological progression as treatment indications for clinically localized prostate cancer. MATERIALS AND METHODS: In this prospective, single arm cohort study patients with favorable clinical parameters (stage T1b to T2b N0M0, Gleason score 7 or less and PSA 15 ng./ml. or less) are conservatively treated with watchful waiting. When a patient meets disease progression criteria, arbitrarily defined by the 3 parameters of the rate of PSA increase, clinical progression or histological upgrade on repeat prostate biopsy, appropriate treatment is implemented. Patients are followed every 3 months for the first 2 years and every 6 months thereafter. Serum PSA measurement and digital rectal examination are done at each visit and repeat prostate biopsy is performed 18 months after study enrollment. RESULTS: Since November 1995, the study has accrued 206 patients with a median followup of 29 months (range 2 to 66). Of these men 137 remain on the surveillance protocol with no disease progression, while 69 were withdrawn from study for various reasons. There was clinical, PSA and histological progression in 16, 15 and 5 cases, respectively. The estimated actuarial probability of remaining on the surveillance protocol was 67% at 2 years and 48% at 4. The probability of remaining progression-free was 81% and 67% at 2 and 4 years, respectively. CONCLUSIONS: A policy of watchful waiting with selectively delayed intervention based on predefined criteria of disease progression is feasible. This strategy offers the benefit of an individualized approach based on the demonstrated risk of clinical or biochemical progression with time and, thus, it may decrease the burden of therapy in patients with indolent disease, while providing definitive therapy for those with biologically active disease

Predicting radionuclide bone scan findings in patients with newly diagnosed, untreated prostate cancer: prostate specific antigen is superior to all other clinical parameters.

Chybowski FM, Keller JJ, Bergstralh EJ, et al.

J Urol. 1991 Feb; 145(2):313-8.

Presently, the standard staging evaluation of prostate cancer includes digital rectal examination, measurement of serum tumor markers and a radionuclide bone scan. To evaluate the ability of local clinical stage, tumor grade, serum acid phosphatase, serum prostatic acid phosphatase (PAP) and serum prostate specific antigen (PSA) to predict bone scan findings, a retrospective review of 521 randomly chosen patients (mean age 70 years, range 44 to 92 years) with newly diagnosed, untreated prostate cancer was performed. Local clinical stage, tumor grade, acid phosphatase, PAP and PSA all correlated positively with bone scan findings (p less than 0.0001). Using receiver operating characteristic curves, however, PSA had the best over-all correlation with bone scan results. The median serum PSA concentration in patients with a positive bone scan was 158.0 ng./ml., whereas men with a negative bone scan had a median serum PSA level of 11.3 ng./ml. (p less than 0.0001). Using multivariate logistic regression analysis, local clinical stage, tumor grade, acid phosphatase and PAP were evaluated in combination with PSA to assess whether these parameters increased the ability of PSA alone to predict bone scan findings. None of these clinical parameters, irrespective of the combination used, contributed appreciably to the predictive power of PSA alone. A probability plot with 95% confidence intervals was constructed that allows the practicing urologist to estimate on an individual basis the probability of a positive bone scan for any given serum PSA value. The most significant finding of this study, however, was the negative predictive value of a low serum PSA concentration for bone scan findings. In 306 men with a serum PSA level of 20 ng./ml. or less only 1 (PSA 18.2 ng./ml.) had a positive bone scan (negative predictive value 99.7%). This finding would suggest that a staging radionuclide bone scan in a previously untreated prostate cancer patient with a low serum PSA concentration may not be necessary

Analysis of PSA velocity in 1666 healthy subjects undergoing total PSA determination at two consecutive screening rounds.

Ciatto S, Bonardi R, Lombardi C, et al.

Int J Biol Markers. 2002 Apr; 17(2):79-83.

The study purpose was to assess PSA velocity (PSAV) in healthy subjects in order to establish a reliable cutoff for the differential diagnosis of prostate cancer in a screening setting. We studied a series of 1666 healthy men aged 55 to 74 years undergoing two total PSA determinations at a four-year interval within a population-based randomized screening trial at the Centro per lo Studio e la Prevenzione Oncologica of Florence. First and second screening round PSA assays (PSA1 and PSA2) were carried out with the same method and by the same laboratory. PSAV (PSA1-PSA2/year) was determined in non-cancer subjects in the overall series or in specific age and PSA subgroups, and in subjects with cancer detected at the second screening round. Average PSAV in 1648 non-cancer subjects was 0.07 ng/mL/year (range -2.18+5.99, 95% CI 0.05-0.09); at least one third of subjects showed a decrease in PSA (negative PSAV), mostly of limited magnitude and in the low PSA range. Average PSAV in the 18 cancer patients was 1.16 ng/mL/year (range 0.10-5.6, 95% CI 0.56-1.77), which is significantly higher (p or =2.5 ng/mL further diagnostic assessment and 22.7% of non-cancer subjects with PSA > or =4 ng/mL random sextant biopsy, while missing no cancers. This study provides a reliable estimate of PSAV based on a large unbiased population sample. PSAV is widely variable over time, particularly at low PSA values. PSAV might be of value as an indicator for diagnostic assessment and random sextant biopsy in a screening setting

Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomized controlled trial. Nutritional Prevention of Cancer Study Group.

Clark LC, Combs GF, Jr., Turnbull BW, et al.

JAMA. 1996 Dec 25; 276(24):1957-63.

OBJECTIVE: To determine whether a nutritional supplement of selenium will decrease the incidence of cancer. DESIGN: A multicenter, double-blind, randomized, placebo-controlled cancer prevention trial. SETTING: Seven dermatology clinics in the eastern United States. PATIENTS: A total of 1312 patients (mean age, 63 years; range, 18-80 years) with a history of basal cell or squamous cell carcinomas of the skin were randomized from 1983 through 1991. Patients were treated for a mean (SD) of 4.5 (2.8) years and had a total follow-up of 6.4 (2.0) years. INTERVENTIONS: Oral administration of 200 microg of selenium per day or placebo. MAIN OUTCOME MEASURES: The primary end points for the trial were the incidences of basal and squamous cell carcinomas of the skin. The secondary end points, established in 1990, were all-cause mortality and total cancer mortality, total cancer incidence, and the incidences of lung, prostate, and colorectal cancers. RESULTS: After a total follow-up of 8271 person-years, selenium treatment did not significantly affect the incidence of basal cell or squamous cell skin cancer. There were 377 new cases of basal cell skin cancer among patients in the selenium group and 350 cases among the control group (relative risk [RR], 1.10; 95% confidence interval [CI], 0.95-1.28), and 218 new squamous cell skin cancers in the selenium group and 190 cases among the controls (RR, 1.14; 95% CI, 0.93-1.39). Analysis of secondary end points revealed that, compared with controls, patients treated with selenium had a nonsignificant reduction in all-cause mortality (108 deaths in the selenium group and 129 deaths in the control group [RR; 0.83; 95% CI, 0.63-1.08]) and significant reductions in total cancer mortality (29 deaths in the selenium treatment group and 57 deaths in controls [RR, 0.50; 95% CI, 0.31-0.80]), total cancer incidence (77 cancers in the selenium group and 119 in controls [RR, 0.63; 95% CI, 0.47-0.85]), and incidences of lung, colorectal, and prostate cancers. Primarily because of the apparent reductions in total cancer mortality and total cancer incidence in the selenium group, the blinded phase of the trial was stopped early. No cases of selenium toxicity occurred. CONCLUSIONS: Selenium treatment did not protect against development of basal or squamous cell carcinomas of the skin. However, results from secondary end-point analyses support the hypothesis that supplemental selenium may reduce the incidence of, and mortality from, carcinomas of several sites. These effects of selenium require confirmation in an independent trial of appropriate design before new public health recommendations regarding selenium supplementation can be made

cis-trans lycopene isomers, carotenoids, and retinol in the human prostate.

Clinton SK, Emenhiser C, Schwartz SJ, et al.

Cancer Epidemiol Biomarkers Prev. 1996 Oct; 5(10):823-33.

An evaluation of the Health Professionals Follow-Up Study has detected a lower prostate cancer risk associated with the greater consumption of tomatoes and related food products. Tomatoes are the primary dietary source of lycopene, a non-provitamin A carotenoid with potent antioxidant activity. Our goal was to define the concentrations of lycopene, other carotenoids, and retinol in paired benign and malignant prostate tissue from 25 men, ages 53 to 74, undergoing prostatectomy for localized prostate cancer. The concentrations of specific carotenoids in the benign and malignant prostate tissue from the same subject are highly correlated. Lycopene and all-trans beta-carotene are the predominant carotenoids observed, with means +/- SE of 0.80 +/- 0.08 nmol/g and 0.54 +/- 0.09, respectively. Lycopene concentrations range from 0 to 2.58 nmol/g, and all-trans beta-carotene concentrations range from 0.09 to 1.70 nmol/g. The 9-cis beta-carotene isomer, alpha-carotene, lutein, alpha-cryptoxanthin, zeaxanthin, and beta-cryptoxanthin are consistently detectable in prostate tissue. No significant correlations between the concentration of lycopene and the concentrations of any other carotenoid are observed. In contrast, strong correlations between prostate beta-carotene and alpha-carotene are noted (correlation coefficient, 0.88; P < 0.0001), as are correlations between several other carotenoid pairs, which reflects their similar dietary origins. Mean vitamin A concentration in the prostate is 1.52 nmol/g, with a range of 0.71 to 3.30 nmol/g. We further evaluated tomato-based food products, serum, and prostate tissue for the presence of geometric lycopene isomers using high-performance liquid chromatography with a polymeric C30 reversed phase column. All-trans lycopene accounts for 79 to 91% and cis lycopene isomers for 9 to 21% of total lycopene in tomatoes, tomato paste, and tomato soup. Lycopene concentrations in the serum of men range between 0.60 and 1.9 nmol/ml, with 27 to 42% all-trans lycopene and 58 to 73% cis-isomers distributed among 12 to 13 peaks, depending upon their chromatographic resolution. In striking contrast with foods, all-trans lycopene accounts for only 12 to 21% and cis isomers for 79 to 88% of total lycopene in benign or malignant prostate tissues. cis Isomers of lycopene within the prostate are distributed among 14 to 18 peaks. We conclude that a diverse array of carotenoids are found in the human prostate with significant intra-individual variation. The presence of lycopene in the prostate at concentrations that are biologically active in laboratory studies supports the hypothesis that lycopene may have direct effects within the prostate and contribute to the reduced prostate cancer risk associated with the reduced prostate cancer risk associated with the consumption of tomato-based foods. The future identification and characterization of geometric lycopene isomers may lead to the development of novel agents for chemoprevention studies

Cryosurgical ablation of the prostate: two-year prostate-specific antigen and biopsy results.

Cohen JK, Miller RJ, Rooker GM, et al.

Urology. 1996 Mar; 47(3):395-401.

OBJECTIVES: Percutaneous cryosurgical ablation of the prostate (CSAP) was performed on patients with localized or locally advanced adenocarcinoma of the prostate. To assess local disease control, post-treatment biopsy and serum prostate-specific antigen (PSA) levels were obtained at 3 and 24 months post-treatment. METHODS: From June 1990 through May 1994, CSAP was performed 448 times on 383 patients under Institutional Review Board protocols. A urethral warming catheter was used for all procedures. A total of 239 patients were followed for a minimum of 21 months after treatment. None of this group had received prior local treatment. The group consisted of patients who were newly diagnosed and treated solely with cryotherapy (virgin); the remainder had been on androgen deprivation therapy (ADT) prior to CSAP. RESULTS: Biopsies were obtained from 114 patients at 21 months or more after treatment. In the virgin group, 79% had a negative biopsy after one or more treatments, and 88% of the ADT group are negative after one or more treatments. Overall, 69% had a negative biopsy after one treatment and 82% had a negative biopsy following one or more CSAP treatments. Of a group of 163 patients, PSA data were evaluable at 21 months or more after treatment. In the virgin group, 60% had a PSA 0.4 ng/mL or less, and 77% had a PSA 1.0 ng/mL or less. In the ADT group, 40% had a PSA 0.4 ng/mL or less, and 69% had a PSA value of 1.0 ng/m Lor less. Complications were minimal, the most common one being urethral tissue sloughing, which occurred in 10% of patients. CONCLUSIONS: CSAP appears to be effective in obtaining local control as measured by biopsy and PSA 21 months or more post-treatment. When retrospectively comparing our results with recently published radiotherapy series, CSAP was more effective in obtaining nadir PSA values 1.0 ng/mL or less and negative biopsies at 21 months or more after treatment

Insulin-like growth factors (IGFs), IGF receptors, and IGF-binding proteins in primary cultures of prostate epithelial cells.

Cohen P, Peehl DM, Lamson G, et al.

J Clin Endocrinol Metab. 1991 Aug; 73(2):401-7.

Insulin-like growth factors (IGFs) are potent mitogens that bind with high affinity and specificity to IGF receptors and IGF-binding proteins (IGFBPs). We studied the roles of these three groups of proteins in prostate epithelial cells (PEC) in primary culture grown under serum-free conditions. Affinity cross-linking of IGF-I and IGF-II to crude membranes prepared from PEC revealed an abundance of type 1 IGF receptors and no evidence of type 2 IGF receptors. Western ligand blots of conditioned media (CM) from PEC demonstrated the presence of two specific IGFBP bands similar to those previously demonstrated in seminal plasma, with approximate mol wt of 31 and 24 kDa. The 31-kDa band was immunoprecipitable with an antibody to IGFBP-2, and neither band could be deglycosylated with endoglycosidase-F. Northern blot analysis of poly(A)+ RNA prepared from PEC with cDNAs for hIGFBP-1, -2, and -3 documented the expression of mRNA for hIGFBP-2 only. Modifications of the serum-free conditions of PEC did not significantly alter the IGFBP profile of PEC CM. The ability of IGF-I, IGF-II, and insulin to stimulate clonal growth of PEC was examined. IGF-I stimulated PEC growth with an ED50 of 0.1 ng/mL. IGF-II and insulin, respectively, were 1 and 3 orders of magnitude less effective than IGF-I in stimulating the growth of PEC. Radioimmunoassayable IGF-I and IGF-II levels in PEC CM were below the assay detection levels. In conclusion, we suggest that IGFs are important growth stimulators of PEC in culture, that their actions are mediated through the type 1 IGF receptor, and that PEC produce hIGFBP-2 and a 24-kDa IGFBP which may modulate IGF action in these cells

Systematic sextant biopsies improve preoperative prediction of pelvic lymph node metastases in patients with clinically localized prostatic carcinoma.

Conrad S, Graefen M, Pichlmeier U, et al.

J Urol. 1998 Jun; 159(6):2023-9.

PURPOSE: An algorithm including the results of systematic sextant biopsies was statistically developed and evaluated to predict the probability of pelvic lymph node metastases in patients with clinically localized carcinoma of the prostate. MATERIALS AND METHODS: Clinical stage, serum prostate specific antigen concentration, Gleason score, number of positive biopsies, number of biopsies containing any Gleason grade 4 or 5 cancer and number of biopsies predominated by Gleason grade 4 or 5 cancer were recorded in 345 patients undergoing pelvic lymph node dissection and correlated with the incidence of lymph node metastases. Multivariate logistic regression, and classification and regression trees analyses were performed. RESULTS: In univariate analysis all variables had a statistically significant influence on lymph node status. Logistic regression showed that the amount and distribution of undifferentiated Gleason grade 4 and 5 cancer in the biopsies were the best predictors of lymphatic spread followed by serum prostate specific antigen. Classification and regression trees analysis classified 79.9% of patients who had 3 or fewer biopsies with Gleason grade 4 or 5 cancer and no biopsies predominated by undifferentiated cancer as a low risk group. In this group positive lymph nodes occurred in only 2.2% (95% confidence interval 0.8 to 4.7%). CONCLUSIONS: Including the results of systematic sextant biopsies substantially enhances the predictive accuracy of algorithms that define the probability of lymph node metastases in prostatic cancer. Patients thus defined as having no lymphatic spread could potentially be spared pelvic lymph node dissection before definitive local treatment

Cyclo-oxygenase 2 expression is associated with angiogenesis and lymph node metastasis in human breast cancer.

Costa C, Soares R, Reis-Filho JS, et al.

J Clin Pathol. 2002 Jun; 55(6):429-34.

AIMS: Cyclo-oxygenases 1 and 2 (COX-1 and COX-2) are key enzymes in prostaglandin biosynthesis. COX-2 is induced by a wide variety of stimuli, and present during inflammation. COX-2 overexpression has been observed in colon, head and neck, lung, prostate, stomach, and breast cancer. In colon and gastric cancer, COX-2 expression was associated with angiogenesis. The aim of this study was to determine the relation between COX-2 expression and angiogenesis in breast cancer, and to correlate the expression of this enzyme with classic clinicopathological parameters. METHODS: COX-2 expression was investigated by immunohistochemistry and western blotting analysis. The expression of COX-2 was then related to age, histological grade, nodal status, oestrogen receptor status, p53 expression,c-erb-B2 overexpression, mitotic counts, MIB-1 labelling index, apoptotic index, sialyl-Tn expression, transforming growth factor alpha expression, microvessel density, and disease free survival in 46 patients with invasive ductal breast carcinoma. RESULTS: By means of immunohistochemistry, COX-2 expression was detected in eight of the 46 carcinomas studied. Western blotting showed COX-2 protein expression in the same breast tumours, but not in normal adjacent tissues. The density of microvessels immunostained with anti-F-VIII related antigen was significantly higher in patients with COX-2 expression than in those without expression (p = 0.03). In addition, COX-2 was significantly associated with the presence of sialyl-Tn expression (p = 0.02), lymph node metastasis (p = 0.03), a high apoptotic index (p = 0.03), and a short disease free survival (p = 0.03) in univariate analyses. CONCLUSIONS: These data suggest that COX-2 expression is associated with angiogenesis, lymph node metastasis, and apoptosis in human breast cancer. Moreover, these results warrant further studies with larger series of patients to confirm the association with short disease free survival in patients with breast cancer

Pamidronate. A review of its use in the management of osteolytic bone metastases, tumour-induced hypercalcaemia and Paget's disease of bone.

Coukell AJ, Markham A.

Drugs Aging. 1998 Feb; 12(2):149-68.

Pamidronate (APD) is a potent inhibitor of bone resorption that is useful in the management of patients with osteolytic bone metastases from breast cancer or multiple myeloma, tumour-induced hypercalcaemia or Paget's disease of bone. After intravenous administration, the drug is extensively taken up in bone, where it binds with hydroxyapatite crystals in the bone matrix. Matrix-bound pamidronate inhibits osteoclast activity by a variety of mechanisms, the most important of which appears to be prevention of the attachment of osteoclast precursor cells to bone. In patients with osteolytic bone metastases associated with either breast cancer or multiple myeloma, administration of pamidronate together with systemic antitumour therapy reduces and delays skeletal events, including pathological fracture, hypercalcaemia and the requirement for radiation treatment or surgery to bone. Pamidronate generally improves pain control. Quality-of-life and performance status scores in pamidronate recipients were generally as good as, or better than, those in patients who did not receive the drug. Overall survival does not appear to be affected by pamidronate therapy. Tumour-induced hypercalcaemia also responds well to pamidronate therapy: 70 to 100% of patients achieve normocalcaemia, generally 3 to 5 days after treatment. Response durations vary, but are commonly 3 weeks or longer, In comparative studies, pamidronate produced higher rates of normocalcaemia and longer normocalcaemic durations than other available osteoclast inhibitors, including intravenous etidronate, clodronate and plicamycin (mithramycin). In most patients with Paget's disease of bone, intravenous pamidronate reduces bone pain and produces biochemical response. Serum alkaline phosphatase levels generally fall 50 to 70% from baseline 3 to 4 months after pamidronate treatment. Biochemical response may be prolonged. Pamidronate is well tolerated by most patients. Transient febrile reactions, sometimes accompanied by myalgias and lymphopenia, occur commonly after the first infusion of pamidronate. Other reported adverse events include transient neutropenia, mild thrombophlebitis, asymptomatic hypocalcaemia and, rarely, ocular complications (uveitis and scleritis). Pamidronate should be considered for routine use together with systemic hormonal or cytotoxic therapy in patients with breast cancer or multiple myeloma and osteolytic metastases. At present, pamidronate is the drug of choice for first-line use in the management of patients with tumour-induced hypercalcaemia. It is an effective treatment for Paget's disease and is the treatment of choice where oral bisphosphonates are not an option

Simultaneous irradiation for prostate cancer: intermediate results with modern techniques.

Critz FA, Williams WH, Levinson AK, et al.

J Urol. 2000 Sep; 164(3 Pt 1):738-41.

PURPOSE: In this study of men with early stage prostate cancer we evaluated treatment outcome after modern simultaneous irradiation, comprising transperineal implantation followed by external beam radiation. Disease-free survival rates were calculated according to an undetectable prostate specific antigen (PSA) nadir. MATERIALS AND METHODS: From 1992 to 1996, 689 men with clinical stage T1-T2, N0, Nx prostate cancer were treated with ultrasound guided transperineal 125iodine seed implantation followed 3 weeks later by external beam radiation. Disease-free status was defined as the achievement and maintenance of a PSA nadir of 0.2 ng./ml. or less. Median followup was 4 years (range 3 to 7). None of these men received neoadjuvant or adjuvant hormonal therapy. RESULTS: Overall 5-year disease-free survival was 88%. The 5-year rate according to PSA 4.0 ng./ml. or less, 4.1 to 10.0, 10.1 to 20.0 and greater than 20.0 was 94%, 93%, 75% and 69%, respectively. Multivariate analysis revealed that pretreatment PSA was the strongest indicator of subsequent disease-free status in regard to Gleason score or clinical stage. CONCLUSIONS: Intermediate treatment outcome analysis of modern simultaneous radiation supports the principles of radiation dose intensification for intracapsular disease plus the treatment of potential microscopic capsular penetration

Alpha1-adrenoceptor antagonists radiosensitize prostate cancer cells via apoptosis induction.

Cuellar DC, Rhee J, Kyprianou N.

Anticancer Res. 2002 May; 22(3):1673-9.

BACKGROUND: Androgen-independent prostate cancer cells can undergo apoptosis in response to non-androgen ablative means such as ionizing radiation. Recent evidence documented the ability of alpha-adrenoceptor antagonists, a widely used medical therapy for the treatment of benign prostatic hypertrophy (BPH), to induce apoptosis in benign and malignant prostate cells. In this study, we evaluated the potential additive/synergistic apoptotic effect of alpha1-adrenoceptor antagonists with ionizing radiation against human prostate cancer cells in vitro. MATERIALS AND METHODS: Androgen-independent human prostate cancer cells (PC-3) were treated with two alpha1-adrenoceptor antagonists, doxazosin and terazosin, for various periods of time prior to and after exposure to ionizing radiation. Apoptosis induction, cell viability and clonogenic assays were then performed to determine loss of clonogenic survival Hoechst staining was performed to detect the apoptotic morphology in prostate cancer cells and the temporal protein expression of the apoptosis regulators bax and caspase-3, was determined using Western blot analysis. RESULTS: No significant difference in cell death of PC-3 cells was detected when either doxazosin or terazosin was combined with ionizing radiation. Terazosin treatment however, 24 hours prior to, or 24 hours post-irradiation resulted in a significant enhancement of radiation-induced loss of clonogenic survival compared to radiation alone (p

A multivariable analysis of clinical factors predicting for pathological features associated with local failure after radical prostatectomy for prostate cancer.

D'Amico AV, Whittington R, Malkowicz SB, et al.

Int J Radiat Oncol Biol Phys. 1994 Sep 30; 30(2):293-302.

PURPOSE: A multivariate analysis is used to determine the predictive value of pretreatment clinical indicators on pathologic features associated with local failure after radical prostatectomy in patients with prostate cancer. METHODS AND MATERIALS: A retrospective review of the pathologic findings of 235 patients with adenocarcinoma of the prostate treated between 1990 and 1993 with a radical retropubic prostatectomy was performed. The preoperative clinical data including the serum prostate specific antigen, clinical stage, Gleason sum, and endorectal magnetic resonance scan findings are used to identify patients prior to definitive treatment who would be at high risk for having pathologic features associated with local failure at radical prostatectomy. Outcome prediction curves are constructed from a logistic regression multivariate analysis displaying the probability of pathologic involvement of the seminal vesicle, extracapsular disease, or positive surgical margins as a function of the preoperative prostate specific antigen and Gleason sum for the cases when the endorectal magnetic resonance scan is positive, negative, or not included in the multivariate analysis. RESULTS: Factors identified on multivariate analysis as significant predictors of seminal vesicle invasion include endorectal magnetic resonance scan findings (p < 0.0001), and preoperative prostate specific antigen (p = "0.017)." Endorectal magnetic resonance scan findings (p = "0.0016)," preoperative prostate specific antigen (p = "0.0002)," and Gleason sum (p < 0.0001) were significant predictors of extracapsular extension and preoperative prostate specific antigen (p 0.05) of pathologic features associated with local failure on multivariate analysis. As a single modality, endorectal surface coil magnetic resonance imaging was accurate 93%, 69%, and 72% of the time for predicting seminal vesicle invasion, transcapsular disease, and final pathologic stage, respectively. Failure to recognize microscopic penetration of the capsule found at the time of pathologic evaluation in a prostate gland with a grossly intact capsule accounts for the majority (70%) of the staging inaccuracies. CONCLUSIONS: The use of the endorectal surface coil magnetic resonance scan findings in conjunction with both the serum prostate specific antigen and Gleason sum improves the clinical accuracy of predicting those patients at high risk for clinically unsuspected extraprostatic disease. In particular, for the subgroup of patients with moderately elevated prostate specific antigen (> 10-20 ng/mL) and intermediate grade clinically organ confined prostate cancer [Gleason sum: 5-7] where the specificity of these tests to predict for occult extraprostatic disease is suboptimal, the additional information obtained from the endorectal coil magnetic resonance scan allows the physician to definitively subgroup these patients into low and high risk for seminal vesicle invasion or transcapsular disease

Prostate cancer volume adds significantly to prostate-specific antigen in the prediction of early biochemical failure after external beam radiation therapy.

D'Amico AV, Propert KJ.

Int J Radiat Oncol Biol Phys. 1996 May 1; 35(2):273-9.

PURPOSE: A new clinical pretreatment quantity that closely approximates the true prostate cancer volume is defined. METHODS AND MATERIALS: The cancer-specific prostate-specific antigen (PSA), PSA density, prostate cancer volume (VCa), and the volume fraction of the gland involved with carcinoma (VCafx) were calculated for 227 prostate cancer patients managed definitively with external beam radiation therapy. 1. PSA density = PSA/ultrasound prostate gland volume. 2. Cancer-specific PSA =

A prostate gland volume of more than 75 cm3 predicts for a favorable outcome after radical prostatectomy for localized prostate cancer.

D'Amico AV, Whittington R, Malkowicz SB, et al.

Urology. 1998 Oct; 52(4):631-6.

OBJECTIVES: Both the benign and malignant prostatic epithelial components of the prostate gland contribute to the serum prostate-specific antigen (PSA) level. Therefore, for a given PSA, the presence of benign hyperplastic prostate tissue (BHPT) may indicate a lower cancer burden. This study was performed to assess the impact of varying amounts of BHPT on PSA failure free (bNED) survival after radical prostatectomy for localized prostate cancer. METHODS: Cox regression multivariable analyses were performed to assess the ability of the clinical stage, PSA, biopsy Gleason score, and prostate gland volume to predict time to postoperative PSA failure in 885 patients. RESULTS: In addition to the PSA (P < 0.0001), biopsy Gleason score of 8 to 10 (P < 0.0001) and of 7 (P = "0.05)," and clinical Stage T2c,3a (P < 0.0001) and T2b (P = "0.0016)," the prostatectomy prostate gland volume (P < 0.0001) was a significant predictor of time to postoperative PSA failure. Patients with a prostatectomy prostate gland volume greater than 75 cm3 had a 100% 4-year bNED survival and favorable pathologic characteristics (pathologic Stage T2, 85%; prostatectomy Gleason score 6 or less, 78% and 7, 22%; and negative margins, 95%) despite a preoperative PSA of 10 to 20 ng/mL and more than 20 ng/mL in 28% and 13% of these men, respectively. In 75% of these cases, lead time bias because of PSA driven repeat biopsies provided an explanation. CONCLUSIONS: Lead time bias because of PSA driven repeat biopsy accounted for the high 4-year bNED survival and favorable pathologic findings for most patients who had prostate cancer coexisting in a prostate gland comprised of BHPT and a total gland volume in excess of 75 cm3. An additional explanation is needed, however, for the remaining patients

The clinical utility of the percent of positive prostate biopsies in predicting biochemical outcome following external-beam radiation therapy for patients with clinically localized prostate cancer.

D'Amico AV, Schultz D, Silver B, et al.

Int J Radiat Oncol Biol Phys. 2001 Mar 1; 49(3):679-84.

PURPOSE: An investigation was performed of the clinical utility of the percent of positive prostate biopsies in predicting prostate-specific antigen (PSA) outcome following external-beam radiation therapy (RT) for men with PSA-detected or clinically palpable prostate cancer. METHODS AND MATERIALS: A Cox regression multivariable analysis was used to determine whether the percent of positive prostate biopsies provided clinically relevant information about PSA outcome following external beam RT in 473 men while accounting for the previously established risk groups based on the pretreatment PSA level, biopsy Gleason score, and the 1992 American Joint Commission on Cancer (AJCC) clinical T stage. RESULTS: Controlling for the known prognostic factors, the percent of positive prostate biopsies added clinically significant information (p = 0.02) regarding time to PSA failure following RT. Specifically, 76% of the patients in the intermediate risk group (1992 AJCC T(2b) or biopsy Gleason 7 or PSA > 10 ng/mL and < or = "20" ng/mL) could be classified into either an 30% or 85% 5-year PSA control cohort using the preoperative prostate biopsy data. CONCLUSION: The previously validated stratification of PSA outcome following radical prostatectomy (RP) using the percent of positive prostate biopsies in intermediate-risk patients is also clinically significant for men treated with external beam RT. The percent positive prostate biopsies should be considered in conjunction with the PSA level, biopsy Gleason score, and 1992 AJCC clinical T stage when counseling patients with newly diagnosed and clinically localized prostate cancer about PSA outcome following RP or external beam RT

Targeting gene therapy to cancer: a review.

Dachs GU, Dougherty GJ, Stratford IJ, et al.

Oncol Res. 1997; 9(6-7):313-25.

In recent years the idea of using gene therapy as a modality in the treatment of diseases other than genetically inherited, monogenic disorders has taken root. This is particularly obvious in the field of oncology where currently more than 100 clinical trials have been approved worldwide. This report will summarize some of the exciting progress that has recently been made with respect to both targeting the delivery of potentially therapeutic genes to tumor sites and regulating their expression within the tumor microenvironment. In order to specifically target malignant cells while at the same time sparing normal tissue, cancer gene therapy will need to combine highly selective gene delivery with highly specific gene expression, specific gene product activity, and, possibly, specific drug activation. Although the efficient delivery of DNA to tumor sites remains a formidable task, progress has been made in recent years using both viral (retrovirus, adenovirus, adeno-associated virus) and nonviral (liposomes, gene gun, injection) methods. In this report emphasis will be placed on targeted rather than high-efficiency delivery, although those would need to be combined in the future for effective therapy. To date delivery has been targeted to tumor-specific and tissue-specific antigens, such as epithelial growth factor receptor, c-kit receptor, and folate receptor, and these will be described in some detail. To increase specificity and safety of gene therapy further, the expression of the therapeutic gene needs to be tightly controlled within the target tissue. Targeted gene expression has been analyzed using tissue-specific promoters (breast-, prostate-, and melanoma-specific promoters) and disease-specific promoters (carcinoembryonic antigen, HER-2/neu, Myc-Max response elements, DF3/MUC). Alternatively, expression could be regulated externally with the use of radiation-induced promoters or tetracycline-responsive elements. Another novel possibility that will be discussed is the regulation of therapeutic gene products by tumor-specific gene splicing. Gene expression could also be targeted at conditions specific to the tumor microenvironment, such as glucose deprivation and hypoxia. We have concentrated on hypoxia-targeted gene expression and this report will discuss our progress in detail. Chronic hypoxia occurs in tissue that is more than 100-200 microns away from a functional blood supply. In solid tumors hypoxia is widespread both because cancer cells are more prolific than the invading endothelial cells that make up the blood vessels and because the newly formed blood supply is disorganized. Measurements of oxygen partial pressure in patients' tumors showed a high percentage of severe hypoxia readings (less than 2.5 mmHg), readings not seen in normal tissue. This is a major problem in the treatment of cancer, because hypoxic cells are resistant to radiotherapy and often to chemotherapy. However, severe hypoxia is also a physiological condition specific to tumors, which makes it a potentially exploitable target. We have utilized hypoxia response elements (HRE) derived from the oxygen-regulated phosphoglycerate kinase gene to control gene expression in human tumor cells in vitro and in experimental tumors. The list of genes that have been considered for use in the treatment of cancer is extensive. It includes cytokines and costimulatory cell surface molecules intended to induce an effective systemic immune response against tumor antigens that would not otherwise develop. Other inventive strategies include the use of internally expressed antibodies to target oncogenic proteins (intrabodies) and the use of antisense technology (antisense oligonucleotides, antigenes, and ribozymes). This report will concentrate more on novel genes encoding prodrug activating enzymes, so-called suicide genes (Herpes simplex virus thymidine kinase, Escherichia coli nitroreductase, E. (ABSTRACT TRUNCATED)

Osteoporosis due to androgen deprivation therapy in men with prostate cancer.

Daniell HW.

Urology. 2001 Aug; 58(2 Suppl 1):101-7.

OBJECTIVES: The frequency of osteoporotic fractures is greatly increased in men receiving androgen deprivation therapy (ADT), but whether the risk of osteoporosis differs between different types of ADT or between continuous and intermittent therapy has not been determined. Techniques for modifying ADT-associated bone loss have not been clearly identified. METHODS: Risk factors for the development of osteoporosis in men receiving ADT will be reviewed. Relations between bone mineral density (BMD) values and the development of osteoporotic fractures, along with methods for preventing both BMD loss and osteoporotic fractures, will be discussed. RESULTS: ADT rapidly accelerates bone loss among men with prostate cancer and multiplies the risk of osteoporotic fractures among them. Factors other than ADT-associated bone loss contributing to this fracture risk include both decreased BMD before ADT and an increased tendency to fall associated with muscle weakness, impaired balance, and postural hypotension. Each of these factors may be associated with poor nutrition, advancing malignant disease, hypogonadism of non-ADT origin, advanced age, and the use of narcotic, antihypertensive, or sedative medications. Although the success of therapy designed to improve BMD values and lower the fracture rate in these patients has not been explored, regular exercise, smoking abstinence, adequate calcium, protein, and vitamin D intake, maintenance of weight, and the use of bisphosphonates or calcitonin may each have a useful therapeutic role. Theoretical considerations suggest that intermittent ADT may decrease the frequency of ADT-associated osteoporosis. CONCLUSIONS: An urgent need exists for the definition of techniques useful in preventing osteoporotic fractures in men receiving ADT for prostate cancer

Prognostic role of serum prostatic acid phosphatase for 103Pd-based radiation for prostatic carcinoma.

Dattoli M, Wallner K, True L, et al.

Int J Radiat Oncol Biol Phys. 1999 Nov 1; 45(4):853-6.

PURPOSE: To establish the prognostic role of serum enzymatic prostatic acid phosphatase (PAP) in patients treated with palladium (103Pd) and supplemental external beam irradiation (EBRT) for clinically localized, high-risk prostate carcinoma. METHODS AND MATERIALS: One hundred twenty-four consecutive patients with Stage T2a-T3 prostatic carcinoma were treated from 1992 through 1995. Each patient had at least one of the following risk factors for extracapsular disease extension: Stage T2b or greater (100 patients), Gleason score 7-10 (40 patients), pretreatment prostate specific antigen (PSA) >15 ng/ml (32 patients), or elevated serum PAP (25 patients). Patients received 41 Gy conformal EBRT to a limited pelvic field, followed 4 weeks later by a 103Pd boost (prescription dose 80 Gy). Biochemical failure was defined as a PSA greater than 1 ng/ml (normal

The procedure of transrectal ultrasound guided biopsy of the prostate: a survey of patient preparation and biopsy technique.

Davis M, Sofer M, Kim SS, et al.

J Urol. 2002 Feb; 167(2 Pt 1):566-70.

PURPOSE: We surveyed urologists in community and academic practice regarding their standard approach to patient preparation and their technique of transrectal ultrasound guided prostate biopsy. MATERIALS AND METHODS: We mailed 110 surveys to community urologists in Florida and urological oncologists at academic centers across the United States. Responses were calculated per group. RESULTS: Of the 88 respondents 34% were at academic centers and 66% were community urologists. Overall 79% of respondents prescribe an enema in preparation for biopsy, 81% administer an oral fluoroquinolone before biopsy, 50% give some type of analgesia, usually an oral agent, 63% obtain 8 or more cores per biopsy session, 36% biopsy the lateral and midline locations, and 83% do not use prostate specific antigen density to plan the biopsy strategy. CONCLUSIONS: The majority of urologists who responded to our survey ask their patients to use an enema in preparation for a transrectal biopsy procedure, prescribe an oral antibiotic and administer some type of analgesia. Few urologists administer a periprostatic nerve block. The majority obtain at least 8 biopsies and only 17% perform sextant biopsy. Some of these practices are not consistent with the literature. This survey provides insight into the practice patterns of urologists in regard to one of the most commonly performed office procedures

Empowerment of men newly diagnosed with prostate cancer.

Davison BJ, Degner LF.

Cancer Nurs. 1997 Jun; 20(3):187-96.

The purpose of this study was to explore the hypothesis that assisting men with prostate cancer to obtain information would enable them to assume a more active role in treatment decision making and decrease their levels of anxiety and depression. Respondents were recruited from one community urology clinic in Winnipeg, Manitoba. Sixty newly diagnosed men were randomly assigned to receive either a self-efficacy information intervention that consisted of a written information package with discussion, a list of questions they could ask their physician, and an audiotape of the medical consultation (n = 30), or a written information package alone (n = 30). Men completed measures of preferred decisional role as the pretest; anxiety and depression before the intervention, and at 6 weeks post-intervention; and assumed decisional role at 6 weeks post-intervention. Results demonstrated that men in the intervention group assumed a significantly more active role in treatment decision making, and had lower state anxiety levels at 6 weeks. Levels of depression were similar for both groups at 6 weeks. This group of older men do want to be informed and participate in medical decisions. Further efforts are required to evaluate the efficacy of such an intervention in other community urology clinics

Cryoablation for clinically localized prostate cancer using an argon-based system: complication rates and biochemical recurrence.

De La TA, Benson MC, Bagiella E, et al.

BJU Int. 2000 Feb; 85(3):281-6.

OBJECTIVE: To determine the complication rates and biochemical recurrence after cryoablation of the prostate, using an argon gas-based system, in patients with localized prostate cancer. PATIENTS AND METHODS: Between October 1997 and June 1999, 35 patients underwent cryoablation of the prostate (19 after radiation therapy failure and 16 as a primary treatment for localized prostate cancer). All patients had biopsy-confirmed prostate cancer with no seminal vesicle invasion, negative bone scans and a negative lymph node dissection. Patients received 3 months of combined hormonal therapy before cryosurgery. One surgeon performed all the procedures. Biochemical recurrence was defined by an increase in prostate specific antigen (PSA) of >/= 0.2 ng/mL above the PSA nadir. RESULTS: The complications were rectal pain (26%), urinary infection (3%), scrotal oedema (12%), haematuria (6%) and incontinence (6%). Complication rates were higher in those patients who failed after radiation therapy than in those who did not receive radiation (incontinence 11% vs 0%, rectal pain 37% vs 12%) but the difference was not statistically significant. Twenty-two patients (63%) had an undetectable serum PSA nadir (< 0.1 ng/mL) after cryotherapy and 30 (84%) patients had a PSA value of < 1.0 ng/mL. After a mean follow-up of 8.3 months (range 0.2-18), nine patients had biochemical recurrence. The biochemical recurrence-free survival (BRFS) was 70% at 9 months. Patients who had an undetectable PSA nadir had a statistically higher BRSF at 9 months than did patients who had a detectable PSA nadir (89% vs 55%, respectively, P = "0.03)." Similarly, patients with a preoperative serum PSA level of 10 ng/mL (86% vs 42% at 9 months, P < 0.001). CONCLUSION: A PSA level before cryotherapy of < 10 ng/mL and an undetectable PSA nadir after cryotherapy were associated with the highest BRFS. Cryoablation of the prostate, with low morbidity, seems to be a viable option in managing patients by salvage therapy after radiation therapy and for the primary treatment of clinically localized prostate cancer

Epidemiologic association between prostatitis and prostate cancer.

Dennis LK, Lynch CF, Torner JC.

Urology. 2002 Jul; 60(1):78-83.

OBJECTIVES: To quantify the relationship between prostatitis and prostate cancer by pooling previous epidemiologic studies of this association. METHODS: A comprehensive search for articles published through 2000 was performed, blinded reviews of each study were conducted, data were abstracted, and all such studies were pooled. RESULTS: In this meta-analysis, an increased risk was seen among men with a history of prostatitis (odds ratio = 1.6), particularly with population-based case-control studies (odds ratio = 1.8). Increased relative risk estimates were also seen among men with a history of syphilis and a history of gonorrhea. CONCLUSIONS: These associations with prostate cancer suggest that infections may represent one mechanism through which prostate cancer develops. However, causality is unclear, because recall bias and detection bias cannot be ruled out. Future cohort studies of prostate cancer should examine sexually transmitted infections, as well as other infections, as potential risk factors

Relations between n-3 fatty acid status and cardiovascular disease risk factors among Quebecers.

Dewailly EE, Blanchet C, Gingras S, et al.

Am J Clin Nutr. 2001 Nov; 74(5):603-11.

BACKGROUND: Epidemiologic evidence shows an inverse relation between fish consumption and death from ischemic heart disease. This beneficial effect is attributed to n-3 fatty acids. OBJECTIVES: The purpose of this study was to examine the association between plasma phospholipid concentrations of the n-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and various cardiovascular disease risk factors among Quebecers. DESIGN: The study population consisted of 1460 subjects aged 18-74 y who participated in the 1990 Quebec Heart Health and Nutrition Survey. Data were obtained through home interviews and clinic visits. RESULTS: Expressed as the percentage of total fatty acids in plasma phospholipids, the geometric means of EPA, DHA, and their combination were 0.47%, 1.19%, and 1.70%, respectively. Concentrations of n-3 fatty acids were positively associated with fish intake. We found positive associations between EPA and total cholesterol, LDL cholesterol, HDL cholesterol, plasma glucose, and systolic and diastolic blood pressure. We found positive associations between DHA and total cholesterol, the ratio of total to HDL cholesterol, triacylglycerols, systolic blood pressure, and plasma glucose and insulin. We also found positive associations between the ratio of EPA to arachidonic acid and total cholesterol, HDL cholesterol, and systolic blood pressure and a negative association with the ratio of total to HDL cholesterol. CONCLUSIONS: Our results indicate that concentrations of EPA and DHA in plasma phospholipids reflected Quebecer fish consumption. Results also show that EPA and the ratio of EPA to arachidonic acid can positively influence HDL-cholesterol concentrations

Risk factors for complications and morbidity after radical retropubic prostatectomy.

Dillioglugil O, Leibman BD, Leibman NS, et al.

J Urol. 1997 May; 157(5):1760-7.

PURPOSE: With recognition of the efficacy of surgical therapy for prostate cancer, there has been a marked increase in the number of radical prostatectomies performed, and substantial changes in surgical technique and perioperative management have decreased the morbidity of this procedure. We assessed the rate of perioperative complications with time and the risk factors for these complications, particularly age, operative time and co-morbidity. MATERIALS AND METHODS: A detailed review of all medical records of a consecutive series of 472 patients treated with radical retropubic prostatectomy by 1 surgeon between 1990 and 1994 was performed to document any complication within 30 days postoperatively. American Society of Anesthesiologists (ASA) physical status classification recorded by the staff anesthesiologist was used as a standard index of co-morbidity. RESULTS: Major complications were identified in 46 patients (9.8%), minor complications in 101 (21.4%) and none in 341 (72.2%). There were 2 deaths (0.42%). Major complications were not associated with age, operative time or year of operation but were significantly associated with ASA class (p = 0.006) and operative blood loss (p = 0.015) in a logistic regression analysis. Only 16% of patients were assigned to ASA class 3, yet this group included both deaths, a 3-fold increase in major complications, prolonged hospital stay, greater need for intensive care unit admission and more frequent blood transfusions. Major complications were almost 3 times more frequent in class 3 (21.3%) than in class 1 or 2 (7.6%) cases (p

Combination and multivariate analysis of PSA-based parameters for prostate cancer prediction.

Djavan B, Remzi M, Zlotta AR, et al.

Tech Urol. 1999 Jun; 5(2):71-6.

The aim of this study was to evaluate the ability of prostate-specific antigen (PSA)-based parameters including PSA density (PSAD), PSAD of the transition zone (PSA-TZ), percent free PSA, PSA velocity, and their combination to enhance the specificity of PSA for prostate cancer detection in men with serum PSA levels between 4 and 10 ng/mL. We evaluated prospectively 559 consecutive men referred for early detection of prostate cancer who had serum PSA levels between 4 and 10 ng/mL. All men underwent prostatic ultrasonography and sextant biopsy with two additional TZ biopsies. In all cases, if first biopsies were negative an additional set of biopsies was obtained within 6 weeks. The ability of PSAD, PSA-TZ, PSA velocity, percent free PSA, and their combination to improve the detection of prostate cancer was evaluated by univariate and multivariate analysis as well as receiver operating characteristic (ROC) curves. In this prospective study of 559 patients, 217 had prostate cancer and 342 had histologically confirmed benign prostatic hyperplasia. Multivariate analysis and ROC curves showed that PSA-TZ and percent free PSA (f/t PSA) were the most powerful and highly significant predictors of prostate cancer. Areas under the ROC curve (AUC) for PSA-TZ and percent free PSA were 0.827 and 0.778, respectively (p = .01). Combination of f/t PSA with PSA-TZ (AUC = 88.1%) significantly increased AUC as compared to each of the other parameters alone as well as their combination (p = .02). The next best combinations were PSA-TZ + PSAD, PSA-TZ + PSA, and f/t PSA + PSA. PSA-TZ followed by f/t PSA and PSAD were the most powerful predictors of prostate cancer in referred patients with a serum PSA between 4 and 10 ng/mL. f/t PSA + PSA-TZ was the most effective combination. When volume-independent PSA parameters were taken into consideration, f/t PSA + PSA clearly outperformed the other options

PSA, PSA density, PSA density of transition zone, free/total PSA ratio, and PSA velocity for early detection of prostate cancer in men with serum PSA 2.5 to 4.0 ng/mL.

Djavan B, Zlotta A, Kratzik C, et al.

Urology. 1999 Sep; 54(3):517-22.

OBJECTIVES: To enhance the specificity of prostate cancer (PCa) detection and reduce unnecessary biopsies in men with prostate-specific antigen (PSA) levels of 2.5 to 4.0 ng/mL, we prospectively evaluated various PSA-based diagnostic parameters. METHODS: This study included 273 consecutive men with serum PSA of 2.5 to 4.0 ng/mL referred for early PCa detection or lower urinary tract symptoms. All men underwent prostate ultrasound and sextant biopsy with two additional transition zone (TZ) biopsies. If the first biopsies were negative, repeated biopsies were performed at 6 weeks. Total PSA, PSA density (PSAD), PSA density of the transition zone (PSA-TZ), free/total PSA ratio (f/t PSA), and PSA velocity (PSAV) were determined, and the sensitivity, specificity, and predictive values of these various parameters were calculated. RESULTS: Of 273 patients, 207 had histologically confirmed benign prostatic hyperplasia (BPH) and 66 had PCa. f/t PSA and PSA-TZ were the most powerful predictors of PCa, followed by PSA, PSAD, and PSAV. Areas under the receiver operating characteristic curves for f/t PSA and PSA-TZ were 74.9% and 70.1%, respectively. With a 95% sensitivity for PCa detection, an f/t PSA cutoff of 41% and a PSA-TZ cutoff of 0.095 would result in the lowest number of unnecessary biopsies (29.3% and 17.2% specificity for f/t PSA and PSA-TZ, respectively) compared with all other PSA-related parameters evaluated. CONCLUSIONS: Compared with standard total PSA assays, f/t PSA and PSA-TZ significantly enhance the sensitivity and specificity of PCa detection in a referral patient population with a total PSA of 2.5 to 4.0 ng/mL

Total and transition zone prostate volume and age: how do they affect the utility of PSA-based diagnostic parameters for early prostate cancer detection?

Djavan B, Zlotta AR, Remzi M, et al.

Urology. 1999 Nov; 54(5):846-52.

OBJECTIVES: To define the role of total prostate (TP) volume, transition zone (TZ) volume, and age as determinants of the utility of prostate-specific antigen (PSA)-based diagnostic parameters for early detection of prostate cancer (PCa) in a prospective multicenter study. METHODS: The study participants were 974 consecutive men with serum total PSA (tPSA) levels of 4 to 10 ng/mL who were referred for early PCa detection or lower urinary tract symptoms. All patients underwent prostate ultrasound examination and sextant biopsy with two additional TZ biopsies. In patients with negative initial biopsies, repeated biopsies were performed at 6 weeks. tPSA, the free/total PSA ratio (f/t PSA), PSA density of the TZ (PSA-TZ), PSA density (PSAD), and PSA velocity (PSAV) were determined and compared across TP volume strata of 30 cm3 or less and greater than 30 cm3, TZ volume strata of 20 cm3 or less and greater than 20 cm3, and various age groups to evaluate the need for volume and/or age-specific reference ranges. RESULTS: PCa was found in 345 (35.4%) of 974 patients and benign prostatic tissue was found in 629 (64.6%) of 947 patients. Across TP volume strata, significantly higher values of tPSA (P

The effect of essential fatty acids on growth and urokinase-type plasminogen activator production in human prostate DU-145 cells.

du Toit PJ, van Aswegen CH, du Plessis DJ.

Prostaglandins Leukot Essent Fatty Acids. 1996 Sep; 55(3):173-7.

Urokinase-type plasminogen activator (uPA) is an important protease enzyme in carcinogenesis, and is involved in both invasion and metastasis of cancer. Increased uPA activity and decreased essential fatty acid (EFA) levels have been reported in cancer. This phenomenon may be explained by the fact that certain EFAs, such as gamma-linolenic acid (GLA) and eicosapentaenoic acid (EPA), inhibit uPA activity. The effect of EFA on human prostate DU-145 cell growth and uPA production is still unknown and was investigated in this study. Data obtained from the different unsaturated fatty acids showed that oleic acid (OA) and EPA enhanced DU-145 cell proliferation at 0.004 and 0.04 mM for up to 4 days. However, alpha-linolenic acid (ALA), linoleic acid (LA), GLA and arachidonic acid (AA) suppressed cell proliferation under the same conditions, possibly as a result of inhibition of DNA and protein synthesis as measured using labelled thymidine and glycine incorporation. In contrast to the cell proliferation, uPA production was inhibited by all the unsaturated fatty acids under investigation. Therefore, the absence of EFAs, as reported, may affect invasion and metastasis of cancer

Baseline characteristics and the effect of selenium supplementation on cancer incidence in a randomized clinical trial: a summary report of the Nutritional Prevention of Cancer Trial.

Duffield-Lillico AJ, Reid ME, Turnbull BW, et al.

Cancer Epidemiol Biomarkers Prev. 2002 Jul; 11(7):630-9.

The Nutritional Prevention of Cancer Trial was a randomized, clinical trial designed to evaluate the efficacy of selenium as selenized yeast (200 microg daily) in preventing the recurrence of nonmelanoma skin cancer among 1312 residents of the Eastern United States. Original secondary analyses through December 31, 1993 showed striking inverse associations between treatment and the incidence of total [hazard ratio (HR) = 0.61, 95% confidence interval (CI) = 0.46-0.82], lung, prostate, and colorectal cancer and total cancer mortality. This report presents results through February 1, 1996, the end of blinded treatment. Effect modification by baseline characteristics is also evaluated. The effects of treatment overall and within subgroups of baseline age, gender, smoking status, and plasma selenium were examined using incidence rate ratios and Cox proportional hazards models. Selenium supplementation reduced total (HR = 0.75, 95% CI = 0.58-0.97) and prostate (HR = 0.48, 95% CI = 0.28-0.80) cancer incidence but was not significantly associated with lung (HR = 0.74, 95% CI = 0.44-1.24) and colorectal (HR = 0.46, 95% CI = 0.21-1.02) cancer incidence. The effects of treatment on other site-specific cancers are also described. The protective effect of selenium was confined to males (HR = 0.67, 95% CI = 0.50-0.89) and was most pronounced in former smokers. Participants with baseline plasma selenium concentrations in the lowest two tertiles (

Prospective evaluation of prostate cancer detection by prostate-specific antigen-related parameters.

Egawa S, Suyama K, Takashima R, et al.

Int J Urol. 1999 Oct; 6(10):493-501.

BACKGROUND: The diagnostic value of prostate-specific antigen (PSA) for differentiating prostate cancer from benign prostatic conditions is limited by its lack of specificity. Several PSA-related parameters have been suggested as enhancing the discriminatory power of total PSA values, but their clinical utility should be considered preliminary until established in a prospectively evaluated cohort. METHODS: In a prospective cohort study, results of ultrasound-guided biopsy and/or transurethral resection of the prostate gland were assessed in 706 consecutive Japanese men. The clinical usefulness of total PSA, free PSA, percentage of free PSA, PSA density (PSAD), PSA density for transition zone (PSADT) and gland volume for predicting prostate cancer was investigated using receiver operating characteristic (ROC) curve analysis in 16 different patient subgroups. RESULTS: Overall, 150 of the 706 patients (21.2%) had prostate carcinoma. The ROC curve analysis showed that PSAD and PSADT were more powerful predictors of prostate cancer than total PSA in most of the 16 patient subgroups tested. The improvement in performance was modest, however. No substantial difference was noted between PSAD and PSADT. Total gland volume did not significantly affect the performance of these parameters. The use of a PSAD threshold value of 0.11-10.15 ng/mL per cm3 (or a PSADT value of 0.23-0.27 ng/mL per cm3) would have avoided 24-48% (or, for PSADT, 34-40%) of unnecessary biopsies at the cost of missing 5-10% of detectable cancers in a patient subgroup with intermediate total PSA levels. The performance of free PSA and percentage of free PSA was worse than that of any other test in this study. This may be due to inappropriate handling of sera prior to measurement. CONCLUSIONS: The discriminatory potential of total PSA for predicting prostate cancer was modestly improved by the use of PSAD and PSADT. No substantial advantage of PSADT over PSAD could be demonstrated. Stringent and standardized storage conditions should always be maintained when applying free PSA-related parameters

Use of artificial neural networks in prostate cancer.

Errejon A, Crawford ED, Dayhoff J, et al.

Mol Urol. 2001; 5(4):153-8.

Artificial neural networks (ANNs) are a type of artificial intelligence software inspired by biological neuronal systems that can be used for nonlinear statistical modeling. In recent years, these applications have played an increasing role in predictive and classification modeling in medical research. We review the basic concepts behind ANNs and examine the role of this technology in selected applications in prostate cancer research

BRCA1 and BRCA2 gene mutations: decision-making dilemmas concerning testing and management.

Fasouliotis SJ, Schenker JG.

Obstet Gynecol Surv. 2000 Jun; 55(6):373-84.

The identification of the BRCA genes, and their possible etiologic relationship with various forms of inherited cancer, has been recognized universally as a cornerstone in the search of cancer's genetic susceptibility. Female BRCA gene mutation carriers are found to carry an increased risk of developing breast or ovarian cancer and to a lesser degree, colon cancer, and male BRCA mutation carriers are also related to an increased risk of breast, colon, or prostate cancer. Although genetic testing promises a possible future presymptomatic determination and treatment of women who are genetically susceptible to cancer, current data reveal certain dilemmas and uncertainties regarding our ability to interpret the results from testing and offer effective management options. In addition, several complex ethical, legal, and social issues have been revealed with the advent of this new information, which also confirm the need for additional research regarding the most effective use of this genetic information and for the establishment of appropriate clinical management strategies

Today men with prostate cancer have larger prostates.

Feneley MR, Landis P, Simon I, et al.

Urology. 2000 Nov 1; 56(5):839-42.

OBJECTIVES: To examine the relationship between prostate size and the method of cancer detection in men with organ-confined prostate cancer, and compare prostate size in men with and without cancer. METHODS: Prostate volume was evaluated in 720 men who had undergone radical prostatectomy for Stage T1c or Stage T2 cancer. Men with Stage T2 cancer were divided into those treated before 1989 (when widespread prostate-specific antigen [PSA] testing began), or not. Gland volume was also examined in 265 men participating in the Baltimore Longitudinal Study of Aging who had no clinical evidence of cancer. Volumes were compared using linear regression to allow for age. RESULTS: Prostate volume in men with Stage T1c cancer was statistically significantly larger than in men with Stage T2 cancer diagnosed in the pre-PSA era after adjusting for age (P = 0.0001), and statistically significantly larger than in men without cancer above age 47 years based on 95% confidence intervals. Prostate volumes in men with Stage T2 cancer diagnosed in the pre-PSA era and in men without cancer were not statistically significantly different. CONCLUSIONS: Prostate volume in men with PSA-detected, organ-confined cancer is larger than in men with palpable organ-confined cancer diagnosed in either the pre-PSA era or PSA era. These discrepancies may reflect a diagnostic bias due to the effect of benign prostatic hyperplasia on serum PSA that results in the selection of men with larger prostates for biopsy

Vitamin E inhibits the high-fat diet promoted growth of established human prostate LNCaP tumors in nude mice.

Fleshner N, Fair WR, Huryk R, et al.

J Urol. 1999 May; 161(5):1651-4.

PURPOSE: Prostate cancer has become an important public health problem in the Western world. It is currently the most common diagnosed cancer and the second leading cause of cancer deaths among North American men. Prostate cancer possesses a unique descriptive epidemiology which suggests that environmental factors (such as dietary fat consumption) play a pivotal role in tumor progression. Data from our institution have demonstrated that diets high in fat content can accelerate the growth of human LNCaP prostate cancer cells. One of the hypothesized mechanisms of dietary fat induced growth is oxidative stress. Our purpose was to determine the effect of supplemental Vitamin E, a potent intracellular antioxidant, on the high-fat promoted growth of transplanted LNCaP cells in the athymic mouse. MATERIALS AND METHODS: Tumors were induced by subcutaneous injection of 10(6) LNCaP cells. Mice were fed a control diet consisting of 40.5% of total calories from dietary fat. Once tumors were formed, PSA values were obtained and animals were randomized into 4 groups of 12. The animals were then assigned to one of 4 dietary plans. Group 1 received the control diet of 40.5%-kcal fat. Group 2 received the 40.5%-kcal fat diet plus supplemental Vitamin E. Group 3 received a diet of 21.2%-kcal fat. Group 4 received the 21.2%-kcal fat diet plus supplemental Vitamin E. Food intake, animal weights, and tumor volumes were recorded weekly. Survival analyses with time to a target volume of 0.523 cm.3 (defined as failure) were used to compare tumor growth among the 4 groups. Two-sided tests (log rank test) with alpha set at 0.05 were used to determine significance. RESULTS: Tumor growth rates were highest in the animals fed a 40.5%-kcal fat diet (p

Review: molecular pathology of cyclooxygenase-2 in cancer-induced angiogenesis.

Fosslien E.

Ann Clin Lab Sci. 2001 Oct; 31(4):325-48.

Cancer-induced angiogenesis is the result of increased expression of angiogenic factors, or decreased expression of anti-angiogenic factors, or a combination of both events. For instance, in colon cancer, the malignant cells, the stromal fibroblasts, and the endothelial cells all exhibit strong staining for cyclooxygenase-2 (COX-2), the rate-controlling enzyme in prostaglandin (PG) synthesis. In various cancer tissues, vascular endothelial growth factor (VEGF) and transforming growth factor beta (TGF-beta) co-localize with COX-2. Strong COX-2 and VEGF expression is highly correlated with increased tumor microvascular density (MCD); new vessels proliferate in areas of the tumor that express COX-2. Moreover, high MVD is a predictor of poor prognosis in breast and cervical cancers. COX-2 and VEGF expression are elevated in breast and prostate cancer tissues and their cell-lines. In vitro, PGE2 induces VEGE Supernatants of cultured cells from breast, prostate, and squamous cell cancers contain angiogenic proteins such as COX-2 and VEGF that induce in vitro angiogenesis. A selective COX-2 inhibitor, NS-398, restores tumor cell apoptosis, reduces microvascular density, and reduces tumor growth of PC-3 prostate carcinoma cells xenografted into nude mice. The COX-2 produced by a malignant tumor and COX-2 produced by the surrounding host tissue both contribute to new vessel formation, which explains how selective COX-2 inhibition reduces tumor growth where the tumor COX-2 gene has been silenced by methylation

Prostate specific antigen regression and progression after androgen deprivation for localized and metastatic prostate cancer.

Fowler JE, Jr., Pandey P, Seaver LE, et al.

J Urol. 1995 Jun; 153(6):1860-5.

To identify prostate specific antigen (PSA) functions of prognostic significance in regard to treatment with androgen deprivation for prostate cancer we analyzed the pretreatment PSA, PSA half-life, PSA nadirs, times to PSA elevation and PSA doubling times in 245 patients with localized and 78 with metastatic disease who were treated with this modality. There was a direct correlation between the pretreatment PSA and the time to PSA elevation in patients with localized cancer (p = 0.000003) but no significant correlation in those with metastatic cancer. The PSA half-life was highly variable and did not correlate with other PSA functions of prognostic significance. Incremental increases in the PSA nadir correlated with the time to PSA elevation in patients with localized and metastatic cancer (p < 0.000001 and p = "0.00009," respectively), and with other parameters of prognostic significance. The median PSA doubling time in 26 patients with localized cancer in whom distant metastases did not develop (7.5 months) was significantly longer than that in 7 in whom new metastases developed (2.5 months) and in 43 with preexisting metastatic cancer (2.5 months) (p < 0.05 and p < 0.0001, respectively). In the 7 patients with localized cancer in whom metastases developed the median of the ratios of the PSA when the metastases were manifest and the pretreatment PSA was 0.14, and in 24 patients with preexisting metastatic cancer the median of the ratios of the antemortem PSA and the pretreatment PSA was 1.2. These data show that PSA synthesis by prostate cancer is reduced after androgen deprivation but that the PSA nadir and PSA doubling time following treatment provide important prognostic information

Predictors of first repeat biopsy cancer detection with suspected local stage prostate cancer.

Fowler JE, Jr., Bigler SA, Miles D, et al.

J Urol. 2000 Mar; 163(3):813-8.

PURPOSE: We determine demographic and tumor related predictors of repeat biopsy cancer detection in men with suspected stage T1c-2 prostate cancer. MATERIALS AND METHODS: The study population included 298 consecutive men with suspected stage T1c-2 prostate cancer who had a benign prostate biopsy at 1 institution between January 1, 1992 and April 1, 1999 and underwent 1 repeat biopsy. Mean age plus or minus standard deviation was 66.8+/-6.7 years for 133 black (55%) and 165 white (45%) patients. Clinical measures included determination of high grade prostatic intraepithelial neoplasia in benign biopsy specimens, Gleason score of malignant biopsy specimens, prostate specific antigen (PSA), PSA density, annualized interbiopsy PSA change, percent free PSA (201 cases) and PSA velocity (171). RESULTS: Cancer was detected on repeat biopsy in 80 cases (27%). Significant differences between patients with benign and malignant repeat biopsies included age (p = 0.001), PSA density (p = 0.0001), percent free PSA (p = 0.0001) and PSA velocity (p = 0.009). High grade prostatic intraepithelial neoplasia in an initial benign biopsy was not predictive of cancer in repeat biopsy (p = 0.12). Multiple logistic regression analysis of all cases showed that age (p = 0.002) and PSA density (p = 0.0002) were independent predictors of cancer. Subset multiple logistic regression analysis modeled with age, PSA density and percent free PSA demonstrated that age (p = 0.002) and percent free PSA (p = 0.0001) were significant independent predictors of malignancy. Subset multiple logistic regression analysis modeled with age, PSA density, percent free PSA and PSA velocity revealed that age (p = 0.02) and percent free PSA (p = 0.0003) were significant independent predictors of cancer. There were no significant differences between the Gleason scores of cancers detected on repeat biopsy compared to 587 stage T1c-2 cancers detected on initial biopsy during the study period (p = 0.09). PSA, PSA density, percent free PSA and PSA velocity were not significantly different among men without a cancer diagnosis who had high grade neoplasia in 1 or 2 benign biopsies. CONCLUSIONS: Greater than 25% of this population of select patients with suspected stage T1c-2 prostate cancer had malignancy detected on repeat biopsy. Percent free PSA was the most powerful predictor of cancer. High grade prostatic intraepithelial neoplasia was not a predictor of repeat biopsy cancer detection and PSA functions were similar among men without cancer who did and did not have high grade neoplasia in 1 or more benign biopsies. This finding suggests that high grade prostatic intraepithelial neoplasia may not be a reliable indicator of clinically significant existing prostate cancer

[Densitometry in suspected preclinical osteoporosis: quantitative computerized tomography versus dual energy roentgen absorptiometry].

Frahm C, Link J, Hakelberg K, et al.

Bildgebung. 1994 Dec; 61(4):256-62.

The bone mineral density of 85 patients with suspicion of a preclinical osteoporosis was measured at the lumbar spine by using quantitative computed tomography (QCT) in single-energy technique (SEQCT) and dual-energy technique (DEQCT) as well as by using dual-energy X-ray absorptiometry (DEXA). Additionally, the bone density of 63 of these patients was measured at the left femoral neck using DEXA. DEQCT und DEXA of the lumbar spine showed only a moderate correlation (R = 0.75) and differed considerably concerning the classification of the patients as normals or individuals with a mineral deficit when compared with age-matched normals (relative mineral deficit). The DEXA proved to be susceptible to degenerative alterations of the lumbar spine. Because of the extremely low dose of radiation and the good reproducibility the DEXA could nevertheless be recommended as a method for the long-time progress control especially for younger patients. SEQCT and DEQCT showed a very strong correlation (R = 0.98). The SEQCT with its lower dose of radiation should be sufficient for a long-time progress control and in many cases also for the initial diagnostics. Significant but only moderate correlations were found between the bone density at the femoral neck and the DEXA or DEQCT results (R = 0.68 respectively R = 0.63) for the lumbar spine, so that the linear regression did not render any useable approximations. Sufficiently exact information about the mineralization status of a certain skeletal site can only be obtained by direct measurement

Fire and Ice.

Frost R.

1975;220.

Cyclooxygenase-2 promotes prostate cancer progression.

Fujita H, Koshida K, Keller ET, et al.

Prostate. 2002 Nov 1; 53(3):232-40.

BACKGROUND: Cyclooxygenase (COX) -2, an inducible isoform of COX, has been observed to be expressed in prostate cancer. Several studies have reported that COX-2 overexpression is associated with carcinogenesis, cell growth, angiogenesis, apoptosis, and invasiveness in a variety of tumor types. METHODS: To investigate the function of COX-2 in prostate cancer directly, we stably transfected human full-length COX-2 cDNA into LNCaP cells (LNCaP-COX-2), which express low levels of endogenous COX-2. RESULTS: The level of COX-2 mRNA and protein and the COX activity in COX-2 LNCaP-COX-2 cells was significantly increased compared with parent and control-transfected cells. Overexpression of COX-2 increased both proliferation in vitro and tumor growth rate in vivo. However, the pro-tumor effect was neither associated with changes of androgen receptor (AR) expression level nor AR activity. Furthermore, addition of the major metabolites of COX-2-mediated arachidonic acid metabolism did not alter the proliferation of LNCaP-COX-2 cells in vitro. LNCaP-COX-2 cells had increased secretion of vascular endothelial growth factor (VEGF) protein, suggesting that angiogenesis induced by COX-2 stimulates tumor growth in vivo. CONCLUSION: These data demonstrate that COX-2 contributes to prostate cancer progression and suggest that it mediates this effect, in part, through increased VEGF

Use of artificial neural networks in the clinical staging of prostate cancer: implications for prostate brachytherapy.

Gamito EJ, Stone NN, Batuello JT, et al.

Tech Urol. 2000 Jun; 6(2):60-3.

PURPOSE: This review describes two studies to evaluate artificial neural networks (ANNs) in prostate cancer staging. In the first study, an ANN was trained to identify prostate cancer patients at low risk of lymph node spread (LNS). The second study evaluated an ANN to predict capsular penetration (CP) in men with clinically localized prostate cancer. An accurate assessment of lymph node status will help identify those brachytherapy patients in whom lymphadenectomy can be avoided. The accurate prediction of CP can help determine the appropriateness of brachytherapy as a treatment option. MATERIALS AND METHODS: An ANN to predict LNS was trained and tested using a database from one institution (n = 4,133) and validated using two databases (n = 330 and n = 227) from different institutions. The clinical variables used were clinical stage (cTNM), Gleason sum, and prostate-specific antigen concentration (PSA). The ANN to predict CP was trained and validated with data from a single institution (n = 409). The variables used were age, race, PSA, PSA velocity, Gleason sum, and cTNM. RESULTS: The LNS ANN was able classify 76%, 75%, and 30% of the patients in each database as being at low risk of LNS with 98% accuracy. The CP ANN correctly identified CP in 25 (84%) of patients and produced 5 (16%) false-negative predictions. CONCLUSIONS: These preliminary results suggest that ANNs can be useful in staging prostate cancer. If sufficiently accurate ANNs can be developed and tested, they have the potential to increase the accuracy of clinical staging and thus improve treatment decisions

Lower prostate cancer risk in men with elevated plasma lycopene levels: results of a prospective analysis.

Gann PH, Ma J, Giovannucci E, et al.

Cancer Res. 1999 Mar 15; 59(6):1225-30.

Dietary consumption of the carotenoid lycopene (mostly from tomato products) has been associated with a lower risk of prostate cancer. Evidence relating other carotenoids, tocopherols, and retinol to prostate cancer risk has been equivocal. This prospective study was designed to examine the relationship between plasma concentrations of several major antioxidants and risk of prostate cancer. We conducted a nested case-control study using plasma samples obtained in 1982 from healthy men enrolled in the Physicians' Health Study, a randomized, placebo-controlled trial of aspirin and beta-carotene. Subjects included 578 men who developed prostate cancer within 13 years of follow-up and 1294 age- and smoking status-matched controls. We quantified the five major plasma carotenoid peaks (alpha- and beta-carotene, beta-cryptoxanthin, lutein, and lycopene) plus alpha- and gamma-tocopherol and retinol using high-performance liquid chromatography. Results for plasma beta-carotene are reported separately. Odds ratios (ORs), 95% confidence intervals (Cls), and Ps for trend were calculated for each quintile of plasma antioxidant using logistic regression models that allowed for adjustment of potential confounders and estimation of effect modification by assignment to either active beta-carotene or placebo in the trial. Lycopene was the only antioxidant found at significantly lower mean levels in cases than in matched controls (P = 0.04 for all cases). The ORs for all prostate cancers declined slightly with increasing quintile of plasma lycopene (5th quintile OR = 0.75, 95% CI = 0.54-1.06; P, trend = 0.12); there was a stronger inverse association for aggressive prostate cancers (5th quintile OR = 0.56, 95% CI = 0.34-0.91; P, trend = 0.05). In the placebo group, plasma lycopene was very strongly related to lower prostate cancer risk (5th quintile OR = 0.40; P, trend = 0.006 for aggressive cancer), whereas there was no evidence for a trend among those assigned to beta-carotene supplements. However, in the beta-carotene group, prostate cancer risk was reduced in each lycopene quintile relative to men with low lycopene and placebo. The only other notable association was a reduced risk of aggressive cancer with higher alpha-tocopherol levels that was not statistically significant. None of the associations for lycopene were confounded by age, smoking, body mass index, exercise, alcohol, multivitamin use, or plasma total cholesterol level. These results concur with a recent prospective dietary analysis, which identified lycopene as the carotenoid with the clearest inverse relation to the development of prostate cancer. The inverse association was particularly apparent for aggressive cancer and for men not consuming beta-carotene supplements. For men with low lycopene, beta-carotene supplements were associated with risk reductions comparable to those observed with high lycopene. These data provide further evidence that increased consumption of tomato products and other lycopene-containing foods might reduce the occurrence or progression of prostate cancer

The extent of biopsy involvement as an independent predictor of extraprostatic extension and surgical margin status in low risk prostate cancer: implications for treatment selection.

Gao X, Mohideen N, Flanigan RC, et al.

J Urol. 2000 Dec; 164(6):1982-6.

PURPOSE: We identify predictors of extraprostatic extension and positive surgical margins in patients with low risk prostate cancer (prostate specific antigen [PSA] 10 ng./ml. or less, biopsy Gleason score 7 or less and clinical stage T1c-2b). MATERIALS AND METHODS: From August 1997 to January 1999, 143 previously untreated patients underwent radical retropubic prostatectomy for clinically localized prostate cancer. A total of 62 patients were low risk, with PSA 10 ng./ml. or less, biopsy Gleason score 7 or less and clinical stage T1c-2b, and had sextant biopsy with separate pathological evaluation of each sextant cores. PSA, clinical stage, biopsy Gleason score, average percentage of cancer in the entire biopsy specimen, maximum percentage of cancer on the most involved core, number of cores involved and bilaterality were evaluated for association with extraprostatic extension, seminal vesicle involvement and positive surgical margins. RESULTS: Of the 62 patients 13 (21%) had extraprostatic extension, 6 (10%) seminal vesicle involvement and 20 (32%) positive surgical margins. Average percentage greater than 10% and maximum percentage greater than 25% were associated with extraprostatic extension (p = 0.01 and 0.004, respectively). Average percentage greater than 10%, maximum percentage greater than 25%, more than 2 cores involved and bilaterality were associated with positive surgical margins (p = 0.007, 0.01, 0.002 and 0.03, respectively). On multivariate analysis maximum percentage remained the only independent predictor of extraprostatic extension (p = 0.03), and the number of cores involved remained an independent predictor of positive surgical margins (p = 0.01). Biopsy Gleason score, PSA and clinical stage did not correlate with extraprostatic extension or positive surgical margins in this patient population. CONCLUSIONS: In low risk prostate cancer the extent of biopsy involvement significantly correlates with the risk of extraprostatic extension and positive surgical margins. Biopsy information should be considered when selecting and modifying treatment modalities

Human prostatic carcinoma cells produce an increase in the synthesis of interleukin-6 by human osteoblasts.

Garcia-Moreno C, Mendez-Davila C, de La PC, et al.

Prostate. 2002 Mar 1; 50(4):241-6.

BACKGROUND: The aim of this work was to evaluate the effect produced by conditioned medium from human prostatic carcinoma cell (PC-3) culture on human osteoblast (HOB) interleukin 6 (IL-6) synthesis. METHODS: PC-3 cells were cultured in Ham's F12K medium with 10% fetal calf serum (FCS) up to confluence. Medium was changed by Dulbecco modified Eagle medium (DMEM)/F12K (1:1) with 0.1% bovine serum albumin. Cells were cultured for 24 hr, and medium (PC-3-CM) was collected. HOBs were cultured up to confluence, and after 48 hr without FCS, medium was removed and PC-3-CM was added to the wells. After 24 hr, supernatant was collected for the determination of IL-6. In another experiment, HOBs were cultured up to confluence in Petri dishes, and after 48 hr without FCS, PC-3-CM or DMEM/F12K (1:1) was added. After different periods of time, medium was removed, and total RNA was extracted. IL-6 mRNA was quantified using reverse transcription polymerase chain reaction. RESULTS: PC-3-CM significantly enhanced IL-6 secretion into HOB culture supernatants (between 1,812% and 372%, depending on the osteoblastic line) with respect to HOBs cultured in DMEM/F12K. PC-3-CM also produced an increase in IL-6 mRNA levels in HOBs. CONCLUSIONS: Prostate carcinoma cells (PC-3) produce a factor or factors that enhance the synthesis and release of IL-6, a known activator of bone resorption

The potential role of lycopene for human health.

Gerster H.

J Am Coll Nutr. 1997 Apr; 16(2):109-26.

Lycopene is one of the major carotenoids in Western diets and is found almost exclusively in tomatoes and tomato products. It accounts for about 50% of carotenoids in human serum. Among the common dietary carotenoids lycopene has the highest singlet oxygen quenching capacity in vitro. Other outstanding features are its high concentration in testes, adrenal gland and prostate. In contrast to other carotenoids its serum values are not regularly reduced by smoking or alcohol consumption but by increasing age. Remarkable inverse relationships between lycopene intake or serum values and risk have been observed in particular for cancers of the prostate, pancreas and to a certain extent of the stomach. In some of the studies lycopene was the only carotenoid associated with risk reduction. Its role in cancer risk reduction still needs to be clarified. Patients with HIV infection, inflammatory diseases and hyperlipidemia with and without lipid lowering treatment may have depleted lycopene serum concentrations. Before embarking on large-scale human trials the distribution of lycopene and its biological functions need to be further evaluated

Salvage cryotherapy using an argon based system for locally recurrent prostate cancer after radiation therapy: the Columbia experience.

Ghafar MA, Johnson CW, De La TA, et al.

J Urol. 2001 Oct; 166(4):1333-7.

PURPOSE: Cryosurgical ablation of the prostate has been reported as potential treatment for radioresistant clinically localized prostate cancer. We report our experience with the safety and efficacy of salvage cryosurgery using the argon based CRYOCare system (Endocare, Inc, Irvine, California). MATERIALS AND METHODS: Between October 1997 and September 2000, 38 men with a mean age of 71.9 years underwent salvage cryosurgery for recurrent prostate cancer after radiation therapy failed. All patients had biochemical disease recurrence, defined as an increase in prostate specific antigen (PSA) of greater than 0.3 ng./ml. above the post-radiation PSA nadir. Subsequently prostate biopsy was positive for cancer. Pre-cryosurgery bone scan demonstrated no evidence of metastatic disease. In addition, these patients received 3 months of neoadjuvant androgen deprivation therapy before cryotherapy. RESULTS: The PSA nadir was 0.1 or less, 1 or less and greater than 1 ng./ml. in 31 (81.5%), 5 (13.2%) and 2 (5.3%) patients, respectively. Biochemical recurrence-free survival calculated from Kaplan-Meier curves was 86% at 1 year and 74% at 2 years. Reported complications included rectal pain in 39.5% of cases, urinary tract infection in 2.6%, incontinence in 7.9%, hematuria in 7.9% and scrotal edema in 10.5%. The rate of rectourethral fistula, urethral sloughing and urinary retention was 0%. CONCLUSIONS: Our study supports cryosurgery of the prostate as safe and effective treatment in patients in whom radiation therapy fails. Using the CRYOCare machine resulted in a marked decrease in complications

Arachidonic acid stimulates prostate cancer cell growth: critical role of 5-lipoxygenase.

Ghosh J, Myers CE.

Biochem Biophys Res Commun. 1997 Jun 18; 235(2):418-23.

Arachidonic acid (5,8,11,14-eicosatetraenoic acid), a member of the omega-6 poly-unsaturated fatty acids, was found to be an effective stimulator of human prostate cancer cell growth in vitro at micromolar concentrations. Selective blockade of the different metabolic pathways of arachidonic acid (e.g. ibuprofen for cyclooxygenase, SKF-525A for cytochrome P-450, baicalein and BHPP for 12-lipoxygenase, AA861 and MK886 for 5-lipoxygenase, etc.) revealed that the growth stimulatory effect of arachidonic acid is inhibited by the 5-lipoxygenase specific inhibitors, AA861 and MK886, but not by others. Addition of the eicosatetraenoid products of 5-lipoxygenase (5-HETEs) showed stimulation of prostate cancer cell growth similar to that of arachidonic acid, whereas the leukotrienes were ineffective. Moreover, the 5-series of eicosatetraenoids could reverse the growth inhibitory effect of MK886. Finally, prostate cancer cells fed with arachidonic acid showed a dramatic increase in the production of 5-HETEs which is effectively blocked by MK886. These experimental observations suggest that arachidonic acid needs to be metabolized through the 5-lipoxygenase pathway to produce 5-HETE series of eicosatetraenoids for its growth stimulatory effects on human prostate cancer cells

Inhibition of arachidonate 5-lipoxygenase triggers massive apoptosis in human prostate cancer cells.

Ghosh J, Myers CE.

Proc Natl Acad Sci U S A. 1998 Oct 27; 95(22):13182-7.

Diets high in fat are associated with an increased risk of prostate cancer, although the molecular mechanism is still unknown. We have previously reported that arachidonic acid, an omega-6 fatty acid common in the Western diet, stimulates proliferation of prostate cancer cells through production of the 5-lipoxygenase metabolite, 5-HETE (5-hydroxyeicosatetraenoic acid). We now show that 5-HETE is also a potent survival factor for human prostate cancer cells. These cells constitutively produce 5-HETE in serum-free medium with no added stimulus. Exogenous arachidonate markedly increases the production of 5-HETE. Inhibition of 5-lipoxygenase by MK886 completely blocks 5-HETE production and induces massive apoptosis in both hormone-responsive (LNCaP) and -nonresponsive (PC3) human prostate cancer cells. This cell death is very rapid: cells treated with MK886 showed mitochondrial permeability transition between 30 and 60 min, externalization of phosphatidylserine within 2 hr, and degradation of DNA to nucleosomal subunits beginning within 2-4 hr posttreatment. Cell death was effectively blocked by the thiol antioxidant, N-acetyl-L-cysteine, but not by androgen, a powerful survival factor for prostate cancer cells. Apoptosis was specific for 5-lipoxygenase-programmed cell death was not observed with inhibitors of 12-lipoxygenase, cyclooxygenase, or cytochrome P450 pathways of arachidonic acid metabolism. Exogenous 5-HETE protects these cells from apoptosis induced by 5-lipoxygenase inhibitors, confirming a critical role of 5-lipoxygenase activity in the survival of these cells. These findings provide a possible molecular mechanism by which dietary fat may influence the progression of prostate cancer

Arachidonic acid metabolism and cancer of the prostate.

Ghosh J, Myers CE, Jr.

Nutrition. 1998 Jan; 14(1):48-9.

A concept analysis of empowerment.

Gibson CH.

J Adv Nurs. 1991 Mar; 16(3):354-61.

In this paper, an objective concept analysis was undertaken to examine the attributes, characteristics and uses of the concept of empowerment. A review of the literature and selected empirical referents indicated that empowerment is a complex and multi-dimensional concept. Within a nursing context, empowerment can be conceptualized as a composite of (a) attributes that relate to the client, (b) attributes that relate to the nurse, and (c) attributes that belong to both the client and the nurse. In a broad sense, empowerment is a process of helping people to assert control over the factors which affect their lives. This process encompasses both the individual responsibility in health care and the broader institutional, organizational or societal responsibilities in enabling people to assume responsibility for their own health. Antecedents to and consequences of empowerment, from a nursing perspective, are presented. To adopt truly an empowerment model in nursing, a radical paradigm shift is needed. The final conclusion is that this concept has great utility for nursing practice, education, administration and research

Predicting extracapsular extension of prostate cancer in men treated with radical prostatectomy: results from the population based prostate cancer outcomes study.

Gilliland FD, Hoffman RM, Hamilton A, et al.

J Urol. 1999 Oct; 162(4):1341-5.

PURPOSE: We investigated whether clinical information routinely available in community practice could predict extracapsular extension of clinically localized prostate cancer in men undergoing radical prostatectomy. MATERIALS AND METHODS: We examined prostate cancer outcomes in a population based sample of 3,826 patients with primary prostate cancer in 6 regions of the United States covered by the Surveillance, Epidemiology, and End Results program. Stratified and weighted logistic regression was used to identify predictors of and probabilities for extracapsular extension of clinically localized tumors treated with radical prostatectomy. RESULTS: Nearly 47% of men undergoing radical prostatectomy had extraprostatic extension. The strongest predictors were elevated prostate specific antigen (PSA) greater than 20 versus less than 4 ng./ml. (odds ratio 5.88, 95% confidence interval 2.90 to 11.15), Gleason score greater than 8 versus less than 6 (1.73, 1.04 to 2.87) and age greater than 70 versus less than 50 years (1.91, 0.98 to 3.70). Ethnicity and region were not associated with increased risk of extraprostatic extension. A nomogram developed from our model predicts extracapsular extension ranging from 24% in men younger than 50 years with PSA less than 4 ng./ml. and a Gleason score of less than 7 to 85% in those 70 years old or older with PSA greater than 20 ng./ml. and a Gleason score of 8 or more. If prostatectomy were limited to patients with less than 60% probability of extraprostatic extension based on the nomogram, 95% of those with organ confined cancers would undergo definitive surgery and 18% of those with extracapsular extension would be spared the morbidity of surgery. CONCLUSIONS: In a population based analysis of prostate cancer practice patterns PSA, Gleason score and age are clinically useful predictors of extracapsular extension. Although extracapsular extension may be an imperfect predictor of cancer outcomes, our nomogram provides more realistic probabilities for extracapsular extension than those based on institutional series

Intake of carotenoids and retinol in relation to risk of prostate cancer.

Giovannucci E, Ascherio A, Rimm EB, et al.

J Natl Cancer Inst. 1995 Dec 6; 87(23):1767-76.

BACKGROUND: Several human studies have observed a direct association between retinol (vitamin A) intake and risk of prostate cancer; other studies have found either an inverse association or no association of intake of beta-carotene (the major provitamin A) with risk of prostate cancer. Data regarding carotenoids other than beta-carotene in relation to prostate cancer risk are sparse. PURPOSE: We concluded a prospective cohort study to examine the relationship between the intake of various carotenoids, retinol, fruits, and vegetables and the risk of prostate cancer. METHODS: Using responses to a validated, semiquantitative food-frequency questionnaire mailed to participants in the Health Professionals Follow-up Study in 1986, we assessed dietary intake for a 1-year period for a cohort of 47,894 eligible subjects initially free of diagnosed cancer. Follow-up questionnaires were sent to the entire cohort in 1988, 1990, and 1992. We calculated the relative risk (RR) for each of the upper categories of intake of a specific food or nutrient by dividing the incidence rate of prostate cancer among men in each of these categories by the rate among men in the lowest intake level. All P values resulted from two-sided tests. RESULTS: Between 1986 and 1992, 812 new cases of prostate cancer, including 773 non-stage A1 cases, were documented. Intakes of the carotenoids beta-carotene, alpha-carotene, lutein, and beta-cryptoxanthin were not associated with risk of non-stage A1 prostate cancer; only lycopene intake was related to lower risk (age- and energy-adjusted RR = 0.79; 95% confidence interval [CI] = 0.64-0.99 for high versus low quintile of intake; P for trend = .04). Of 46 vegetables and fruits or related products, four were significantly associated with lower prostate cancer risk; of the four--tomato sauce (P for trend = .001), tomatoes (P for trend = .03), and pizza (P for trend = .05), but not strawberries--were primary sources of lycopene. Combined intake of tomatoes, tomato sauce, tomato juice, and pizza (which accounted for 82% of lycopene intake) was inversely associated with risk of prostate cancer (multivariate RR = 0.65; 95% CI = 0.44-0.95, for consumption frequency greater than 10 versus less than 1.5 servings per week; P for trend = .01) and advanced (stages C and D) prostate cancers (multivariate RR = 0.47; 95% CI = 0.22-1.00; P for trend = .03). No consistent association was observed for dietary retinol and risk of prostate cancer. CONCLUSIONS: These findings suggest that intake of lycopene or other compounds in tomatoes may reduce prostate cancer risk, but other measured carotenoids are unrelated to risk. IMPLICATIONS: Our findings support recommendations to increase vegetable and fruit consumption to reduce cancer incidence but suggest that tomato-based foods may be especially beneficial regarding prostate cancer risk

Calcium and fructose intake in relation to risk of prostate cancer.

Giovannucci E, Rimm EB, Wolk A, et al.

Cancer Res. 1998 Feb 1; 58(3):442-7.

Laboratory and clinical data indicate an antitumor effect of 1,25(OH)2 vitamin D (1,25(OH)2D) on prostate cancer. High calcium intake suppresses formation of 1,25(OH)2D from 25(OH)D, thereby decreasing the 1,25(OH)2D level. Ingestion of fructose reduces plasma phosphate transiently, and hypophosphatemia stimulates 1,25(OH)2D production. We thus conducted a prospective study among 47,781 men of the Health Professionals Follow-Up Study free of cancer in 1986 to examine whether calcium and fructose intake influenced risk of prostate cancer. Between 1986 and 1994, 1369 non-stage A1 and 423 advanced (extraprostatic) cases of prostate cancer were diagnosed. Higher consumption of calcium was related to advanced prostate cancer [multivariate relative risk (RR), 2.97; 95% confidence interval (CI), 1.61-5.50 for intakes > or = 2000 mg/day versus < 500 mg/day; P, trend, 0.002] and metastatic prostate cancer (RR, 4.57; CI, 1.88-11.1; P, trend, 70 versus 5 versus < or = "1" serving per day), and this association was accounted for by fructose intake. Non-fruit sources of fructose similarly predicted lower risk of advanced prostate cancer. A moderate positive association between energy-adjusted fat intake and advanced prostate cancer was attenuated and no longer statistically significant when controlled for calcium and fructose. Our findings provide indirect evidence for a protective influence of high 1,25(OH)2D levels on prostate cancer and support increased fruit consumption and avoidance of high calcium intake to reduce the risk of advanced prostate cancer

Tomatoes, tomato-based products, lycopene, and cancer: review of the epidemiologic literature.

Giovannucci E.

J Natl Cancer Inst. 1999 Feb 17; 91(4):317-31.

The epidemiologic literature in the English language regarding intake of tomatoes and tomato-based products and blood lycopene (a compound derived predominantly from tomatoes) level in relation to the risk of various cancers was reviewed. Because the data are from observational studies, a cause-effect relationship cannot be established definitively. However, the consistency of the results across numerous studies in diverse populations, for case-control and prospective studies, and for dietary-based and blood-based investigations argues against bias or confounding as the explanation for these findings. Lycopene may account for or contribute to these benefits, but this possibility is not yet proven and requires further study. Numerous other potentially beneficial compounds are present in tomatoes, and, conceivably, complex interactions among multiple components may contribute to the anticancer properties of tomatoes. The consistently lower risk of cancer for a variety of anatomic sites that is associated with higher consumption of tomatoes and tomato-based products adds further support for current dietary recommendations to increase fruit and vegetable consumption

A review of epidemiologic studies of tomatoes, lycopene, and prostate cancer.

Giovannucci E.

Exp Biol Med (Maywood ). 2002 Nov; 227(10):852-9.

Prostate cancer is the most common cancer in American men. Preventable measures for this malignancy are not well established. Among potentially beneficial natural compounds is the carotenoid lycopene, which is derived largely from tomato-based products. Recent epidemiologic studies have suggested a potential benefit of this carotenoid against the risk of prostate cancer, particularly the more lethal forms of this cancer. Five studies support a 30% to 40% reduction in risk associated with high tomato or lycopene consumption, three are consistent with a 30% reduction in risk, but the results were not statistically significant, and seven were not supportive of an association. The largest relevant dietary study, a prospective study in male health professionals found that consumption of two to four servings of tomato sauce per week was associated with about a 35% risk reduction of total prostate cancer and a 50% reduction of advanced (extraprostatic) prostate cancer. Tomato sauce was by far the strongest predictor of plasma lycopene levels in this study. In the largest plasma-based study, very similar risk reductions were observed for total and advanced prostate cancer for the highest versus lowest quintile of lycopene. Other studies, mostly dietary case-control studies, have not been as supportive of this hypothesis. The reasons for these inconsistencies are unclear, but in three of the seven null studies, tomato consumption or serum lycopene level may have been too low to observe an effect. Because the concentration and bioavailability of lycopene vary greatly across the various food items, dietary questionnaires vary markedly in their usefulness of estimating the true variation in tissue lycopene concentrations across individuals. To optimize the interpretation of future findings, the usefulness of the questionnaire to measure lycopene levels in a population should be directly assessed. Although not definitive, the available data suggest that increased consumption of tomatoes and tomato-based products may be prudent

A prospective study of tomato products, lycopene, and prostate cancer risk.

Giovannucci E, Rimm EB, Liu Y, et al.

J Natl Cancer Inst. 2002 Mar 6; 94(5):391-8.

BACKGROUND: Some data, including our findings from the Health Professionals Follow-Up Study (HPFS) from 1986 through January 31, 1992, suggest that frequent intake of tomato products or lycopene, a carotenoid from tomatoes, is associated with reduced risk of prostate cancer. Overall, however, the data are inconclusive. We evaluated additional data from the HPFS to determine if the association would persist. METHODS: We ascertained prostate cancer cases from 1986 through January 31, 1998, among 47 365 HPFS participants who completed dietary questionnaires in 1986, 1990, and 1994. We used pooled logistic regression to compute multivariate relative risks (RR) and 95% confidence intervals (CIs). All statistical tests were two-sided. RESULTS: From 1986 through January 31, 1998, 2481 men in the study developed prostate cancer. Results for the period from 1992 through 1998 confirmed our previous findings---that frequent tomato or lycopene intake was associated with a reduced risk of prostate cancer. Similarly, for the entire period of 1986 through 1998, using the cumulative average of the three dietary questionnaires, lycopene intake was associated with reduced risk of prostate cancer (RR for high versus low quintiles = 0.84; 95% CI = 0.73 to 0.96; P(trend) =.003); intake of tomato sauce, the primary source of bioavailable lycopene, was associated with an even greater reduction in prostate cancer risk (RR for 2+ servings/week versus

Combined effect of terazosin and finasteride on apoptosis, cell proliferation, and transforming growth factor-beta expression in benign prostatic hyperplasia.

Glassman DT, Chon JK, Borkowski A, et al.

Prostate. 2001 Jan 1; 46(1):45-51.

BACKGROUND: Medical treatment of benign prostatic hyperplasia (BPH) targets relief of symptoms by causing either relaxation of the prostatic smooth muscle with alpha1 adrenergic blockade, or shrinkage of the gland with 5alpha-reductase inhibitors. We recently demonstrated that alpha1-blockers, such as terazosin, induce apoptosis in prostatic cells. In this study, we examined the combined effect of finasteride and terazosin on the rate of apoptosis and cellular proliferation to investigate their potential synergy at the cellular level. METHODS: Prostate specimens were obtained from men who were treated with either finasteride (n = 24), terazosin (n = 42), or combination therapy (n = 10) for varying time periods (1 week to 36 months) for the relief of the symptoms of BPH. The proliferative and apoptotic indices of both stromal and epithelial prostatic cell populations were determined. Antibodies against TGF-beta1 and TbetaRII were used to examine the immunoreactivity of TGF-beta1 and TbetaRII, respectively, in all prostate tissue sections. RESULTS: The apoptotic index in both prostate cell populations was significantly higher following the combination treatment compared to terazosin or finasteride alone. There were no significant changes in the rate of cellular proliferation with any treatment. Furthermore, there was a significant increase in TGF-beta1 expression in the prostates of patients treated with terazosin or combination therapy, while there was no change in TbetaRII expression. CONCLUSIONS: These results support the concept that induction of prostate apoptosis is a potential molecular mechanism underlying the combination effect of alpha1 blockade with 5alpha-reductase inhibitors in the effective treatment of BPH. The upregulation of TGF-beta1 implies a role for this ligand as an effector of apoptosis induction in response to alpha1-blockade or finasteride therapy of BPH patients

The influence of percentage of preradiation needle biopsies with adenocarcinoma and total radiation dose on the pathologic response of unfavorable prostate adenocarcinoma.

Goldstein NS, Kestin LL, Vicini FA, et al.

Am J Clin Pathol. 2002 Jun; 117(6):927-34.

We studied relationships among clinicopathologic factors in 78 patients with unfavorable prostate adenocarcinoma treated in a dose-escalation radiation therapy (RT) study using pre- and 18-month protocol post-RT biopsy specimens. Pre-RT factors analyzed were serum prostate-specific antigen (PSA) level, Gleason score, and percentage of needle cores with adenocarcinoma; post-RT factors were percentage of needle cores with adenocarcinoma and amount of radiation effect on the adenocarcinoma. Of 78 patients, 42 (54%) had residual adenocarcinoma in the post-RT biopsy specimen. Lower total RT dose and dose per implant and greater serum PSA level were associated with an increasing percentage of needle cores with residual post-RT adenocarcinoma. Lower RT dose, an increasing percentage of pre-RT needle cores with adenocarcinoma, and a greater serum PSA level were associated with an increasing percentage of post-RT needle cores with no to moderate RT effect scores in adenocarcinoma. The mean percentage of pre-RT and post-RT needle cores with adenocarcinoma was greater in patients with post-RT biopsy specimens with no to moderate RT effect. The percentage of pre-RT needle cores with adenocarcinoma (a surrogate marker of adenocarcinoma volume), serum PSA level, and RT dose are the key components in the dose-response relationship. Gleason score and gland volume did not contribute significantly to this relationship

Treatment of early recurrent prostate cancer with 1,25-dihydroxyvitamin D3 (calcitriol).

Gross C, Stamey T, Hancock S, et al.

J Urol. 1998 Jun; 159(6):2035-9.

PURPOSE: Substantial experimental and epidemiological data indicate that 1,25-dihydroxyvitamin D3 (calcitriol) has potent antiproliferative effects on human prostate cancer cells. We performed an open label, nonrandomized pilot trial to determine whether calcitriol therapy is safe and efficacious for early recurrent prostate cancer. Our hypothesis was that calcitriol therapy slows the rate of rise of prostate specific antigen (PSA) compared with the pretreatment rate. MATERIALS AND METHODS: After primary treatment with radiation or surgery recurrence was indicated by rising serum PSA levels documented on at least 3 occasions. Seven subjects completed 6 to 15 months of calcitriol therapy, starting with 0.5 microg. calcitriol daily and slowly increasing to a maximum dose of 2.5 microg. daily depending on individual calciuric and calcemic responses. Each subject served as his own control, comparing the rate of PSA rise before and after calcitriol treatment. RESULTS: As determined by multiple regression analysis, the rate of PSA rise during versus before calcitriol therapy significantly decreased in 6 of 7 patients, while in the remaining man a deceleration in the rate of PSA rise did not reach statistical significance. Overall the decreased rate of PSA rise was statistically significant (p = 0.02 Wilcoxon signed rank test). Dose dependent hypercalciuria limited the maximal calcitriol therapy given (range 1.5 to 2.5 microg. daily). CONCLUSIONS: This pilot study provides preliminary evidence that calcitriol effectively slows the rate of PSA rise in select cases, although dose dependent calciuric side effects limit its clinical usefulness. The development of calcitriol analogues with decreased calcemic side effects is promising, since such analogues may be even more effective for treating prostate cancer

Lipoxygenase-5 is overexpressed in prostate adenocarcinoma.

Gupta S, Srivastava M, Ahmad N, et al.

Cancer. 2001 Feb 15; 91(4):737-43.

BACKGROUND: Epidemiologic studies suggest that populations that consume large amounts of dietary fat are at greater risk for prostate carcinoma. Arachidonic acid and its precursor, linoleic acid, are major ingredients of animal fats and many vegetable oils that are used in the regions where prostate carcinoma is prevalent. The metabolism of arachidonic acid by either the cyclooxygenase pathway or the lipoxygenase pathway generates eicosanoids, which have been implicated in the pathogenesis of a variety of human diseases, including cancer, and are now believed to play important roles in tumor promotion, progression, and metastasis. Studying these pathways in specimens from patients with prostate carcinoma, the authors recently demonstrated the overexpression of cyclooxygenase-2 in prostate adenocarcinoma. In the current study, the authors report the overexpression of lipoxygenase-5 (5-LO) in samples from patients with prostate adenocarcinoma. METHODS: Employing 22 pair-matched benign and malignant tissue samples that were obtained from the same patients with prostate carcinoma, the expression of 5-LO was determined using reverse transcriptase-polymerase chain reaction, immunoblotting, and immunohistochemistry and by measuring the levels of 5-hydroxyeicosatetraenoic acid (5-HETE) by radioimmunoassay. RESULTS: The mean level of 5-LO mRNA was six-fold greater (P < 0.001) in malignant tissue compared with benign tissue. The immunoblot analysis demonstrated that, compared with benign tissue, 5-LO protein was overexpressed in 16 of 22 samples examined and was 2.6 fold greater (P < 0.001) in malignant tissue. Immunohistochemical studies further verified 5-LO up-regulation in malignant tissue that was not present in benign tissue. The levels of 5-HETE, which is a metabolic product of arachidonic acid, was found to be 2.2-fold greater (P < 0.001) in malignant tumor tissue compared with benign tissue. CONCLUSIONS: To the authors' knowledge, this is the first in vivo study showing overexpression of 5-LO in patients with prostate carcinoma. This study suggests that inhibitors of arachidonic acid pathway in general and selective 5-LO inhibitors in particular may be useful for prevention or therapy in patients with prostate carcinoma

Role of fasting serum C-peptide as a predictor of cardiovascular risk associated with the metabolic X-syndrome.

Haban P, Simoncic R, Zidekova E, et al.

Med Sci Monit. 2002 Mar; 8(3):CR175-CR179.

BACKGROUND: Insulin resistance with increased insulin and C-peptide levels is the basis of the metabolic X-syndrome, so it is reasonable to expect them to be a good predictor of associated cardiovascular risk factors. MATERIAL/METHODS: A total of 29 patients (21 postmenopausal women and 8 men) with type 2 diabetes mellitus (mean duration 14.6 years, 95% CI 11.9 to 17.3 years), all older than 50, were studied for possible links between fasting serum C-peptide levels and other vascular risk factors. The mean value of the C-peptide in the group was 0.627 nmol/l (95% CI: 0.464 to 0.789 nmol/l). RESULTS: We found statistically significant correlations between C-peptide and triacylglycerols (TG; r=0.474; p=0.009), HDL-cholesterol (inverse; r = -0.567; p = 0.001) and various lipoprotein ratios: atherogenic index (= total/HDL cholesterol: r = 0.599; p = 0.0006) or TG/HDL (r = 0.587; p = 0.0008). C-peptide also correlated with the body mass index (BMI: r = 0.519; p= 0.004) and leptin (r = 0.492; p = 0.007). After the coefficient CpG (C-peptide x fasting glycemia) was introduced, the correlations with lipoproteins became even stronger. CONCLUSIONS: We suggest that elevated (fasting) serum C-peptide levels constitute a clinically important marker of the cardiovascular risks associated with the metabolic X-syndrome. It can be used as an effective tool for the early detection of diabetic patients at particular risk for atherosclerotic cardiovascular diseases and needing early preventive measures or aggressive treatment

Prostatic volume and ratio of free-to-total prostate specific antigen in patients with prostatic cancer or benign prostatic hyperplasia.

Haese A, Graefen M, Noldus J, et al.

J Urol. 1997 Dec; 158(6):2188-92.

PURPOSE: We correlated prostatic volume with the ratio of free-to-total prostate specific antigen (PSA) in serum from patients with prostatic cancer or benign prostatic hyperplasia (BPH) to evaluate how prostatic volume influences the ratio. MATERIALS AND METHODS: We evaluated sera from 395 patients (mean age 65 years, range 45 to 88) with prostate cancer (239) or BPH (156) for total PSA, free PSA and ratio of free-to-total PSA. For detection of total and free PSA we used an Immulite free and total PSA assay. Prostatic volume was determined with transrectal ultrasonography. Prostatic volume in BPH and prostate cancer patients was divided into 10 ml. groups, and mean ratio of free-to-total PSA was calculated for each volume group and both diseases. For statistical analysis Mann-Whitney U and Kruskal-Wallis tests were performed in addition to calculation of sensitivity and specificity, and receiver operator curves for prostates 60 ml. or less and greater than 60 ml. RESULTS: For BPH patients the mean ratio of free-to-total PSA was 14.64 to 25.14% without a close relation to prostatic volume. In prostate cancer patients a proportional increase from 8.45 to 19.37% in the ratio of free-to-total PSA with volume was found. Mann-Whitney U analysis revealed significant differences in prostate cancer versus BPH only in patients with prostates of 60 ml. or smaller (p = 0.0008 to 0.029). No significant differences were seen when prostate cancer and BPH patients with prostates larger than 60 ml. were compared (p = 0.082 to 0.868). Kruskal-Wallis test confirmed independence of the ratio of free-to-total PSA from prostatic volume in BPH patients (p = 0.285) but dependence in prostate cancer patients (p

Effects of finasteride on vascular endothelial growth factor.

Haggstrom S, Torring N, Moller K, et al.

Scand J Urol Nephrol. 2002; 36(3):182-7.

OBJECTIVE: Finasteride has been shown to reduce prostate bleeding in patients with benign prostatic hyperplasia (BPH). The mechanisms behind this are not known, but it has been suggested that finasteride reduces bleeding by inhibiting angiogenesis in the prostate. Studies in animals have shown that castration rapidly induces involution of the prostate vasculature, and androgen-stimulated prostate growth may be angiogenesis dependent. The objective of this study was to explore the response to finasteride on the vasculature and the expression of vascular endothelial growth factor (VEGF), a potent regulatory factor of angiogenesis in human prostate tissue. MATERIAL AND METHODS: Patients with BPH were randomly assigned to 3 months of treatment either with finasteride (5 mg/day) or placebo before undergoing transurethral resection of the prostate (TURP). Prostate tissue VEGF expression was quantified by Western blot and the vascular density determined in Factor VIII immunostained tissue sections. Serum concentrations of VEGF were measured with ELISA technique. RESULTS: Patients treated with finasteride (n = 15) showed a decrease in prostate tissue VEGF(165) expression compared with placebo (n = 13) treated patients (p < 0.05), but the vascular density and the serum VEGF levels were unaffected. CONCLUSIONS: This study shows that finasteride treatment decreases VEGF expression in the human prostate

A neural network predicts progression for men with gleason score 3+4 versus 4+3 tumors after radical prostatectomy.

Han M, Snow PB, Epstein JI, et al.

Urology. 2000 Dec 20; 56(6):994-9.

OBJECTIVES: To determine the significance of Gleason scores 3+4 (GS3+4) versus 4+3 (GS4+3) with respect to biochemical recurrence in a retrospective review of a series of men with clinically localized prostate cancer who underwent radical retropubic prostatectomy (RRP) and to develop and test an artificial neural network (ANN) to predict the biochemical recurrence after surgery for this group of men using the pathologic and clinical data. METHODS: From 1982 to 1998, 600 men had pathologic Gleason score 7 disease without lymph node or seminal vesicle involvement. We analyzed the freedom from biochemical (prostate-specific antigen) progression after RRP on 564 of these men on the basis of their GS3+4 versus GS4+3 (Gleason 7) status. The Cox proportional hazards model was used to determine the importance of Gleason 7 status as an independent predictor of progression. In addition, an ANN was developed using randomly selected training and validation sets for predicting biochemical recurrence at 3 or 5 years. Different input variable subsets, with or without Gleason 7 status, were compared for the ability of the ANN to maximize the prediction of progression. Standard logistic regression was used concurrently on the same random patient population sets to calculate progression risk. RESULTS: A significant recurrence-free survival advantage was found in men who underwent RRP for GS3+4 compared with those with GS4+3 disease (P

Serum acid phosphatase level and biochemical recurrence following radical prostatectomy for men with clinically localized prostate cancer.

Han M, Piantadosi S, Zahurak ML, et al.

Urology. 2001 Apr; 57(4):707-11.

OBJECTIVES: Serum acid phosphatase (ACP) was once used as the marker for advanced prostate cancer. However, with the development of assays for prostate-specific antigen (PSA), a more sensitive and specific tumor marker, the use of ACP has diminished. We investigated the prognostic value of preoperative serum ACP in predicting prognosis for men with localized prostate cancer following radical retropubic prostatectomy (RRP). METHODS: Of 2293 men treated from 1982 to 1998, 1681 men had a preoperative ACP measurement using an enzymatic assay. We analyzed the actuarial freedom from biochemical (PSA) progression following RRP according to ACP levels. We used multivariate logistic regression and proportional hazards models to determine the independent prognostic value of ACP level with respect of pathologic stage and biochemical recurrence. RESULTS: ACP was not an independent predictor of organ confinement or lymph node involvement in the multivariate logistic regression models using preoperative variables. However, in the proportional hazards model, ACP was an independent predictor of tumor recurrence following RRP, and there was a statistically significant improvement in biochemical recurrence-free survival for men with lower levels of ACP (P

Pretreatment prostate-specific antigen doubling times: clinical utility of this predictor of prostate cancer behavior.

Hanks GE, Hanlon AL, Lee WR, et al.

Int J Radiat Oncol Biol Phys. 1996 Feb 1; 34(3):549-53.

PURPOSE: The distribution of pretreatment and posttreatment prostate specific antigen (PSA) doubling times (PSADT) varies widely. This report examines the pretreatment PSADT as an independent predictor of biochemical freedom from disease (bNED) and describes the clinical utility of PSADT. METHODS AND MATERIALS: Ninety-nine patients with T1-3 NX, M-0 prostate cancer treated between February 1989 and November 1993 have pretreatment PSADTs calculated from three or more PSA levels. Biochemical disease-free (bNED) survival (failure is PSA > or = 1.5 ngm/ml and rising) is evaluated by multivariate analysis of common prognostic indicators and PSADT. RESULTS: Prostate-specific antigen doubling time (PSADT) is a significant predictor of survival along with radiation dose. Patients with a pretreatment PSADT of < 12 months show 50% failure by 18 months, while those with a PSADT that is not increasing show only 3% failure at 3 years. CONCLUSIONS: Prostate-specific antigen doubling time (PSADT) is a predictor of bNED outcome in prostate cancer. Patients with PSADT or = 5 years) is observed in 57% of patients, and this end point may be considered in the decision to observe rather than to treat. After treatment failure, the PSADT may be used to determine which patients do not need immediate androgen deprivation

Posttreatment prostate-specific antigen nadir highly predictive of distant failure and death from prostate cancer.

Hanlon AL, Diratzouian H, Hanks GE.

Int J Radiat Oncol Biol Phys. 2002 Jun 1; 53(2):297-303.

PURPOSE: To link posttreatment biochemical profiles to distant failure and cause-specific survival by assessing the relationship between posttreatment prostate-specific antigen (PSA) nadir and PSA doubling time (PSADT) with these outcome measures. METHODS AND MATERIALS: A total of 615 men were treated at the Fox Chase Cancer Center between April 1989 and December 1995 with three-dimensional conformal radiotherapy alone (median dose 73 Gy). The median follow-up was 64 months (range 2-135). Kaplan-Meier methods were used to estimate the rates of biochemical control, freedom from distant metastasis (FDM), and cause-specific survival. Multivariate predictors of outcome were assessed using stepwise Cox regression analysis. RESULTS: Multivariate analyses demonstrated that the predictors of improved biochemical control were a lower PSA nadir (p

Prospective longitudinal evaluation of men with initial prostate specific antigen levels of 4.0 ng./ml. or less.

Harris CH, Dalkin BL, Martin E, et al.

J Urol. 1997 May; 157(5):1740-3.

PURPOSE: We evaluated the 3-year longitudinal changes in serial serum prostate specific antigen (PSA) levels in men with an initial PSA of 4.0 ng./ml. or less and no suspicion of prostate cancer. MATERIALS AND METHODS: A total of 760 men with an initial PSA of 4.0 ng./ml. or less plus a normal or suspicious digital rectal examination and a benign prostate biopsy was enrolled into an every 4-month PSA monitoring study. RESULTS: Of the 559 men with an initial PSA of 2.0 ng./ml. or less only 3 (0.5%) had a persistently abnormal PSA for 3 years and 1 cancer (0.2%) was detected, and 48 men had a PSA velocity of 0.8 ng./ml. per year or more at year 1 but only 1 (2%) had a persistent rate of increase (2.4 ng./ml. per year) at 3 years. Of the 201 men with a PSA of 2.1 to 4.0 ng./ml. 85 had an abnormal PSA but only 37 (43%) met the criteria for biopsy. Only 8 of 23 biopsies (35%) revealed cancer. Of the 201 men 24 had a PSA velocity of 0.8 ng./ml. per year or more at year 1 but only 4 had persistence for 3 years. All 4 men had cancer but they were identified as at high risk by PSA criteria. CONCLUSIONS: Men with a PSA of 2.0 ng./ml. or less are at low risk for an abnormal PSA or cancer within 3 years and annual monitoring may not be necessary. However, annual monitoring is clinically useful in men with an initial PSA of 2.1 to 4.0 ng./ml. Also, serial monitoring with interval testing in men whose PSA becomes greater than 4.0 ng./ml. is beneficial in identifying a high risk group requiring biopsy. Finally, PSA velocity did not add further to cancer detection in this population

Prediagnostic level of fatty acids in serum phospholipids: omega-3 and omega-6 fatty acids and the risk of prostate cancer.

Harvei S, Bjerve KS, Tretli S, et al.

Int J Cancer. 1997 May 16; 71(4):545-51.

Ecological and case-control studies have demonstrated a positive correlation between consumption of fat and the risk of prostate cancer. Two recent human studies have focused on alpha-linolenic acid as a risk factor for prostate cancer. Animal experiments have shown that dietary omega-6 polyunsaturated fatty acids have generally stimulated tumour development, whereas omega-3 polyunsaturated fatty acids have diminished it. The aim of our study was to investigate the association between these fatty acids and the subsequent risk of prostate cancer. Blood donors to the Janus serum data bank in Norway, who later developed prostate cancer, were matched to blood donors without prostate cancer (141 matched sets); the proportional level of fatty acids measured before diagnosis in the donors' serum was examined. The risk of later prostate cancer was analysed by conditional logistic regression. Increasing risk for prostate cancer was found with increasing quartiles of palmitoleic, palmitic and alpha-linolenic acid. An inverse risk association was found with increasing levels of tetracosanoic acid, for the ratios of linoleic to alpha-linolenic acid and arachidonic to eicosapentaenoic acid. There was no clear association between the risk effect of total omega-3 and total omega-6 fatty acids. There were no indications of a relationship between fatty acids and more aggressive cancers. Our results verify recent findings of a positive association between alpha-linolenic acid and a negative association between the ratio of linoleic to alpha-linolenic acid and the risk of prostate cancer

Overview of mechanisms of action of lycopene.

Heber D, Lu QY.

Exp Biol Med (Maywood ). 2002 Nov; 227(10):920-3.

Dietary intakes of tomatoes and tomato products containing lycopene have been shown to be associated with decreased risk of chronic diseases such as cancer and cardiovascular diseases in numerous studies. Serum and tissue lycopene levels have also been inversely related to the risk of lung and prostate cancers. Lycopene functions as a very potent antioxidant, and this is clearly a major important mechanism of lycopene action. In this regard, lycopene can trap singlet oxygen and reduce mutagenesis in the Ames test. However, evidence is accumulating for other mechanisms as well. Lycopene at physiological concentrations can inhibit human cancer cell growth by interfering with growth factor receptor signaling and cell cycle progression specifically in prostate cancer cells without evidence of toxic effects or apoptosis of cells. Studies using human and animal cells have identified a gene, connexin 43, whose expression is upregulated by lycopene and which allows direct intercellular gap junctional communication (GJC). GJC is deficient in many human tumors and its restoration or upregulation is associated with decreased proliferation. The combination of low concentrations of lycopene with 1,25-dihydroxyvitamin D3 exhibits a synergistic effect on cell proliferation and differentiation and an additive effect on cell cycle progression in the HL-60 promyelocytic leukemia cell line, suggesting some interaction at a nuclear or subcellular level. The combination of lycopene and lutein synergistically interact as antioxidants, and this may relate to specific positioning of different carotenoids in membranes. This review will focus on the growing body of evidence that carotenoids have unexpected biologic effects in experimental systems, some of which may contribute to their cancer preventive properties in models of carcinogenesis. Consideration of solubility in vitro, comparison with doses achieved in humans by dietary means, interactions with other phytochemicals, and other potential mechanisms such as stimulation of xenobiotic metabolism, inhibition of cholesterogenesis, modulation of cyclooxygenase pathways, and inhibition of inflammation will be considered. This review will point out areas for future research where more evidence is needed on the effects of lycopene on the etiology of chronic disease

Clinical management of breast cancer in males: a report of four cases.

Heinig J, Jackisch C, Rody A, et al.

Eur J Obstet Gynecol Reprod Biol. 2002 Apr 10; 102(1):67-73.

Breast cancer in men is a rare cancer manifestation, accounting for less then 1% of all breast cancers in both genders. The incidence in Germany during the last years has been approximately 1.0 per year/100,000. In the US, only 0.2% of all malignancies in men. Predisposing risk factors seem to include radiation exposure, hereditary factors, estrogen administration, and diseases associated with hyperestrogenism, such as cirrhosis of the liver or genetic syndromes (i.e. Klinefelter disease). The incidence of male breast cancer is increased in families with a number of first degree relatives affected with breast or prostate cancer. An increased risk of male breast cancer has been reported in families with a mutation of the breast cancer susceptibility gene BRCA-2. For a period of decades, prognosis of breast cancer in males was thought to be worse than that of female patients. Data and cases being published demonstrate that prognosis and strategies of treatment in male breast cancer do not differ from those in females. The cases presented clearly demonstrate that diagnostic work-up, staging procedures and treatment options for primary treatment and advanced stages are identical compared to the recommendation for female breast cancer

Prostate cancer and supplementation with alpha-tocopherol and beta-carotene: incidence and mortality in a controlled trial.

Heinonen OP, Albanes D, Virtamo J, et al.

J Natl Cancer Inst. 1998 Mar 18; 90(6):440-6.

BACKGROUND: Epidemiologic studies have suggested that vitamin E and beta-carotene may each influence the development of prostate cancer. In the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, a controlled trial, we studied the effect of alpha-tocopherol (a form of vitamin E) and beta-carotene supplementation, separately or together, on prostate cancer in male smokers. METHODS: A total of 29133 male smokers aged 50-69 years from southwestern Finland were randomly assigned to receive alpha-tocopherol (50 mg), beta-carotene (20 mg), both agents, or placebo daily for 5-8 years (median, 6.1 years). The supplementation effects were estimated by a proportional hazards model, and two-sided P values were calculated. RESULTS: We found 246 new cases of and 62 deaths from prostate cancer during the follow-up period. A 32% decrease (95% confidence interval [CI] = -47% to -12%) in the incidence of prostate cancer was observed among the subjects receiving alpha-tocopherol (n = 14564) compared with those not receiving it (n = 14569). The reduction was evident in clinical prostate cancer but not in latent cancer. Mortality from prostate cancer was 41% lower (95% CI = -65% to -1%) among men receiving alpha-tocopherol. Among subjects receiving beta-carotene (n = 14560), prostate cancer incidence was 23% higher (95% CI = -4%-59%) and mortality was 15% higher (95% CI = -30%-89%) compared with those not receiving it (n = 14573). Neither agent had any effect on the time interval between diagnosis and death. CONCLUSIONS: Long-term supplementation with alpha-tocopherol substantially reduced prostate cancer incidence and mortality in male smokers. Other controlled trials are required to confirm the findings

Hereditary breast cancer. Identifying and managing BRCA1 and BRCA2 carriers.

Heisey RE, Carroll JC, Warner E, et al.

Can Fam Physician. 1999 Jan; 45:114-24.

OBJECTIVES: To present a strategy for identifying candidates for consideration of BRCA1 and BRCA2 mutation testing. To discuss the implications of identifying patients as BRCA1 or BRCA2 mutation carriers, and to provide recommendations for managing them. QUALITY OF EVIDENCE: A MEDLINE search from January 1990 to May 1998 was performed using the terms genetic breast screening, BRCA1, and BRCA2. The bibliographies of articles found were searched for further relevant titles. There are no published, randomized controlled clinical trials of management strategies for known BRCA carriers. Many recommendations for management are based on expert opinion only. MAIN FINDINGS: About 5% of women with breast cancer are carriers of genetic mutations. An accurate and detailed family history is the most important tool for identifying potential BRCA1 and BRCA2 mutation carriers. Women identified as carriers have a substantially increased risk of breast and ovarian cancer. Male carriers have a moderately increased risk of prostate cancer. Management strategies for carriers are not well studied but include increased surveillance, preventive surgery, chemoprevention, and lifestyle modification. CONCLUSION: Family physicians must be able to identify people at risk, to discuss management strategies, and when appropriate, to offer referral for consideration of genetic testing. There is an urgent need for research to determine the effectiveness of surveillance strategies, preventive surgery, chemoprevention, and lifestyle modification for BRCA1 and BRCA2 mutation carriers

Association between alpha-tocopherol, gamma-tocopherol, selenium, and subsequent prostate cancer.

Helzlsouer KJ, Huang HY, Alberg AJ, et al.

J Natl Cancer Inst. 2000 Dec 20; 92(24):2018-23.

BACKGROUND: Selenium and alpha-tocopherol, the major form of vitamin E in supplements, appear to have a protective effect against prostate cancer. However, little attention has been paid to the possible role of gamma-tocopherol, a major component of vitamin E in the U.S. diet and the second most common tocopherol in human serum. A nested case-control study was conducted to examine the associations of alpha-tocopherol, gamma-tocopherol, and selenium with incident prostate cancer. METHODS: In 1989, a total of 10,456 male residents of Washington County, MD, donated blood for a specimen bank. A total of 117 of 145 men who developed prostate cancer and 233 matched control subjects had toenail and plasma samples available for assays of selenium, alpha-tocopherol, and gamma-tocopherol. The association between the micronutrient concentrations and the development of prostate cancer was assessed by conditional logistic regression analysis. All statistical tests were two-sided. RESULTS: The risk of prostate cancer declined, but not linearly, with increasing concentrations of alpha-tocopherol (odds ratio (highest versus lowest fifth) = 0.65; 95% confidence interval = 0.32--1.32; P(trend) =.28). For gamma-tocopherol, men in the highest fifth of the distribution had a fivefold reduction in the risk of developing prostate cancer than men in the lowest fifth (P:(trend) =.002). The association between selenium and prostate cancer risk was in the protective direction with individuals in the top four fifths of the distribution having a reduced risk of prostate cancer compared with individuals in the bottom fifth (P(trend) =.27). Statistically significant protective associations for high levels of selenium and alpha-tocopherol were observed only when gamma-tocopherol concentrations were high. CONCLUSIONS: The use of combined alpha- and gamma- tocopherol supplements should be considered in upcoming prostate cancer prevention trials, given the observed interaction between alpha-tocopherol, gamma-tocopherol, and selenium

A large scale cohort study on cancer risks by diet--with special reference to the risk reducing effects of green-yellow vegetable consumption.

Hirayama T.

Princess Takamatsu Symp. 1985; 16:41-53.

Using materials obtained in a large scale cohort study of 265,118 adults in Japan from 1966 to 1982, effects of diet and nutrition on cancer mortality were reviewed. Daily consumption of green-yellow vegetables (GYV) rich in beta-carotene, vitamin C, calcium, and dietary fiber was observed to lower risks for selected cancers such as lung, stomach, prostate, and cervix. The risk reducing effect appeared more striking in cigarette smokers. Risks for cancer of the stomach in males and females and cancer of the breast in females were observed to be lower with the increase in frequency of soybean paste soup consumption which frequently contains GYV. In daily meat consumers risks were higher for cancer of the lung in both sexes and for cancer of the breast in females. The habit of cigarette smoking was found to confound the apparently elevated risk in daily meat consumers for lung cancer. For breast cancer daily smoking interacted with daily meat consumption in raising the risk. The extent of risk elevation by daily meat consumption was limited when GYV was taken daily. Those who do not consume GYV daily with habits of daily smoking, daily drinking and daily meat intake were found to carry the highest risks for cancer of all sites and for cancers of selected sites such as the mouth and pharynx, esophagus, stomach, liver, larynx, lung, and urinary bladder. When GYV were consumed daily, considerably lower risk was observed for each of these cancers, even if other habits remained unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

p53 and bcl-2 immunohistochemical alterations in prostate cancer treated with radiation therapy.

Huang A, Gandour-Edwards R, Rosenthal SA, et al.

Urology. 1998 Feb; 51(2):346-51.

OBJECTIVES: Radiation therapy is definitive treatment for localized prostate cancer. It causes cellular deoxyribonucleic acid (DNA) damage, which, if irreparable, results in apoptosis or programmed cell death. Overexpression of mutant p53 and/or bcl-2 proteins prolongs cell survival despite exposure to damaging agents. We examined whether abnormal expression of either gene could help to explain radiation therapy failures in prostate cancer. METHODS: Archival tissue from patients who had failed radiation therapy as treatment for prostate cancer was obtained before and after treatment. These cancer samples were examined immunohistochemically for accumulation of p53 and bcl-2 proteins. Comparison was made with specimens from patients who had no evidence of recurrent or persistent disease at least 3 years following radiation therapy. RESULTS: High rates of p53 immunopositivity were found in the prostate tissue from all groups studied. More patients who had failed radiation therapy were found to have bcl-2 immunopositive specimens than were those without evidence for recurrent disease (41% preradiation and 61% postradiation versus 8%, P

Fatty acid regulates gene expression and growth of human prostate cancer PC-3 cells.

Hughes-Fulford M, Chen Y, Tjandrawinata RR.

Carcinogenesis. 2001 May; 22(5):701-7.

It has been proposed that the omega-6 fatty acids increase the rate of tumor growth. Here we test that hypothesis in the PC-3 human prostate tumor. We found that the essential fatty acids, linoleic acid (LA) and arachidonic acid (AA), and the AA metabolite PGE(2) stimulate tumor growth while oleic acid (OA) and the omega-3 fatty acid, eicosapentaenoic acid (EPA) inhibited growth. In examining the role of AA in growth response, we extended our studies to analyze changes in early gene expression induced by AA. We demonstrate that c-fos expression is increased within minutes of addition in a dose-dependent manner. Moreover, the immediate early gene cox-2 is also increased in the presence of AA in a dose-dependent manner, while the constitutive cox-1 message was not increased. Three hours after exposure to AA, the synthesis of PGE(2) via COX-2 was also increased. Previous studies have demonstrated that AA was primarily delivered by low density lipoprotein (LDL) via its receptor (LDLr). Since it is known that hepatomas, acute myelogenous leukemia and colorectal tumors lack normal cholesterol feedback, we examined the role of the LDLr in growth regulation of the PC-3 prostate cancer cells. Analysis of ldlr mRNA expression and LDLr function demonstrated that human PC-3 prostate cancer cells lack normal feedback regulation. While exogenous LDL caused a significant stimulation of cell growth and PGE(2) synthesis, no change was seen in regulation of the LDLr by LDL. Taken together, these data show that normal cholesterol feedback of ldlr message and protein is lost in prostate cancer. These data suggest that unregulated over-expression of LDLr in tumor cells would permit increased availability of AA, which induces immediate early genes c-fos and cox-2 within minutes of uptake

Serum prostate-specific antigen as a predictor of radiographic staging studies in newly diagnosed prostate cancer.

Huncharek M, Muscat J.

Cancer Invest. 1995; 13(1):31-5.

The standard staging evaluation of prostate cancer includes digital rectal examination, measurement of serum tumor markers, radionuclide bone scan, and abdominal pelvic computed tomography (CT) or nuclear magnetic resonance imaging (MRI). We retrospectively reviewed 300 cases of newly diagnosed, untreated adenocarcinoma of the prostate to evaluate the ability of serum prostate-specific antigen (PSA) to predict results of staging radiographic studies (bone scan, CT/MRI). The medical records of 300 newly diagnosed, untreated prostate cancer patients were reviewed. The following information was collected on a standard data form: age, clinical stage based on digital rectal examination, method of diagnosis, histological grade, serum PSA level, results of radionuclide bone scan and additional radiographic studies to confirm bone scan results, results of abdominal pelvic CT/MRI, and presence or absence of bone pain. The results of this review were tabulated and analyzed with regard to the ability of serum PSA level to predict positive results of radiographic staging studies. The mean PSA level of the study group was 24.6 ng/ml. Ten patients (3.6%) presented with positive bone scan results with 5 of these having serum PSA levels greater than 20 ng/ml (range 27.6 ng/ml-144 ng/ml, mean 66.3 ng/ml). The 5 remaining patients all had elevated PSA levels ranging between 4.1 and 20.0 ng/ml. No patient with a positive staging bone scan presented with a normal serum PSA. Ten patients (4.0%) presented with a positive abdominal/pelvic CT/MRI (adenopathy only; no patients had radiographic evidence of abnormalities of the upper urinary tract). Eight had serum PSA levels greater than 20 ng/ml, ranging from 30.0 to 234 ng/ml. No patient with a positive study presented with a normal serum PSA level. No patient with either positive bone scan or abdominal pelvic CT/MRI presented with bone pain. We conclude that in asymptomatic patients with newly diagnosed, untreated prostate cancer and serum PSA levels of less than 10 ng/ml, a staging radionuclide bone scan may not be necessary. Likewise, in patients with serum PSA levels of less than 20 ng/ml the likelihood of positive findings on abdominal/pelvic CT/MRI is extremely low. Abdominal/pelvic CT/MRI does not appear necessary in this setting. With over 130,000 cases of newly diagnosed prostate cancer each year in the United States, elimination of staging radiographic studies in the patients outlined above could result in economic savings on the order of 30-80 million dollars per year

Serum prostate-specific antigen as a predictor of staging abdominal/pelvic computed tomography in newly diagnosed prostate cancer.

Huncharek M, Muscat J.

Abdom Imaging. 1996 Jul; 21(4):364-7.

BACKGROUND: The standard staging evaluation for prostate cancer includes digital rectal examination, measurement of serum tumor markers, and radionuclide bone scan. In many institutions, abdominal/pelvic computed tomography (CT) scan or nuclear magnetic resonance imaging (MRI) is performed. We retrospectively reviewed 425 cases of newly diagnosed, untreated adenocarcinoma of the prostate to evaluate the ability of serum prostate-specific antigen (PSA) to predict results of staging abdominal pelvic CT. METHODS: The medical records of 425 newly diagnosed, untreated prostate cancer patients were reviewed. The following information was collected on a standard data form: age, clinical stage based on digital rectal exam, method of diagnosis, histological grade, serum PSA level, and results of abdominal pelvic CT including adenopathy and abnormalities of the upper urinary tract. The results of this review were tabulated and analyzed with regard to the ability of serum PSA level to predict positive results of abdominal pelvic CT. RESULTS: The mean PSA level of the study group was 22.1 ng/ml. Fourteen patients (3.6%) presented with a positive abdominal/pelvic CT (12 with adenopathy, one with a renal cell tumor, and one with an adrenal metastasis). Eleven of these (79%) had serum PSA levels of 30.0 ng/ml or greater, ranging from 30.0 to 234 ng/ml. No patient with a positive study presented with a normal serum PSA level. Two patients with a positive study had a serum PSA level between 4.1 and 10.0 ng/ml (0.6%), and one had a PSA level between 10.1 and 20 ng/ml (0.3%). CONCLUSION: We conclude that in asymptomatic patients with newly diagnosed, untreated prostate cancer and serum PSA levels of less than 20 ng/ml the likelihood of positive findings on abdominal/pelvic CT is extremely low (

Reduction of ventral prostate weight by finasteride is associated with suppression of insulin-like growth factor I (IGF-I) and IGF-I receptor genes and with an increase in IGF binding protein 3.

Huynh H, Seyam RM, Brock GB.

Cancer Res. 1998 Jan 15; 58(2):215-8.

Finasteride, a competitive and specific inhibitor of 5alpha-reductase, is widely used in the treatment of symptomatic benign prostatic hyperplasia. We demonstrate here that finasteride, when administered in an in vivo experimental system, caused ventral prostate regression. Intraprostatic dihydrotestosterone levels decreased, whereas testosterone levels increased in a dose-dependent manner following finasteride treatment. Finasteride also inhibited the expression of insulin-like growth factor (IGF)-I and IGF-I receptor genes in the ventral prostate. Finasteride significantly increased IGF binding protein-3 and slightly decreased IGF binding protein-2, -4, and -5 gene expression. Because IGFs are potent mitogens for prostate epithelial cells, this newly described activity of finasteride may contribute to its antiproliferative properties, particularly with regard to the inhibition of prostate growth seen clinically and in animal models

Clinical significance of prostate specific antigen for early stage prostate cancer detection.

Imai K, Ichinose Y, Kubota Y, et al.

Jpn J Clin Oncol. 1994 Jun; 24(3):160-5.

The characteristics of serum prostate specific antigen (PSA) in normal Japanese men were studied in 1480 subjects examined by mass screening (MS) for prostate cancer (Pca) in Gunma Prefecture in 1992. The serum PSA concentration was correlated with patient age. The average serum PSA level increased by 0.04 ng/ml/year. The upper normal limits (95 percentiles) of age specific PSA for normal men are 1.33 ng/ml for those aged 39-49 years, 3.65 ng/ml for those aged 50-59 years, 4.06 ng/ml for those aged 60-69 years, 5.09 ng/ml for those aged 70-79 years and 5.66 ng/ml for those aged 80-89 years. Among 227 normal men examined by our MS in 1991 and 1992, the PSA velocity (PSAV) was calculated to be 0.05 ng/ml/year. Among 10 Pca patients with normal PSA levels (< 6 ng/ml) detected previously by our MS, three had an abnormal PSAV. We demonstrated the possibility that PSA density could distinguish between Pca and benign prostate hypertrophy. The significance of PSA as a Pca screening modality should be evaluated across multiple age ranges and in combination with previous PSA data and/or prostate volume estimated by sonography

Patient tolerance of transrectal ultrasound-guided biopsy of the prostate.

Irani J, Fournier F, Bon D, et al.

Br J Urol. 1997 Apr; 79(4):608-10.

OBJECTIVES: To determine the acceptability by patients of ultrasound-guided prostatic biopsy without anaesthesia. PATIENTS AND METHODS: From January 1995 to January 1996, 81 patients in our department undergoing transrectal ultrasound-guided prostate biopsy were asked to assess the tolerability of the procedure using an immediate post-operative questionnaire including a 10 cm linear visual analogue scale (VAS). RESULTS: The mean VAS score was 3 (standard error 0.24) and 16% of the patients had a VAS score of > or = 5. Responses to the questionnaire showed that 6% of patients judged that the procedure should have been performed under general anaesthesia, while 19% would not agree to undergo it again without some form of anaesthesia. CONCLUSIONS: Even when anaesthesia-free, transrectal ultrasound-guided prostatic biopsy was felt to be only mildly uncomfortable by most patients, but 19% judged that it should be accompanied by some form of anaesthesia. Consequently, local anaesthetic techniques to enhance tolerance to this type of intervention without sacrificing the advantages of the current out-patient setting should be reassessed

Second primary malignancies in T1-3N0 prostate cancer patients treated with radiation therapy with 10-year followup.

Johnstone PA, Powell CR, Riffenburgh R, et al.

J Urol. 1998 Mar; 159(3):946-9.

PURPOSE: The risk of patients with prostate cancer to have second primary malignancies is unclear. Population and autopsy based studies have shown no increased risk, which is at variance with several institutional analyses. A retrospective review was performed with comparison to expected cancer data from the Connecticut Tumor Registry. MATERIALS AND METHODS: Records of a cohort of prostate cancer patients treated with staging pelvic lymphadenectomy and definitive radiotherapy between November 1, 1974 and July 7, 1987 were reviewed. Median potential followup from date of diagnosis was 10.9 years. RESULTS: Of the 164 patients 150 (91.5%) had followup to death or to August 1995, with data available in part on 4 of the remaining patients. In 43 patients 51 second primary malignancies developed. Increased frequency of lymphomas, and kidney, bladder and rectal lesions (all p < 0.001) was observed concurrently with diagnosis of prostate cancer, although this may be due to bias since full staging for the prostate cancer may have led to their diagnosis. An increased frequency of renal lesions in the 1 to 4-year followup period (p = "0.032)" also was observed. Two sarcomas and a leukemia were putatively radiation induced but their frequency was not significantly different from the comparison baseline. CONCLUSIONS: Much of the apparent increase in second primary malignancies associated with prostate cancer noted by some authors may be attributed to bias in the staging process. Renal cancers may occur more frequently in patients with prostate cancer but the distribution of these lesions is inconsistent with a field defect mechanism of cancer induction

Health is empowerment.

Jones PS, Meleis AI.

ANS Adv Nurs Sci. 1993 Mar; 15(3):1-14.

A consideration of health in relation to global and diverse social and economic contexts forces nurses to reexamine the centrality of health in the discipline of nursing and to confront the issue of whether health is a personal matter. In this article, the authors review development of the concept of health in nursing science, discuss the limitations of some current definitions in addressing diverse clients, and challenge members of the discipline to develop a contextualized definition of health congruent with societal needs and the mission of nursing

Antiangiogenic treatment with linomide as chemoprevention for prostate, seminal vesicle, and breast carcinogenesis in rodents.

Joseph IB, Vukanovic J, Isaacs JT.

Cancer Res. 1996 Aug 1; 56(15):3404-8.

There are two distinct phases during prostatic carcinogenesis with regard to tumor blood vessel development. During the first or prevascular phase, which may persist for years, cells that have undergone some but not all of the transformation steps undergo a limited amount of net growth, producing premalignant prostatic intraepithelial neoplastic (PIN) lesions. Most of these PIN lesions do not continue net growth and do not progress to produce histologically detectable cancer. Even the PIN lesions that do progress to cancer remain of limited virulence unless they undergo conversion to the second or angiogenic phase. Once this angiogenic phase is reached, new blood vessel development is greatly enhanced within the cancer. It is this enhanced tumor angiogenesis which allows these cancers both to grow continuously and to metastasize. Thus, inhibition of angiogenesis should be an effective chemopreventive approach for prostatic carcinogenesis. Linomide is a low molecular weight, water-soluble agent with excellent p.o. absorption and bioavailability. We have previously demonstrated that daily p.o. treatment with Linomide has antiangiogenic abilities against a series of rat and human prostatic cancer xenografts growing in vivo. In the present studies, we have demonstrated using Matrigel in in vivo angiogenesis assays that daily p.o. Linomide at 25 mg/kg/day inhibits angiogenesis induced by tumor necrosis factor alpha, acidic fibroblast growth factor, basic fibroblast growth factor, and vascular endothelial growth factor. Using an N-methylnitrosourea initiation-androgen promotion model, Linomide was given p.o. at a daily dose as high as 25 mg/kg/day for at least 1 year without major toxicity while inhibiting the development of seminal vesicle/prostate cancers in male rats by >50%. Dose-response analysis demonstrated that a Linomide blood level of 50-100 microM is optimal for such chemoprevention. In addition, Linomide treatment at a dose of 25 mg/kg/day was able to inhibit by approximately 60% the incidence of N-methylnitrosourea and approximately 50% of 7,12-dimethyl-benz(a)anthracine-induced mammary carcinogenesis in female rats

Macrophage role in the anti-prostate cancer response to one class of antiangiogenic agents.

Joseph IB, Isaacs JT.

J Natl Cancer Inst. 1998 Nov 4; 90(21):1648-53.

BACKGROUND: Tumor-associated macrophages (TAMs) can either promote angiogenesis (i.e., the formation of new blood vessels) in tumors by secreting tumor necrosis factor-alpha (TNF-alpha) or inhibit angiogenesis by producing granulocyte-macrophage colony-stimulating factor (GM-CSF), which in turn stimulates production of the antiangiogenic protein plasminogen activator inhibitor type 2 (PAI-2). We tested, alone or in combination, the anti-prostate cancer activity of agents that perturb macrophage function. METHODS: By use of enzyme-linked immunosorbent assays, we measured the effects of Linomide (roquinimex), thalidomide, pentoxifylline, and genistein on TNF-alpha and GM-CSF production in vitro by virally transformed RAW 264.7 mouse macrophages and on PAI-2 production in vitro by human macrophages. The antitumor effects of these agents were tested in vivo on transplanted Dunning R-3327 MAT-Lu rat prostate cancers; TAM numbers and blood vessel densities in these cancers were determined by use of immunocytochemistry. RESULTS: Linomide selectively inhibited mouse macrophage secretion of TNF-alpha but not of GM-CSF; however, thalidomide, pentoxifylline, and genistein inhibited the production of both cytokines. Linomide, but not thalidomide or pentoxifylline, increased production of PAI-2 by human macrophages. When administered to rats bearing MAT-Lu tumors, each of the tested agents reduced TAM numbers (Linomide, by 46%; thalidomide, by 94%; pentoxifylline, by 71%; and genistein, by 96%). However, all of the agents reduced tumor blood vessel density and tumor growth, with Linomide being the most effective (44% reduction in blood vessel density and 69% inhibition of tumor growth). None of the other agents potentiated Linomide's antitumor effect. CONCLUSIONS: Linomide is unique among the antiangiogenic agents tested, in that it inhibits the stimulatory effects of TAMs on tumor angiogenesis without eliminating their antiangiogenic effects, and may thus prove to be more effective against prostate cancer

Pitfalls in interpreting prostate specific antigen velocity.

Kadmon D, Weinberg AD, Williams RH, et al.

J Urol. 1996 May; 155(5):1655-7.

PURPOSE: The concept of prostate specific antigen (PSA) velocity as an improved marker for prostate cancer detection is intriguing. However, before this concept is applied to individual patients several confounding parameters must be addressed. We determined the variability of serum PSA levels in men without prostate cancer. MATERIALS AND METHODS: We reviewed data from a prostate cancer screening program, and determined inter-assay and individual variability of the serum PSA values for a 2-year followup period in 265 men clinically free of prostate cancer. RESULTS: Our average inter-assay coefficient of variation was 7.5%. Therefore, we considered only PSA changes exceeding +/- 15% as significant. Fluctuations in serum PSA occurred in 78% of the men during the observation period, and 12.5% had at least a single PSA increase exceeding 0.75 ng/ml. per year. Fluctuations were noted throughout the entire range of serum PSA levels but became progressively larger with an increasing mean PSA. CONCLUSIONS: The inter-assay variability must be considered when interpreting PSA velocity. Individual fluctuations in serum PSA dictate an observation period of at least 2 years before PSA velocity is considered abnormal

Localizing prostate cancer in the presence of postbiopsy changes on MR images: role of proton MR spectroscopic imaging.

Kaji Y, Kurhanewicz J, Hricak H, et al.

Radiology. 1998 Mar; 206(3):785-90.

PURPOSE: To assess whether magnetic resonance (MR) spectroscopic imaging with MR imaging can improve prostate cancer localization in postbiopsy hemorrhage cases. MATERIALS AND METHODS: Records of 175 patients with prostate cancer were retrospectively reviewed; 42 patients (135 hemorrhagic sites) had spatially correlated biopsy data. Patients underwent both phased-array coil-endorectal coil MR imaging and three-dimensional MR spectroscopic imaging within 180 days after transrectal ultrasound (US)-guided biopsy. High-signal-intensity hemorrhage on T1-weighted images and corresponding high- or low-signal-intensity areas on T2-weighted images and the metabolic ratio (choline + creatine)/citrate were recorded. Cancer was identified as a low-signal-intensity area at T2-weighted MR imaging or a metabolite ratio greater than 3 standard deviations above normal at MR spectroscopic imaging. MR imaging, spectroscopic, and biopsy findings were compared. RESULTS: Forty-nine patients had postbiopsy hemorrhage. On T2-weighted images, a higher (P < .01) percentage of hemorrhagic sites demonstrated low signal intensity (80% [108 of 135 sites]), which is similar to the signal intensity seen with cancer. The addition of MR spectroscopic imaging to MR imaging resulted in a significant increase (P < .01) in the accuracy (52% to 75%) and specificity (26% to 66%) of tumor detection. CONCLUSION: The addition of MR spectroscopic imaging to MR imaging significantly improves the ability to determine the presence of prostate cancer and spatial extent when postbiopsy changes hinder interpretation with MR imaging alone

Relationship between prostate volume, prostate-specific antigen nadir, and biochemical control.

Kaminski JM, Hanlon AL, Horwitz EM, et al.

Int J Radiat Oncol Biol Phys. 2002 Mar 15; 52(4):888-92.

PURPOSE: In patients treated with definitive three-dimensional conformal radiotherapy (3D-CRT) for localized prostatic adenocarcinoma, we sought to evaluate the relationship between pretreatment prostate gland volume and posttreatment prostate-specific antigen (PSA) nadir, as well as the relationship of prostate volume and PSA nadir with biochemical control (bNED). Two subgroups were studied: favorable (PSA /=10 ng/mL, Gleason score 7-10, T2B-T3). MATERIALS AND METHODS: A total of 655 men (n = 271 favorable and 384 unfavorable) were treated with 3D-CRT alone between May 1989 and November 1997. All patients had information on prostate volume and a minimum follow-up of 24 months (median 56, range 24-126). Of the 655 men, 481 (n = 230 favorable and 251 unfavorable) remained bNED at time of analysis, with biochemical failure defined in accordance with the American Society for Therapeutic Radiology and Oncology consensus definition. Factors analyzed for predictors of bNED included pretreatment prostate volume, posttreatment PSA nadir, pretreatment PSA, palpation T stage, Gleason score, center of the prostate dose, and perineural invasion (PNI). We also analyzed pretreatment prostate volume and its correlation to prognostic factors. For bNED patients, the relationship between PSA nadir and prostate volume was evaluated. RESULTS: On multivariate analysis, prostate volume (p = 0.04) and palpation T stage (p = 0.02) were the only predictors of biochemical failure in the favorable group. On multivariate analysis of the unfavorable group, pretreatment PSA (p

Postoperative nomogram for disease recurrence after radical prostatectomy for prostate cancer.

Kattan MW, Wheeler TM, Scardino PT.

J Clin Oncol. 1999 May; 17(5):1499-507.

PURPOSE: Although models exist that place patients into discrete groups at various risks for disease recurrence after surgery for prostate cancer, we know of no published work that combines pathologic factors to predict an individual's probability of disease recurrence. Because clinical stage and biopsy Gleason grade only approximate pathologic stage and Gleason grade in the prostatectomy specimen, prediction of prognosis should be more accurate when postoperative information is added to preoperative variables. Therefore, we developed a postoperative nomogram that allows more accurate prediction of probability for disease recurrence for patients who have received radical prostatectomy as treatment for prostate cancer, compared with the preoperative nomogram we previously published. PATIENTS AND METHODS: By Cox proportional hazards regression analysis, we modeled the clinical and pathologic data and disease follow-up for 996 men with clinical stage T1a-T3c NXM0 prostate cancer who were treated with radical prostatectomy by a single surgeon at our institution. Prognostic variables included pretreatment serum prostate-specific antigen level, specimen Gleason sum, prostatic capsular invasion, surgical margin status, seminal vesicle invasion, and lymph node status. Treatment failure was recorded when there was either clinical evidence of disease recurrence, a rising serum prostate-specific antigen level (two measurements of 0.4 ng/mL or greater and rising), or initiation of adjuvant therapy. Validation was performed on this set of men and a separate sample of 322 men from five other surgeons' practices from our institution. RESULTS: Cancer recurrence was noted in 189 of the 996 men, and the recurrence-free group had a median follow-up period of 37 months (range, 1 to 168 months). The 7-year recurrence-free probability for the cohort was 73% (95% confidence interval, 68% to 76%). The predictions from the nomogram appeared to be accurate and discriminating, with a validation sample area under the receiver operating characteristic curve (ie, a comparison of the predicted probability with the actual outcome) of 0.89. CONCLUSION: A postoperative nomogram has been developed that can be used to predict the 7-year probability of disease recurrence among men treated with radical prostatectomy

Pretreatment nomogram for predicting the outcome of three-dimensional conformal radiotherapy in prostate cancer.

Kattan MW, Zelefsky MJ, Kupelian PA, et al.

J Clin Oncol. 2000 Oct 1; 18(19):3352-9.

PURPOSE: Several studies have defined risk groups for predicting the outcome after external-beam radiotherapy of localized prostate cancer. However, most models formed patient risk groups, and none of these models considers radiation dose as a predictor variable. The purpose of this study was to develop a nomogram to improve the accuracy of predicting outcome after three-dimensional conformal radiotherapy. MATERIALS AND METHODS: This study was a retrospective, nonrandomized analysis of patients treated at the Memorial Sloan-Kettering Cancer Center between 1988 and 1998. Clinical parameters of the 1,042 patients included stage, biopsy Gleason score, pretreatment serum prostate-specific antigen (PSA) level, whether neoadjuvant androgen deprivation therapy was administered, and the radiation dose delivered. Biochemical (PSA) treatment failure was scored when three consecutive rises of serum PSA occurred. A nomogram, which predicts the probability of remaining free from biochemical recurrence for 5 years, was validated internally on this data set using a bootstrapping method and externally using a cohort of patients treated at the Cleveland Clinic, Cleveland, OH. RESULTS: When predicting outcomes for patients in the validation data set from the Cleveland Clinic, the nomogram had a Somers' D rank correlation between predicted and observed failure times of 0.52. Predictions from this nomogram were more accurate (P

Pretreatment nomogram for predicting freedom from recurrence after permanent prostate brachytherapy in prostate cancer.

Kattan MW, Potters L, Blasko JC, et al.

Urology. 2001 Sep; 58(3):393-9.

OBJECTIVES: To develop a prognostic nomogram to predict the freedom from recurrence for patients treated with permanent prostate brachytherapy for localized prostate cancer. METHODS: We performed a retrospective analysis of 920 patients treated with permanent prostate brachytherapy between 1992 and 2000. The clinical parameters included clinical stage, biopsy Gleason sum, pretreatment prostate-specific antigen (PSA) value, and administration of external beam radiation. Patients who received neoadjuvant androgen deprivation therapy were excluded. Failure was defined as any post-treatment administration of androgen deprivation, clinical relapse, or biochemical failure, defined as three PSA rises. Patients with fewer than three PSA rises were censored at the time of the first PSA rise. Data from two outside institutions served as validation. RESULTS: A nomogram that predicts the probability of remaining free from biochemical recurrence for 5 years after brachytherapy without adjuvant hormonal therapy was developed using Cox proportional hazards regression analysis. External validation revealed a concordance index of 0.61 to 0.64, and calibration of the nomogram suggested confidence limits of +5% to -30%. CONCLUSIONS: The pretreatment nomogram we developed may be useful to physicians and patients in estimating the probability of successful treatment 5 years after brachytherapy for clinically localized prostate cancer

Clinical predictors in the use of finasteride for control of gross hematuria due to benign prostatic hyperplasia.

Kearney MC, Bingham JB, Bergland R, et al.

J Urol. 2002 Jun; 167(6):2489-91.

PURPOSE: We identify predictors of clinical response as well as response time in patients treated with finasteride for gross hematuria due to benign prostatic hyperplasia. MATERIALS AND METHODS: A retrospective chart review was preformed of 53 patients who had been given 5 mg. finasteride daily for the treatment of active bleeding or a recent history of recurrent bleeding. Urological evaluations were negative for tumor in all patients. A history of prostatectomy, anticoagulant status and prostate size was determined. The degree of hematuria was then graded before and after finasteride treatment according to our previously described system. Of the 53 patients who were actively bleeding at initial evaluation 16 were followed to determine time required for complete resolution of hematuria. RESULTS: Hematuria grade improved after finasteride in 50 (94%) patients. Overall 77% of patients (41 of 53) experienced no further bleeding while taking finasteride. Mean followup was 38 months (range 3 to 86). Of the patients 86% (12 of 14) taking coumadin, 77% (10 of 13) taking aspirin and 73% (19 of 26) on no anticoagulants had no further bleeding once on finasteride. Of the patients who had undergone prior transurethral prostatectomy 84% (26 of 31) experienced no further bleeding versus 68% (15 of 22) of those who had not undergone previous surgery. In the 16 patients who began finasteride while actively bleeding the average time to clear urine was 12 days (range 2 to 45). Prostatic volume correlated with the average time needed for resolution of hematuria, which was 2.7 days or longer for small (less than 40 gm.), 10.3 days or longer for large (40 to 100), 19 days or longer for extra large (100 to 150) and 45 days or longer for extra extra large (greater than 150) glands. Hematuria resolved an average of 5.5 days versus 18.6 days in those who had or had not undergone previous prostatectomy, respectively. CONCLUSIONS: Our long-term followup demonstrates finasteride as a useful treatment for benign prostatic hyperplasia related gross hematuria, which is effective in patients who are on anticoagulants. In patients with larger prostatic volumes a longer time to response and higher incidence of recurrent but lower grade bleeding should be anticipated compared to those who have undergone prior prostatectomy or have a smaller prostate

Prostate specific antigen density versus prostate specific antigen slope as predictors of prostate cancer in men with initially negative prostatic biopsies.

Keetch DW, McMurtry JM, Smith DS, et al.

J Urol. 1996 Aug; 156(2 Pt 1):428-31.

PURPOSE: We determined if prostate specific antigen (PSA) density and PSA slope alone or in combination could be used to predict which men with persistently elevated serum PSA and prior negative prostate biopsies will have prostate cancer on repeat evaluation. MATERIALS AND METHODS: In our PSA-1 data base we identified 327 men 50 years old or older with an initially negative prostate biopsy who had persistent PSA elevation, and compared those who did and did not have prostate cancer on subsequent serial prostatic biopsy. RESULTS: Of 70 men with a PSA density of 0.15 or more and PSA slope of 0.75 ng./ml. or more annually compared to 83 with a PSA density of less than 0.15 and PSA slope of less than 0.75 ng./ml. annually 32 (46%) and only 11 (13%), respectively, had prostate cancer on subsequent prostate biopsies (p < 0.0001). In a hierarchical logistic regression analysis PSA density and PSA slope were predictive of prostate cancer on subsequent biopsy (p = "0.001" and 0.03, respectively). PSA density of 0.15 or more alone or PSA slope of 0.75 ng./ml. or more annually alone as the indicator for repeat biopsy would have missed 35 and 40% of cancers, respectively. CONCLUSIONS: In men with persistently elevated serum PSA after an initially negative prostate biopsy, PSA density and PSA slope alone or in combination provide useful predictive information about the results of repeat prostate biopsies. However, these parameters are not sufficiently sensitive to identify all patients with detectable prostate cancer

Concordant induction of 15-lipoxygenase-1 and mutant p53 expression in human prostate adenocarcinoma: correlation with Gleason staging.

Kelavkar UP, Cohen C, Kamitani H, et al.

Carcinogenesis. 2000 Oct; 21(10):1777-87.

We recently reported that the mutant form of the tumor-suppressor gene p53 up-regulates 15-LO-1 gene expression in a murine cell line. Here, we examine the expression of 15-lipoxygenase (LO)-1 and mutant p53 (mtp53) in human prostatic tissues and 15-LO-1 in the human prostate adenocarcinoma cell line PC-3. Reverse transcription-PCR and western analyses conclusively demonstrated expression of 15-LO-1 in PC-3 cells. Western blotting for 15-LO-1 in freshly resected 'normal' and prostate adenocarcinoma specimens showed 15-LO-1 expression in normal tissue, but significantly higher levels were detected in prostate adenocarcinomas. Prostate adenocarcinoma tissues generated chirally pure 13-S-hydroxyoctadecadienoic acid from exogenous linoleic acid, a preferred substrate of 15-LO-1. To study the correlation of 15-LO-1 expression with mtp53 in prostate cancer, we immunostained 48 prostatectomy specimens obtained by transurethral resection of the prostate and needle biopsy (median age 68 years, range 52-93) of different Gleason grades (n = 48), using antibodies specific for 15-LO-1, mtp53 and MIB-1 (a proliferation marker). We compared staining in cancerous foci with adjacent normal appearing prostate tissues. In only 5 of 48 patients did 'normal' tissue adjacent to cancerous foci display staining for 15-LO-1. However, no staining for mtp53 was observed in any of the normal tissues. In cancer foci, robust staining was observed for both 15-LO-1 (36 of 48, 75%) and mtp53 (19 of 48, 39%). Furthermore, the intensities of expression of 15-LO-1 and mtp53 correlated positively with each other (P < 0.001) and with the degree of malignancy, as assessed by Gleason grading (P < 0.01). By immunohistochemistry, 15-LO-1 was located in secretory cells of peripheral zone glands, prostatic ducts and seminal vesicles, but not in the basal cell layer or stroma. Based on these and other studies, we propose a model describing a possible role for 15-LO-1 expression in influencing the malignant potential and pathobiological behavior of adenocarcinomas

Reduction of human prostate tumor vascularity by the alpha1-adrenoceptor antagonist terazosin.

Keledjian K, Borkowski A, Kim G, et al.

Prostate. 2001 Jul 1; 48(2):71-8.

BACKGROUND: We previously demonstrated that the quinazoline-derived a1-adrenoceptor antagonists doxazosin and terazosin suppress prostate cancer growth via apoptosis induction. The aim of this study was to determine the potential effect of a1-adrenoceptor antagonists on tumor vascularity of the human prostate. METHODS: A total of 34 men with benign prostatic hyperplasia (BPH) who have been on terazosin treatment (for the obstructive symptoms) were pathologically diagnosed with prostate cancer following surgery. These patients were stratified according to the length of treatment periods with terazosin into two groups, 1 week-6 months, and 6-17 months. The control group consisted of prostatectomy specimens from 25 untreated prostate cancer patients undergoing surgery for localized disease. Formalin-fixed, paraffin-embedded prostate specimens were analyzed for apoptosis (TUNEL assay), cell proliferation (Ki-67), microvessel density (MVD) (von Willebrand factor/Factor VIII), vascular endothelial growth factor (VEGF) expression, and prostate specific antigen (PSA) immunoreactivity. RESULTS: A significant induction of apoptosis was observed among cancerous prostatic epithelial cells in the terazosin-treated, as compared to the untreated prostate cancer specimens, while there was no significant change in the proliferative index of the same tumor cell populations after treatment. Furthermore, terazosin resulted in a significant decrease in prostate tissue MVD compared with the untreated group (P < 0.01), that correlated with the increased apoptotic index of the cancerous areas. Tissue PSA expression in the prostatic tumor foci was also markedly reduced after terazosin treatment, while no significant changes in VEGF expression were detected. CONCLUSIONS: These findings provide the first evidence that terazosin, a quinazoline-based a1-blocker decreases prostate tumor vascularity. Our study has significant clinical implications in identifying selected alpha1-adrenoceptor antagonists as potential anti-tumor agents with apoptotic and anti-angiogenic effects in the human prostate that can be exploited for the treatment of advanced prostate cancer

Prostate specific antigen inhibits immune responses in vitro: a potential role in prostate cancer.

Kennedy-Smith AG, McKenzie JL, Owen MC, et al.

J Urol. 2002 Aug; 168(2):741-7.

PURPOSE: Prostate specific antigen (PSA) is found in high concentration in prostate tissue and in semen, in which its physiological function appears to be liquefaction. In prostate cancer the peripheral PSA concentration is elevated, which may be used as a disease marker. Systemic and local immune defects have been demonstrated in prostate cancer and we postulated a role for PSA in this immunosuppression. We explored the effects of PSA on human T-lymphocyte proliferation in vitro. MATERIALS AND METHODS: PSA was purified from normal seminal plasma using a modified chromatographic technique. The effect of PSA or control protein on lymphocyte responses to mitogens, tetanus toxoid and alloantigens was tested. The inhibitory effect observed was further explored by varying the time of PSA addition, denaturing PSA and including interleukin-2 and anti-PSA antibodies. RESULTS: PSA suppressed in vitro phytohemagglutinin and alloantigen stimulated lymphocyte proliferation in a dose dependent manner. This effect was reversed by adding anti-PSA antibodies but not by interleukin-2. CONCLUSIONS: These in vitro PSA effects suggest another T-lymphocyte mediated immunosuppressive mechanism. In vivo high levels of PSA may compromise natural immune responses to cancer and current attempts at immunotherapy for prostate cancer

Angiotensin II type 1 receptor antagonist (losartan) down-regulates transforming growth factor-beta in experimental acute pyelonephritis.

Khalil A, Tullus K, Bakhiet M, et al.

J Urol. 2000 Jul; 164(1):186-91.

PURPOSE: To study the effect of an angiotensin II type 1 receptor antagonist, losartan, on cytokine expression, kidney growth and renal scarring in experimental acute pyelonephritis. MATERIALS AND METHODS: Female Bki NMRI mice, 8 weeks old were infected with E. coli CFT 073 via the urethra. Mice were divided into four groups; either left untreated; or treated with NaCl 0.9%; or an angiotensin II type 1 receptor antagonist, losartan, in doses of 1 mg. or 40 mg. /kg. body weight. The treatment was given daily i.p. for 48 hours, 3 weeks or 8 weeks respectively. Kidneys were weighed and sectioned for histo-pathology and in situ hybridization for mRNA of IL-1beta, TNF-alpha, IL-4, IL-6, IL-10, IL-12, TGF-beta and IFN-gamma. Homogenized kidneys were used for EIA of TGF-beta and bacterial growth. RESULTS: The mRNA expression of the studied cytokines generally peaked at 48 hours in all four groups. In animals treated with losartan, kidney TGF-beta, IFN-gamma and IL-6 decreased significantly at 3 and 8 weeks as compared with controls, untreated or those treated with NaCl, (p

The role of cyclooxygenase-2 in prostate cancer.

Kirschenbaum A, Liu X, Yao S, et al.

Urology. 2001 Aug; 58(2 Suppl 1):127-31.

Cyclooxygenase-2 (COX-2) is the inducible isozyme of COX, a key enzyme in the conversion of arachidonic acid to prostaglandins and other eicosanoids. COX-2 is highly expressed in a number of human cancers and cancer cell lines, including prostate cancer. We studied the immunohistochemical expression of COX-2 in the human prostate gland. The enzyme is strongly expressed in smooth muscle cells of both the normal and cancerous prostate. Its expression in noncancerous epithelial cells is limited to the basal cell layer. In prostatic inflammation, luminal epithelial cells surrounded by lymphocytes are induced to express the enzyme. COX-2 is expressed in the epithelial cells of high-grade prostatic intraepithelial neoplasia and cancer. We have demonstrated that treatment of human prostate-cancer cell lines with a selective COX-2 inhibitor induces apoptosis both in vitro and in vivo. The in vivo results also indicate that the COX-2 inhibitor decreases tumor microvessel density and angiogenesis. COX-2 inhibitors can prevent the hypoxic upregulation of a potent angiogenic factor, vascular endothelial growth factor. These results indicate that COX-2 inhibitors may, therefore, serve as effective chemopreventive and therapeutic agents in cancer of the prostate

Suppression of human prostate cancer cell growth by alpha1-adrenoceptor antagonists doxazosin and terazosin via induction of apoptosis.

Kyprianou N, Benning CM.

Cancer Res. 2000 Aug 15; 60(16):4550-5.

Recent evidence from our laboratory has demonstrated that alpha1-adrenoceptor antagonists doxazosin and terazosin induced apoptosis in prostate epithelial and smooth muscle cells in patients with benign prostatic hypertrophy (BPH; J. Urol., 159: 1810-1815, 1998; J. Urol., 161: 2002-2007, 1999). In this study, we investigated the biological action of three alpha1-adrenoceptor antagonists, doxazosin, terazosin, and tamsulosin, against prostate cancer cell growth. The antigrowth effect of the three alpha1-adrenoceptor antagonists was examined in two human prostate cancer cell lines, PC-3 and DU-145, and a prostate smooth muscle cell primary culture, SMC-1, on the basis of: (a) cell viability assay; (b) rate of DNA synthesis; and (c) induction of apoptosis. Our results indicate that treatment of prostate cancer cells with doxazosin or terazosin results in a significant loss of cell viability, via induction of apoptosis in a dose-dependent manner, whereas tamsulosin had no effect on prostate cell growth. Neither doxazosin nor terazosin exerted a significant effect on the rate of cell proliferation in prostate cancer cells. Exposure to phenoxybenzamine, an irreversible inhibitor of alpha1-adrenoceptors, does not abrogate the apoptotic effect of doxazosin or terazosin against human prostate cancer or smooth muscle cells. This suggests that the apoptotic activity of doxazosin and terazosin against prostate cells is independent of their capacity to antagonize alpha1-adrenoceptors. Furthermore, an in vivo efficacy trial demonstrated that doxazosin administration (at tolerated pharmacologically relevant doses) in SCID mice bearing PC-3 prostate cancer xenografts resulted in a significant inhibition of tumor growth. These findings demonstrate the ability of doxazosin and terazosin (but not tamsulosin) to suppress prostate cancer cell growth in vitro and in vivo by inducing apoptosis without affecting cell proliferation. This evidence provides the rationale for targeting both drugs, already in clinical use and with established adverse-effect profiles, against prostatic tumors for the treatment of advanced prostate cancer

Prostate-specific antigen cancer volume: a significant prognostic factor in prostate cancer patients at intermediate risk of failing radiotherapy.

Lankford SP, Pollack A, Zagars GK.

Int J Radiat Oncol Biol Phys. 1997 May 1; 38(2):327-33.

PURPOSE: Although the pretreatment serum prostate-specific antigen level (PSAL) is the single-most significant predictor of local and biochemical control in prostate cancer patients treated with radiotherapy, it is relatively insensitive for patients with a PSAL in the intermediate range (4-20 ng/ml). PSA density (PSAD) has been shown to be slightly more predictive of outcome than PSAL for this intermediate risk group; however, this improvement is small and of little use clinically. PSA cancer volume (PSACV), an estimate of cancer volume based on PSA, has recently been described and has been purported to be more significant than PSAL in predicting early biochemical failure after radiotherapy. We report a detailed comparison between this new prognostic factor, PSAL, and PSAD. METHODS AND MATERIALS: The records of 356 patients treated with definitive external beam radiotherapy for regionally localized (T1-4,Nx,M0) adenocarcinoma of the prostate were reviewed. Each patient had a PSAL, biopsy Gleason score, and pretreatment prostate volume by transrectal ultrasonography. The median PSAL was 9.3 ng/ml and 66% had Gleason scores in the 2-6 range. The median radiation dose was 66.0 Gy and the median follow-up for those living was 27 months. PSACV was calculated using a formula which takes into account PSAL, pretreatment prostate ultrasound volume, and Gleason score. The median PSACV was 1.43 cc. Biochemical failure was defined as increases in two consecutive follow-up PSA levels, one increase by a factor > 1.5, or an absolute increase of > 1 ng/ml. Local failure was defined as a cancer-positive prostate biopsy, obtained for evidence of tumor progression. RESULTS: The distributions of PSACV and PSAL were similar and, when normalized by log transformation, were highly correlated (p < 0.0001, linear regression). There was a statistically significant relationship between PSACV and several potential prognostic factors including PSAL, PSAD, stage, Gleason score, and pretreatment prostatic acid phosphatase (PAP). In univariate analyses, PSACV, PSAL, and PSAD proved to be the most significant predictors of both biochemical and local control. In multivariate analyses using Cox proportional hazards models with PSAL, PSAD, PSACV, and PAP as continuous variables, PSAL, PSACV, and Gleason score were significant in predicting biochemical control. Only PSAL was significantly correlated with local control. However, when these analyses were restricted to patients with intermediate PSALs (4-20 ng/ml), only PSACV was significant for predicting both biochemical and local control. CONCLUSION: PSACV was highly correlated with actuarial local and biochemical control and was superior to both PSAL and PSAD in predicting these outcomes in patients with PSALs between 4 and 20 ng/ml

Fast neutron radiotherapy for locally advanced prostate cancer: results of an RTOG randomized study.

Laramore GE, Krall JM, Thomas FJ, et al.

Int J Radiat Oncol Biol Phys. 1985 Sep; 11(9):1621-7.

Between June 1977 and April 1983, the Radiation Therapy Oncology Group (RTOG) sponsored a Phase III randomized study investigating fast neutron radiation therapy in the treatment of patients with locally advanced (Stage C and D1) adenocarcinoma of the prostate gland. Patients were randomized to receive either conventional photon radiation therapy or fast neutron irradiation used in a mixed-beam treatment schedule (neutron/photon). A total of 91 analyzable patients were entered in the study; 78 of them were treated without major protocol deviations. The two treatment groups were balanced in regard to all major prognostic variables. Actuarial curves for "overall" survival, "determinantal" survival and local/regional control are presented both for the entire group of 91 patients and the 78 patients treated within protocol guidelines. The overall local/regional tumor recurrence rate is 7% for the mixed-beam treated group of patients and is 22% for the photon (X ray) treated group of patients. The difference is statistically significant at the p = 0.05 level. For the entire group of 91 evaluable patients, the 5-year "overall" survival rate is 62% for the mixed-beam-treated group and 35% for the photon-treated group. This difference is also statistically significant (p less than 0.05). However, this statistical significance is lost when the smaller number of patients treated strictly within protocol guidelines is considered. The significance is regained (p less than 0.02) when one looks at "determinantal" survival, which uses active cancer at time of death as the failure endpoint. This study demonstrates that a regional treatment modality, in this case mixed-beam irradiation, can influence both local/regional tumor control and survival in patients with locally-advanced adenocarcinoma of the prostate gland

Quantitative evaluation of glandular and stromal compartments in hyperplastic dog prostates: effect of 5-alpha reductase inhibitors.

Laroque PA, Prahalada S, Molon-Noblot S, et al.

Prostate. 1995 Sep; 27(3):121-8.

The objective of this study was to determine the effects of 2 different 5-alpha reductase inhibitors (finasteride and MK-0434) on the glandular and stromal compartments of hyperplastic canine prostates. In this study, dogs received 1 of the 2 compounds orally, at a dose of 1 mg/kg/day for 16 weeks; control dogs received a placebo. The morphological changes in the glandular and stromal compartments in the prostate were quantitated by a point-counting method on Masson's trichrome-stained sections. Treatment with 5-alpha reductase inhibitors resulted in significant (P < or = "0.05)" decreases in mean prostatic volumes, microscopic evidence of prostatic atrophy, and significant (P < or = "0.05)" decreases in the absolute volumes of the prostatic glandular and stromal compartments compared to controls. In finasteride-treated dogs, the mean percent change from baseline was: epithelium, -52; lumens, -58; fibrovascular stroma, -41; and smooth muscle, -29. In MK-0434-treated dogs, the mean percent change from baseline was: epithelium, -77; lumens, -58; fibrovascular stroma, -38; and smooth muscle, -42. The effect on the glandular compartment in dogs treated with MK-0434 was slightly greater than in dogs treated with finasteride; however, the effect on the stroma was similar. These results clearly demonstrate that inhibition of 5-alpha reductase enzyme activity affects growth and maintenance of both glandular and stromal compartments of dog hyperplastic prostates. It is likely that the decrease in size of the prostate in finasteride-treated (Proscar) men is due to shrinkage of both glandular and stromal compartments

In vivo interstitial temperature mapping of the human prostate during cryosurgery with correlation to histopathologic outcomes.

Larson TR, Rrobertson DW, Corica A, et al.

Urology. 2000 Apr; 55(4):547-52.

OBJECTIVES: To determine the critical temperatures below which human prostatic tissue can be cryoablated in situ and the comparative cryoablative efficacy of single versus double-freeze cryosurgery. METHODS: Six patients with prostate cancer previously scheduled for prostatectomy underwent unilateral or bilateral cryosurgery using a single cryosurgery probe per hemiprostate. Intraprocedural interstitial prostatic temperatures were measured by thermocouple junctions placed at various radial distances from the probe. After subsequent prostatectomy, whole-mount sections of the prostate gland were subjected to histopathologic evaluation. RESULTS: Uniform coagulative necrosis was observed in proximity to the cryosurgery probe. The percentage of the prostate volume falling within the zone of necrosis produced by a single probe was significantly greater (P = 0.048) after a double freeze (median 13%; range 8% to 20%) than a single freeze (median 4%; range 0% to 12%). The critical temperature for cryoablation with a double freeze was -41.4 degrees C (95% confidence interval -49.9 degrees to -33.0 degrees C) compared with -61.7 degrees C (95% confidence interval -74.5 degrees to -48.9 degrees C) for a single freeze (P

Transforming growth factor-beta in benign and malignant prostate.

Lee C, Sintich SM, Mathews EP, et al.

Prostate. 1999 Jun 1; 39(4):285-90.

BACKGROUND: The present review summarizes the cellular action of TGF-beta in benign and malignant growth of the prostate. METHODS: TGF-beta is a pleiotropic growth factor. It plays an important role in the regulation of growth and differentiation in many cells. In benign prostatic epithelia, its action is mediated through a paracrine mechanism. It inhibits proliferation and induces apoptosis in prostatic epithelia. It provides a mechanism to maintain epithelial homeostasis in the prostate. In prostatic stroma, its continual action leads to smooth muscle differentiation. This effect of TGF-beta may regulate the development of prostatic smooth muscle nodules in benign prostatic hyperplasia. RESULTS: As prostatic epithelial cells undergo malignant transformation, two major events occur regarding TGF-beta action. These include the loss of expression of functional TGF-beta receptors and overproduction of TGF-beta in malignant cells. The loss of expression of functional TGF-beta receptors provides a growth advantage to cancer cells over their benign counterparts. The overproduction of TGF-beta by cancer cells has a multitude of adverse consequences. TGF-beta can promote extracellular matrix production, induce angiogenesis, and inhibit host immune function. The biological consequence of these activities is an enhanced tumorigenicity in prostate cancer. Results of our recent studies with a rat prostate cancer model suggest that the immunosuppressive effect of TGF-beta seems to be the primary cause of tumor progression. This is because, if these cancer cells were engineered to reduce the production of TGF-beta, tumor growth was inhibited in syngeneic hosts but not in immune compromised hosts. CONCLUSIONS: Our future research should take advantage of this knowledge to devise therapeutic strategies aimed at eradicating prostate cancer

The use of transrectal ultrasound in the study of normal and abnormal anatomy of the prostate gland.

Lee F.

2004; First Edition:23-36.

Cryosurgery of prostate cancer. Use of adjuvant hormonal therapy and temperature monitoring--A one year follow-up.

Lee F, Bahn DK, McHugh TA, et al.

Anticancer Res. 1997 May; 17(3A):1511-5.

OBJECTIVE: To determine the clinical outcomes at one year of Stages T2-T3 prostate cancer by cryosurgery utilizing pretreatment with total androgen ablation therapy and temperature monitoring to control the freezing process. Study Group To date, 347 patients have had 356 cryosurgical procedures, 280 have reached one year post treatment. Of these 131 had re-evaluation with prostatic biopsy and serum PSA. METHODS: Transrectal ultrasound (TRUS) measurement of tumor size and biopsy of extraprostatic space was used to stage patients into two main groups: confined (66.6%) versus nonconfined (19.3%). Radiation failures (14.1%) formed a separate group. Failure rates for the 131 men include all cancer diagnosed during the one year period following cryosurgery. RESULTS: The one year failure rate for the study group was 19.8% (26/131). For stages T2a, T2h C, T3 and radiation failures, the rates of positive biopsies were 13.9%, 12.9%, 33.3% and 35%, respectively. For those with local control of cancer (negative biopsy), 80% had prostate specific antigen (PSA) levels of 0.5 ng/ml were: sensitivity of 66.7%, PPV of 16.7%, NPV of 98% and specificity of 83.7%. A statistically significant difference exist between stages T2 vs T3 and radiation failures (p = < 0.5). Major complications of rectal fistula and total incontinence for previously non-treated cancer versus radiation failures were 0.33% and 8.7% respectively, a 26 times greater risk. CONCLUSION: Results of cryosurgery for all stages of prostate cancer at one year are encouraging, being 80% free of disease (biopsy and prostate specific antigen). The morbidity of the previously non-treated cancers from this procedure for us was minimal with high patient acceptance. For radiation failures a local control rate of 65% was achieved. However, early in our experience significant morbidity did occur and our enthusiasm for attempted salvage was initially tempered

Increasing prostate-specific antigen profile following definitive radiation therapy for localized prostate cancer: clinical observations.

Lee WR, Hanks GE, Hanlon A.

J Clin Oncol. 1997 Jan; 15(1):230-8.

PURPOSE: To examine the natural history of patients who have received definitive radiation therapy alone for clinically localized prostate cancer and have an increasing prostate-specific antigen (PSA) profile. PATIENTS AND METHODS: One hundred fifty-one men with an increasing PSA profile after definitive radiotherapy were identified. The subsequent natural history of these men, including local recurrence, distant metastasis, and survival, was examined. In 119 men, posttreatment PSA doubling times (PSADT) were calculated using linear regression. Cox regression models were used to examine the effect of clinical and treatment variables on clinical failure and survival. RESULTS: Patients with high pretreatment PSA values, high Gleason scores, and T3 tumors were more likely to develop a PSA elevation. The median calculated post-treatment PSADT was 13 months, and 95% of patients had posttreatment PSADT of less than 3 years. PSADT was correlated with tumor stage and Gleason score. Five years after PSA elevation, the estimated rate of clinical local recurrence is 26% and the estimated rate of distant metastases is 47%. Rapid PSADT (< 12 months) and a short interval from the end of treatment to PSA elevation (< 12 months) were significant independent predictors of distant metastases. The estimated rates of overall and cause-specific survival 5 years after PSA elevation are 65% and 76%, respectively. Gleason grade is the only significant independent predictor of overall and cause-specific survival after PSA elevation. CONCLUSION: The natural history of men who have an increasing PSA profile following definitive radiotherapy is heterogeneous. In the absence of salvage therapy, at least three quarters of men will have clinical evidence of recurrent disease 5 years after a PSA elevation is detected. Men with a rapid posttreatment PSADT and a short interval from the end of treatment to an increasing PSA profile are at a very high risk of developing distant metastasis within 5 years of PSA elevation

Intrinsic and extrinsic characteristics of human tumors relevant to radiosurgery: comparative cellular radiosensitivity and hypoxic percentages.

Leith JT, Cook S, Chougule P, et al.

Acta Neurochir Suppl (Wien ). 1994; 62:18-27.

We have collected the in vitro x-ray radiation survival characteristics of 181 lines from 12 different classes of exponentially growing human tumor cells (sarcomas, lung cancers, colo-rectal cancers, medulloblastomas, melanoma, breast cancers, prostate cancers, renal cell cancers, grades III and IV brain tumors, ovarian, and head and neck cancers). This information was used to intercompare survival after single high doses of 20-40 Gy for each tumor line. Radiosensitivities could roughly be divided into two groups. The more radiosensitive group included: sarcoma, small-cell lung cancer, non-small cell lung cancer, colorectal cancer, medulloblastoma and melanoma. The more radioresistant group included breast, prostate, renal cell, primary brain tumors, ovarian tumors, and head and neck cancers. Using a model of a 3 cm diameter brain lesion containing about 1.4 x 10(9) oxic cells, the single doses calculated to reduce survival to 1 cell were: sarcoma and small cell lung cancers-22-23 Gy; melanoma-25 Gy; non-small cell lung and colorectal cancer-26 Gy; medullo-blastoma-28 Gy; breast, prostate, renal cell, primary brain tumors, ovarian tumors, and head and neck cancers-30-36 Gy. If, however, tumors contained on average 20 percent hypoxic cells, the dose needed for equivalent cell killing increased by about a factor of 2.6-2.8. Also, there was no correlation between the ranking of relative radiosensitivities of the various classes of tumor cells at high doses (as in radiosurgery) to the sensitivity at low doses (as in conventional fractionated radiotherapy). CONCLUSION: available information on the intrinsic radiosensitivity of human tumor cells indicates that meaningful differences exist among different histological classes of neoplasm that are relevant to the single high doses used in radioneurosurgery, and which could constitute a basis for "tailoring" the administered dose to the particular neoplasm. However, if intracerebral lesions contain a large number of hypoxic cells (e.g., 20%), this may constitute a significant problem

Analysis of risk factors for progression in patients with pathologically confined prostate cancers after radical retropubic prostatectomy.

Lerner SE, Blute ML, Bergstralh EJ, et al.

J Urol. 1996 Jul; 156(1):137-43.

PURPOSE: Up to 26% of patients with pathologically organ confined prostate cancer will experience clinical progression after radical prostatectomy. We attempted to identify patients at greatest risk for future clinical failure despite a favorable pathological outcome. MATERIALS AND METHODS: The study group included 904 patients treated with bilateral pelvic lymphadenectomy and radical retropubic prostatectomy for disease confined to the prostate gland. Preoperative serum prostate specific antigen (PSA), clinical stage, pathological grade and stage, and deoxyribonucleic acid (DNA) ploidy were evaluated by multivariate analysis to determine relative value in predicting treatment failure. A prognostic scoring system was created using the regression coefficients from the Cox multivariate model to classify patients further according to risk of progression. RESULTS: Preoperative PSA concentration, clinical stage, grade and DNA ploidy were significant univariate predictors of progression (p < 0.0001), whereas pathological stage was not (p = "0.2)." Multivariate analysis identified pathological grade (p < 0.0001), preoperative serum PSA concentration (p = "0.0006)" and DNA ploidy (p = "0.0089)" as independent predictors of progression. The prognostic scoring system separated the patients into 5 distinct groups. Patients with the lowest score had a 92% progression-free survival rate at 5 years, compared to only 39% of those with the highest scores. CONCLUSIONS: Patients believed to be at higher risk for cancer progression despite having organ confined disease might be targeted for adjuvant therapy and closer surveillance, while those at low risk may be followed less often

The effects of exercise and activity on serum prostate specific antigen levels.

Leventhal EK, Rozanski TA, Morey AF, et al.

J Urol. 1993 Sep; 150(3):893-4.

To determine the effects of exercise and activity on serum prostate specific antigen (PSA) levels, we studied an inpatient adult male population, and evaluated the PSA levels before and after a graded exercise stress test. We confirmed a prior finding showing a significant difference between inpatient and outpatient values, yet found that stressful exercise had no definitive effect on serum PSA values

Androgens induce the expression of vascular endothelial growth factor in human fetal prostatic fibroblasts.

Levine AC, Liu XH, Greenberg PD, et al.

Endocrinology. 1998 Nov; 139(11):4672-8.

Androgens are known to directly stimulate prostate cancer cell growth. We have previously reported that LNCaP prostate cancer cells were dependent upon stromal coinoculation for growth in nude mice and that the stromal cells secreted a potent angiogenic factor, vascular endothelial growth factor (VEGF), which stimulated tumor angiogenesis. Immunohistochemical staining localized VEGF expression primarily to the stromal cells of human fetal and adult hyperplastic prostates, with both stromal and epithelial cell VEGF expression in prostate cancer. In the present studies, we test the hypothesis that androgens, in addition to their direct effects on prostate epithelial cells, have indirect effects on these cells via up-regulation of stromal VEGF production and angiogenesis. Primary cultures of human prostate fetal fibroblasts were treated with dihydrotestosterone (DHT), and the effects on VEGF messenger RNA (mRNA) expression were determined by Northern blotting. DHT (10 nM) increased VEGF mRNA levels maximally after 2 h. Nuclear run-on transcription assays demonstrated a 2-fold increase in the VEGF transcription rate 2 h after the addition of DHT. VEGF mRNA stability was unaffected by DHT addition. VEGF protein levels were determined by enzyme-linked immunosorbent assay and were increased 2-fold 4 h after DHT addition. These data indicate that androgens increase VEGF transcription and secretion of biologically active VEGF from human prostatic stroma. Androgens, therefore, may indirectly enhance prostate growth via up-regulation of VEGF from the surrounding stroma

Evaluation of the needs of male carriers of mutations in BRCA1 or BRCA2 who have undergone genetic counseling.

Liede A, Metcalfe K, Hanna D, et al.

Am J Hum Genet. 2000 Dec; 67(6):1494-504.

To date, the concerns of men at risk of inheriting a BRCA1 mutation or a BRCA2 mutation have received little attention. It had been anticipated that few men would be interested in predictive testing when a BRCA mutation was identified in their family. However, these men are often affected emotionally by diagnoses of breast cancer in their relatives and may themselves harbor fears that cancer will develop. Male carriers of BRCA1/2 mutations are at increased risk of development of cancers of several types, including those of the breast and prostate. We conducted an evaluation of the needs and experiences of 59 male carriers of BRCA1/2 mutations followed at either the University of Toronto or Creighton University. We assessed their motivations for seeking genetic counseling and testing, involvement in family discussions of breast and ovarian cancer, risk perception, changes in cancer-screening practices, and overall satisfaction with the genetic-counseling process. The principal motivation for seeking genetic counseling was concern for their daughters. The majority (88%) of men participated in family conversations about breast and ovarian cancer, and 47% participated in conversations about prophylactic surgery. Most men believed that they were at increased risk of development of cancer (prostate, breast, colorectal, and skin cancers). However, fewer than one-half (43%) of the men with no previous diagnosis of cancer stated that their prostate cancer-surveillance practices had changed after they had received genetic test results. More than one-half (55%) had intrusive thoughts about their cancer risk. Although levels of satisfaction were high, practitioners should be aware of (a) potential pressures influencing men to request predictive testing, (b) the difficulties that men encounter in establishing surveillance regimens for breast and prostate cancer, and (c) the general lack of information about men's particular experiences in the medical community

Inhibition of cyclooxygenase-2 suppresses angiogenesis and the growth of prostate cancer in vivo.

Liu XH, Kirschenbaum A, Yao S, et al.

J Urol. 2000 Sep; 164(3 Pt 1):820-5.

PURPOSE: Cyclooxygenase (COX)-2, an inducible enzyme which catalyzes the formation of prostaglandins from arachidonic acid, is expressed in prostate cancer specimens and cell lines. To evaluate the in vivo efficacy of a COX-2 inhibitor in prostate cancer, NS398 was administered to mice inoculated with the PC-3 human prostate cancer cell line. MATERIALS AND METHODS: A total of 28 male nude mice were inoculated subcutaneously with 1 million PC-3 cells. Tumors were palpable in all 28 animals 1 week after inoculation and mice were randomized to receive either vehicle (control) or NS398, 3 mg./kg. body weight, intraperitoneally three times weekly for 9 weeks. Tumors were measured at weekly intervals. After a 10-week experimental period, mice were euthanized and tumors were immuno- histochemically assayed for proliferation (PCNA), apoptosis (TUNEL) and microvessel density (MVD) (Factor-VIII-related antigen). Tumor VEGF content was assayed by Western blotting. RESULTS: NS398 induced a sustained inhibition of PC-3 tumor cell growth and a regression of existing tumors. Average tumor surface area from control mice was 285 mm.2 as compared with 22 mm.2 from treated mice (93% inhibition, p

Prostaglandin E(2) stimulates prostatic intraepithelial neoplasia cell growth through activation of the interleukin-6/GP130/STAT-3 signaling pathway.

Liu XH, Kirschenbaum A, Lu M, et al.

Biochem Biophys Res Commun. 2002 Jan 11; 290(1):249-55.

Cyclooxygenase (COX)-2 expression and prostaglandin E(2) (PGE(2)) secretion are increased in prostatic intraepithelial neoplasia (PIN) and prostate cancer. PGE(2) biosynthesis by cyclooxygenase (COX)-2 plays a pivotal role in inflammation and carcinogenesis. One of the critical proinflammatory cytokines in the prostate is interleukin-6 (IL-6). We hypothesized that increased expression of COX-2, with resultant increased levels of PGE(2) in human PIN cells, activates the IL-6 signaling pathway. We demonstrate an autocrine upregulation of PGE(2) mediated by IL-6 in a human PIN cell line. We further demonstrate that PGE(2) stimulates soluble IL-6 receptor (sIL-6R) release, gp130 dimerization, Stat-3 protein phosphorylation, and DNA binding activity. These events, induced by PGE(2), lead to increased PIN cell growth. Treatment of PIN cells with a selective COX-2 inhibitor decreases cell growth. Finally, PGE(2)-stimulated PIN cell growth was abrogated by the addition of IL-6 neutralizing antibodies. These data provide mechanistic evidence that increased expression of COX-2/PGE(2) contributes to prostate cancer development and progression via activation of the IL-6 signaling pathway

Inhibition of cell proliferation, invasion, tumor growth and metastasis by an oral non-antimicrobial tetracycline analog (COL-3) in a metastatic prostate cancer model.

Lokeshwar BL, Selzer MG, Zhu BQ, et al.

Int J Cancer. 2002 Mar 10; 98(2):297-309.

Antibiotic forms of tetracycline exhibit antitumor activity in some tumor models. However, their low in vivo efficacy and associated morbidity limit their long-term application in cancer therapy. This report appraises the efficacy of doxycycline (DC) and non-antimicrobial, chemically modified tetracyclines (CMTs) against prostate cancer. Both DC and several CMTs inhibited prostate tumor cell proliferation in vitro. Some of the CMTs were significantly more potent than DC. One of the CMTs, 6-deoxy, 6-demethyl, 4-de-dimethylamino tetracycline (CMT-3, COL-3), was the most potent inhibitor (50% inhibition dose [GI(50)] 90% (CMT-3). CMT-3 and DC decreased matrix metalloproteinase (MMP)-2, tissue inhibitor of MMP (TIMP)-1 and TIMP-2 secretion in treated cultures and inhibited activity of secreted MMPs, CMT-3 was a stronger inhibitor. Daily oral gavage of DC and CMT-3 inhibited tumor growth and metastasis in the Dunning MAT LyLu rat prostate tumor. Decreases in tumor growth (27-35%) and lung metastases were observed (28.9 +/- 15.4 sites/animal [CMT-3-treated] versus 43.6 +/- 18.8 sites/animal [DC-treated] versus 59.5 +/- 13.9 [control]; p < 0.01]. A delay in tumor growth (27 +/- 9.3%, p < 0.05), reduction in metastases (58 +/- 8%) and decrease in tumor incidences (55 +/- 9%, CMT-3-treated) were also observed, when rats were predosed for 7 days. No significant drug-induced morbidity was observed in any of the animals. These results, along with a recently concluded clinical trial, suggest a potential use of CMT-3 as an oral, nontoxic drug to treat metastatic prostate and other cancers

Five-year retrospective, multi-institutional pooled analysis of cancer-related outcomes after cryosurgical ablation of the prostate.

Long JP, Bahn D, Lee F, et al.

Urology. 2001 Mar; 57(3):518-23.

OBJECTIVES: To define the potential role of cryosurgical ablation of the prostate (CSAP) as a treatment option for patients with localized prostate carcinoma (PCA), we performed a retrospective outcomes analysis of a large database of patients undergoing CSAP constructed from five institutions and compared this with matching outcomes from contemporary reports of patient outcomes after radiotherapy. METHODS: A total of 975 patients who underwent CSAP as primary therapy from January 1993 to January 1998 with sufficient outcomes data available were identified. Patients were stratified into three groups on the basis of their clinical features. Biochemical-free survival (BFS), post-CSAP biopsy results, and post-CSAP morbidities were calculated and recorded. RESULTS: The median follow-up for all patients was 24 months. The percentages of patients in the low, medium, and high-risk groups were 25%, 34%, and 41%, respectively. For prostate-specific antigen thresholds of less than 0.5 and less than 1.0 ng/mL, the 5-year actuarial BFS ranged from 36% to 61% and 45% to 76%, respectively, depending on the risk category. Overall, the positive biopsy rate was 18%. Morbidities included impotence in 93%, incontinence in 7.5%, rectourethral fistula in 0.5%, and transurethral resection of the prostate in 13% of patients (10% approved warming catheters versus 40% nonapproved). CONCLUSIONS: For each risk group, the 5-year BFS and positive biopsy rate after CSAP was comparable to matching outcomes reported after radiotherapy. Morbidities also seemed comparable, with impotence rates higher and rectal injury rates lower after CSAP than after radiotherapy. These data indicate that CSAP can be performed with low morbidity and can produce cancer-related results comparable to those reported for patients undergoing radiotherapy

Inverse associations between plasma lycopene and other carotenoids and prostate cancer.

Lu QY, Hung JC, Heber D, et al.

Cancer Epidemiol Biomarkers Prev. 2001 Jul; 10(7):749-56.

Although dietary intake of tomatoes and tomato products containing lycopene has been reported to reduce the risk of prostate cancer, few studies have been done on the relationship between plasma lycopene and other carotenoids and prostate cancer. This case-control study was conducted to investigate the effects of plasma lycopene, other carotenoids, and retinol, as well as alpha- and gamma-tocopherols on the risk of prostate cancer. The study included 65 patients with prostate cancer and 132 cancer-free controls; all of them were interviewed using a standard epidemiological questionnaire at the Memorial Sloan-Kettering Cancer Center from 1993 to 1997. Plasma levels of carotenoids, retinol, and tocopherols were measured by high performance liquid chromatography. An unconditional logistic regression model was used in bivariate and multivariate analyses using Statistical Analysis System (SAS). After adjusting for age, race, years of education, daily caloric intake, pack-years of smoking, alcohol consumption, and family history of prostate cancer, significantly inverse associations with prostate cancer were observed with plasma concentrations of the following carotenoids: lycopene [odds ratio (OR), 0.17; 95% confidence interval (CI), 0.04-0.78; P for trend, 0.0052] and zeaxanthin (OR, 0.22; 95% CI, 0.06-0.83; P for trend, 0.0028) when comparing highest with lowest quartiles. Borderline associations were found for lutein (OR, 0.30; 95% CI, 0.09-1.03; P for trend, 0.0064) and beta-cryptoxanthin (OR, 0.31; 95% CI, 0.08-1.24; P for trend, 0.0666). No obvious associations were found for alpha- and beta-carotenes, retinol, and alpha- and gamma-tocopherols. Our study confirmed the inverse associations between lycopene, other carotenoids such as zeaxanthin, lutein, and beta-cryptoxanthin, and prostate cancer. This study provides justification for further research on the associations between lycopene and other antioxidants and the risk of prostate cancer

[Adverse effects of transrectal prostatic biopsy. Analysis of 303 procedures].

Lujan GM, Paez BA, Fernandez G, I, et al.

Actas Urol Esp. 2001 Jan; 25(1):46-9.

INTRODUCTION AND OBJECTIVE: Prostate biopsy is a basic step towards prostate cancer (Pca) diagnosis, but usually not free from complications. In this article we have reviewed the adverse effects of this procedure in our setting. MATERIAL AND METHODS: We studied in a prospective fashion the complications arising from transrectal prostate biopsy with the aid of a questionnaire fulfilled by 303 patients who underwent this procedure, within the context of a Pca screening program. All biopsies were transrectal ultrasound guided and randomly taken (sextant). A cleaning enema was applied the night before, and 100 mg of intramuscular tobramycin were administered prior of the procedure. RESULTS: Ninety patients (29.7%) had no adverse effects at all, and 136 (44.9%) reported at least one minor complication (hematuria, hemospermia, or autolimited dysuria). Lastly 77 (25.4%) presented with major complications--urinary retention, fever, need for medical assistance (primary or hospital care) or treatment. Thirty-five patients (11.5%) reported to present with fever after biopsy, 145 (47.8%) hematuria, 95 (31.3%) hemospermia, 77 (25.4%) rectal bleeding, 67 (22.1%) urinary difficulty, and 9 (2.9%) urinary retention. Up to 39 (12.8%) needed to visit their G.P., and 19 of them were referred to Hospital, where only 6 (1.9%) were admitted longer than 24 hours. No intensive care unit admittances or deaths were reported. CONCLUSIONS: The rate of post-transrectal biopsy adverse effects is high in our experience. This phenomenon could be explained, in part, due to data collecting by means of a self-administered questionnaire. Probably the high fever rate presented here could be diminished with other type of antibiotic prophylaxis

Prostate specific antigen variation in patients without clinically evident prostate cancer.

Lujan M, Paez A, Sanchez E, et al.

J Urol. 1999 Oct; 162(4):1311-3.

PURPOSE: We address long-term within individual variation of serum prostate specific antigen (PSA) in men without clinical or biopsy evidence of prostate cancer. MATERIALS AND METHODS: We studied 943 men from a prostate cancer screening program with 2 PSA (PSA1 and PSA2) measurements available. A third PSA (PSA3) was obtained from 571 men. Only participants with no clinical evidence of cancer were included in the study. Within individual PSA variability was calculated based on indexes of percent coefficient of variation, ratio difference and PSA velocity. The relationship among these indexes, interval between measurements and number of PSA samples was assessed. RESULTS: Mean interval was 670.4 days between PSA1 and PSA2, and 801.8 days between PSA2 and PSA3 (p

Periprostatic nerve block gives better analgesia for prostatic biopsy.

Lynn NN, Collins GN, Brown SC, et al.

BJU Int. 2002 Sep; 90(4):424-6.

OBJECTIVE: To prospectively compare two local anaesthetic techniques for prostatic biopsies, which are usually taken with no anaesthesia; because multiple biopsy techniques are becoming more common and there is an increasing need for analgesia/anaesthesia during the procedure. PATIENTS AND METHODS: The study group comprised 86 consecutive men (median age 67.7 years) undergoing prostatic biopsy because of either an abnormality of prostate specific antigen level or digital rectal examination. They were randomized into four groups; men in group 1 received 10 mL of 1% lignocaine infiltrated into the periprostatic nerve plexus bilaterally; men in group 2 received 11 mL of 2% lignocaine gel rectally; men in groups 3 and 4 were recruited as controls, and given either plain gel rectally or an injection with saline into the periprostatic nerve plexus. Sextant prostate biopsies were taken in all cases using a standardized protocol. Immediately after the procedure patients were asked to indicate the degree of pain on a 10-cm visual analogue scale. RESULTS: Men in group 1 had significantly less pain than the others (P < 0.001). There was no statistically significant difference in pain between men who received plain gel rectally or saline injection (P = "0.35)." The rectal instillation of 2% lignocaine gel did not reduce pain significantly (P = "0.186)" compared with the controls. CONCLUSION: A periprostatic nerve block with 1% lignocaine was associated with significantly less pain during prostatic biopsy than was rectal lignocaine gel or placebo

Invited review: manganese superoxide dismutase in disease.

MacMillan-Crow LA, Cruthirds DL.

Free Radic Res. 2001 Apr; 34(4):325-36.

Manganese superoxide dismutase (MnSOD) is essential for life as dramatically illustrated by the neonatal lethality of mice that are deficient in MnSOD. In addition, mice expressing only 50% of the normal compliment of MnSOD demonstrate increased susceptibility to oxidative stress and severe mitochondrial dysfunction resulting from elevation of reactive oxygen species. Thus, it is important to know the status of both MnSOD protein levels and activity in order to assess its role as an important regulator of cell biology. Numerous studies have shown that MnSOD can be induced to protect against pro-oxidant insults resulting from cytokine treatment, ultraviolet light, irradiation, certain tumors, amyotrophic lateral sclerosis, and ischemia/reperfusion. In addition, overexpression of MnSOD has been shown to protect against pro-apoptotic stimuli as well as ischemic damage. Conversely, several studies have reported declines in MnSOD activity during diseases including cancer, aging, progeria, asthma, and transplant rejection. The precise biochemical/molecular mechanisms involved with this loss in activity are not well understood. Certainly, MnSOD gene expression or other defects could play a role in such inactivation. However, based on recent findings regarding the susceptibility of MnSOD to oxidative inactivation, it is equally likely that post-translational modification of MnSOD may account for the loss of activity. Our laboratory has recently demonstrated that MnSOD is tyrosine nitrated and inactivated during human kidney allograft rejection and human pancreatic ductal adenocarcinoma. We have determined that peroxynitrite (

Value of the free to total prostate specific antigen ratio and prostate specific antigen density for detecting prostate cancer in Japanese patients.

Maeda H, Arai Y, Okubo K, et al.

Int J Urol. 1998 Jul; 5(4):343-8.

BACKGROUND: This study evaluated the free to total serum prostate specific antigen (f/t PSA) ratio and prostate specific antigen density (PSAD) in detecting prostate cancer in Japanese males with a PSA level between 2.5 and 20.0 ng/mL in a community-based urology practice. METHODS: Twenty-six patients with clinically localized prostate cancer and 44 patients with histologically-proven benign prostatic hyperplasia (BPH) were studied. The serum levels of free PSA (fPSA) and total (t) PSA were determined using a chemiluminescent enzyme immunoassay. The f/t PSA ratio was calculated by dividing the fPSA value by the total PSA value and was compared with the PSA and PSAD via the receiver operating characteristic (ROC) curves. RESULTS: Patients with prostate cancer had a significantly lower f/t PSA ratio than patients with BPH. The PSAD was a superiordiagnostic tool over PSA (P< 0.01) when analyzed by ROC curves. The f/t PSA ratio was also superior to PSA, but lacked significance (P="0.12)," and similarly, the PSAD was superior, but not significant, to the f/t PSA ratio. Using a cut-off value of 0.19, the PSAD had a sensitivity of 81% and a specificity of 82%. With a cut-off value of 14.0%, the f/t PSA ratio had a sensitivity of 81% and a specificity of 66%. CONCLUSION: This study showed that PSAD alone improved cancer detection significantly better than PSA. However, it is still unclear whether the f/t PSA ratio is superior to PSA or PSAD in the discrimination between BPH and prostate cancer in Japanese male patients

Nitrous oxide (Entonox) inhalation and tolerance of transrectal ultrasound guided prostate biopsy: a double-blind randomized controlled study.

Masood J, Shah N, Lane T, et al.

J Urol. 2002 Jul; 168(1):116-20.

PURPOSE: We performed a randomized, placebo controlled double-blind trial to evaluate the effectiveness of Entonox (BOC Gases, Manchester, United Kingdom), that is 50% nitrous oxide and oxygen, as analgesia during transrectal ultrasound guided prostate biopsy. MATERIALS AND METHODS: Patients referred for transrectal ultrasound guided prostate biopsy for the first time as an outpatient procedure were recruited subject to exclusion criteria and randomized to breathe Entonox or air via similar breath activated devices. At the end of the procedure patients completed a visual pain analog scale. Patients who refused study participation also completed the visual analog pain scale to assess the placebo effect of receiving gas through a mask. RESULTS: A total of 110 patients were studied. Statistical analysis using 1-way analysis of variance showed a highly significant difference in pain perception among the 3 groups (F [2,107] = 73.348, p

A double-blind, randomized, placebo-controlled trial of n-3 versus n-6 fatty acid-based lipid infusion in atopic dermatitis.

Mayser P, Mayer K, Mahloudjian M, et al.

JPEN J Parenter Enteral Nutr. 2002 May; 26(3):151-8.

BACKGROUND: In the involved epidermis of patients with atopic dermatitis, changes in the metabolism of eicosanoids with increased quantities of the arachidonic acid (AA)-derived lipoxygenase products have been observed. Free eicosapentaenoic acid (EPA), a fish oil-derived alternative (n-3) fatty acid, may compete with AA, resulting in an anti-inflammatory effect. METHODS: In a 10-day double-blind, randomized, placebo-controlled trial, 22 patients hospitalized for moderate-to-severe atopic dermatitis were randomly assigned to receive daily infusions of either a n-3 fatty acid-based lipid emulsion (fish oil, 10%; 200 mL/d) or a conventional n-6-lipid emulsion (soybean oil, 10%; 200 mL/d). Topical treatment was restricted to emollients. The severity of disease was evaluated daily with scoring of erythema, infiltration, and desquamation and by subjective patient scoring of clinical manifestations. In addition, plasma-free and total-bound fatty acids and the composition of membrane fatty acids in blood cells (thrombocytes, granulocytes, and erythrocytes), lipid mediators from isolated neutrophils and platelets, and lymphocyte-activation parameters were determined. RESULTS: Twenty patients completed the trial. Marked improvement from baseline was seen in both groups. On days 6, 7, 8, and 10, disease severity score-defined as the sum of all scores-was more pronounced (p < .05) in the n-3 group compared with the n-6 group. Free arachidonic acid in plasma did not change substantially in both groups, whereas plasma-free EPA, total-bound EPA, and the membrane EPA/AA ratio markedly increased in response to n-3-lipid infusion. In parallel, EPA-derived lipid mediators appeared, whereas lymphocyte functions were unaffected. In the post-treatment period (2/4 weeks), relapse was observed in some patients after n-3 psoralene-ultraviolet A (PUVA) infusion, whereas there was a marked long-term improvement in the n-6 group. CONCLUSIONS: IV n-3-fatty acid administration is effective in acutely improving the severity of atopic dermatitis, paralleled by changes in plasma and membrane fatty acid composition and lipid mediator synthesis. The long-term beneficial effects of IV n-6 fatty acids should be evaluated further

Watchful waiting or watchful progression?: Prostate specific antigen doubling times and clinical behavior in patients with early untreated prostate carcinoma.

McLaren DB, McKenzie M, Duncan G, et al.

Cancer. 1998 Jan 15; 82(2):342-8.

BACKGROUND. Prostate specific antigen doubling time (PSAdt) is a dynamic model of prostate tumor biology. It predicts aggressive disease and subsequent clinical recurrence after radical treatment. However, as yet there is only limited evidence for its validity in the watchful waiting population. METHODS. One hundred and thirteen previously untreated patients with adenocarcinoma of the prostate who were referred to the British Columbia Cancer Agency for a management opinion subsequently were placed into a prospective watchful waiting program. The reasons for watchful waiting, previous medical history, serial PSA, and histopathologic data were recorded. RESULTS. The median age of patients was 75 years (range, 49-85 years). The median follow-up from the time of the first appointment was 14 months (range, 0-58 months). The reasons for watchful waiting were correlated highly with T classification (P = 0.003) and past medical history (P = 0.002). Approximately 40% of T1 patients and 51% of T2 patients had clinical progression by 2 years, increasing to 60% at 3 years. On multivariate analysis PSAdt strongly correlated with clinical progression (P < 0.0001), stage progression (P = "0.01)," and time to treatment (P = "0.0001);" tumor grade and initial stage were not found to be predictive for any of the endpoints studied. Initial PSA only was significant in predicting for time to treatment (P = "0.03)." Approximately 50% of patients with a PSAdt of

The zonal anatomy of the prostate.

McNeal JE.

Prostate. 1981; 2(1):35-49.

Earlier morphologic studies of the prostate, though often extensive, have never systematically delineated its completed structure. Recent comprehensive analysis of 500 prostates has more precisely defined its anatomic composition, identifying previously undetected features and unsuspected complexities. Using a three-dimensional model, these structures and relationships are demonstrated. Four basic anatomic regions are described. The relationship of each to the urethra provides a central anatomic reference point. 1. The peripheral zone constitutes over 70% of the glandular prostate. It forms a disc of tissue whose ducts radiate laterally from the urethra lateral and distal to the verumontanum. Almost all carcinomas arise here. 2. The central zone constitutes 25% of the glandular prostate. Its ducts arise close to the ejaculatory duct orifices and follow these ducts proximally, branching laterally near the prostate base. Its lateral border fuses with the proximal peripheral zone border, completing in continuity with the peripheral zone, a full disc of secretory tissue oriented in a coronal plane. Marked histologic differences between central and peripheral zones suggest important biologic differences. 3. Preprostatic region. The urethral segment proximal to the verumontanum is kinked anteriorly at a 35-degree angle to the distal segment. No major ducts arise in the proximal segment, but the lateral rows of peripheral zone orifices continue. Duct development is aborted here, producing only a small transition zone and several tinier periurethral ducts. The development of these small ducts is possibly determined and limited by their intimate relationship to a periurethral smooth muscle sphincter that exists only proximal to the verumontanum. These small ducts in a restricted area are the exclusive site of nodular hyperplasia (BPH) origin. 4. The anterior fibromuscular stroma forms the entire anterior surface of the prostate as a thick, nonglandular apron, shielding from view the anterior surface of the three glandular regions. Its inseparable fusion to the glandular prostate has probably delayed recognition of the anatomic features described here

A screening study of prostate cancer in high risk families.

McWhorter WP, Hernandez AD, Meikle AW, et al.

J Urol. 1992 Sep; 148(3):826-8.

In a study of the familial risk of prostate cancer 17 sets of 2 brothers with prostate cancer were identified. A total of 34 first-degree relatives of these probands (sons and brothers, 55 to 80 years old) underwent an intensive screening examination that included prostate specific antigen, digital rectal examination, transrectal ultrasound and systematic as well as clinically directed core needle biopsies. Previously unsuspected and clinically relevant cancers were found in 8 men (24%), compared to the approximately 1 expected (p less than 0.01). Of these cancers 2 were detected by the systematic biopsies. This study emphasizes the importance of thorough screening in first-degree relatives of prostate cancer patients

Influence of disease activity and chronicity on ankylosing spondylitis bone mass loss.

Meirelles ES, Borelli A, Camargo OP.

Clin Rheumatol. 1999; 18(5):364-8.

We investigated 30 consecutive Brazilian patients with definite ankylosing spondylitis (AS) fulfilling the New York and the European spondyloarthropathy study group classification criteria. The mean age at study was 37 years old and the mean disease duration was 17 years. Bone densitometry employed the dual-energy X-ray absorptiometry (DEXA) technique, using a Hologic QDR-1000/W densitometer. Axial bone mineral density (BMD) was measured in the lumbar spine (L1-L4) and appendicular BMD was measured in the total proximal femur and sub-regions (neck, greater trochanter, intertrochanter and Ward's triangle). Based on World Health Organisation criteria, the lumbar spine showed osteopenia or osteoporosis in 50% of the patients, while 86% had osteopenia or osteoporosis in the total proximal femur. When compared with the normal population, the patients showed a significant BMD decrease in the lumbar spine and total proximal femur with sub-regions, except for the femoral neck. A comparison of BMD between patients with active and inactive disease did not reveal a significant effect of clinical disease activity on the lumbar spine and total proximal femur with sub-regions, except for Ward's triangle. Concerning disease chronicity, there were significant positive correlations between disease duration and lumbar spine, total proximal femur, greater trochanter and intertrochanteric regional BMD. This false increase in lumbar spine BMD found mostly in patients with long standing AS was due to the presence of paravertebral calcification and ossification. We conclude that the bone mass loss in AS is better evaluated in the proximal femur, because of the greater sensitivity of bone densitometry in this region, which is almost free of artefacts

Temporal resolution of urinary morbidity following prostate brachytherapy.

Merrick GS, Butler WM, Lief JH, et al.

Int J Radiat Oncol Biol Phys. 2000 Apr 1; 47(1):121-8.

PURPOSE: To report the short-term urinary morbidity for prostate brachytherapy patients without a preimplant history of a transurethral resection of the prostate gland and who received prophylactic and prolonged alpha-blockers. alpha-blockers may decrease radiation-induced urethritis and increase urinary flow. Multiple clinical and treatment parameters were evaluated to identify factors associated with increased acute urinary morbidity. MATERIALS AND METHODS: One hundred seventy consecutive patients without a prior history of a transurethral resection of the prostate gland underwent transperineal ultrasound guided prostate brachytherapy for clinical T1c-T3a carcinoma of the prostate gland. For all patients, an alpha-blocker was initiated prior to implantation and continued at least until the international prostate symptom score (IPSS) returned to baseline levels. Clinical parameters evaluated for short-term urinary morbidity included patient age, clinical T stage, preimplant IPSS (obtained within 3 weeks of implantation), and prostate ultrasound volume. Treatment parameters included the utilization of neoadjuvant hormonal manipulation, the utilization of moderate dose external beam radiation therapy before implantation, the choice of isotope, the urethral dose, the total implant activity in millicuries, and a variety of dosimetric quality indicators (D(90) and V(100)/V(150)/V(200)). Catheter dependency and the duration of alpha-blocker dependency was also evaluated. On average, 11.2 IPSS surveys were obtained for each patient. RESULTS: One hundred fifty of the 170 patients (88.2%) had the urinary catheter permanently removed on day 0. Only one patient required an urinary catheter for > 5 days. Two patients (1.2%) required a subsequent transurethral resection of the prostate gland because of prolonged obstructive/irritative symptoms. To date, no patient has developed an urinary stricture or urinary incontinence. The IPS score on average peaked at 2 weeks following implantation. This score returned to within 1 point of the antecedent value at a median of 6 weeks and a mean of 13.3 weeks. At 26 and 50 weeks, 85% and 56% of the patients, respectively, continued with alpha-blockers. Of the clinical and treatment parameters evaluated for short-term urinary morbidity, only variants of the IPSS such as the maximum, maximum increase, and preimplant IPSS values correlated with time to return to the referent zone with p < 0.05. CONCLUSION: The return of the IPS score to baseline occurred more rapidly in our series than what has previously been reported. The 1.2% incidence of transurethral resections also compares favorably with the published literature. We believe these results may be due to maintaining the average urethral dose to approximately 115% of the prescribed dose and the prophylactic and long-term use of alpha-blockers

Relationship between the transition zone index of the prostate gland and urinary morbidity after brachytherapy.

Merrick GS, Butler WM, Galbreath RW, et al.

Urology. 2001 Mar; 57(3):524-9.

OBJECTIVES: To evaluate whether urinary symptomatology after prostate brachytherapy is related to the preimplant transition zone index (TZI = transition zone volume/prostate gland volume). METHODS: A total of 170 consecutive patients without a prior history of transurethral resection of the prostate gland (TURP) underwent transperineal ultrasound-guided prostate brachytherapy for clinical T1c-T3a carcinoma of the prostate gland. Prostate gland and transition zone dimensions and volumes were measured by prolate ellipsoid calculation from the static ultrasound images. The relationship between TZI and various measures of urinary dysfunction including normalization of International Prostate Symptom Scores (IPSS), catheter dependency, the need for a subsequent TURP, and the duration of alpha-blocker dependency were evaluated. Additional clinical parameters evaluated included the relationship between TZI and patient age, clinical T stage, prostate ultrasound volume, neoadjuvant hormonal manipulation, and preimplant IPSS. For all indices of urinary dysfunction other than serial IPSS, the median patient follow-up was 89.3 weeks. The median follow-up for serial IPSS evaluations was 37.3 weeks with a mean of 11.2 questionnaires per patient. RESULTS: The mean TZI for the 170 patients was 0.23 +/- 0.06 (prostate gland volume 30.3 +/- 8.7 cm(3), transition zone volume 7.3 +/- 3.6 cm(3)). The TZI correlated with the time for IPSS normalization, the maximum IPSS after brachytherapy, and the maximum increase in IPSS. Conversely, the TZI did not correlate with either catheter dependency or alpha-blocker dependency. Two of 170 patients (1.2%) required a postimplant TURP. The TZI in these 2 patients (0.34) was statistically different (P = 0.016) from the mean. CONCLUSIONS: In prostate brachytherapy patients, the preimplant TZI predicted the need for a subsequent transurethral resection. The TZI also correlated with multiple variants of IPSS. Conversely, TZI did not correlate with either catheter dependency or alpha-blocker dependency

Men's attitudes regarding genetic testing for hereditary prostate cancer risk.

Miesfeldt S, Jones SM, Cohn W, et al.

Urology. 2000 Jan; 55(1):46-50.

OBJECTIVES: Little is known about the attitudes of men unselected for a family history for prostate cancer concerning genetic testing for prostate cancer risk or genetic testing for inherited cancer predisposition. To explore this, we examined the interest in molecular testing for hereditary prostate cancer (HPC) predisposition among a self-selected cohort of 342 men presenting for prostate cancer screening. METHODS: Participants were surveyed concerning their attitudes about DNA testing for HPC predisposition and knowledge of prostate cancer-associated risk factors, including heredity. RESULTS: Of the participants completing the survey, 92% expressed interest in learning about DNA testing, and 89% stated that they would undergo DNA analysis for HPC predisposition, if available. Twenty-eight percent of respondents failed to demonstrate an adequate understanding of the concept of "inherited tendency." The demonstrated level of understanding of this concept did not differ by the respondent's family history, although it varied by race. An interest in learning about or undergoing testing did not vary by race, family history, or demonstrated understanding of the concept of inherited risk. CONCLUSIONS: Among men presenting for routine prostate cancer screening, interest in learning about testing for HPC predisposition and in having such testing performed may be high. The data also provide evidence that, in a population of men unselected for family history, interest in molecular testing for this common, male-specific cancer may parallel the high interest level demonstrated among women in DNA testing for inherited breast and ovarian cancer risk

Elevation of serum levels of urokinase-type plasminogen activator and its receptor is associated with disease progression and prognosis in patients with prostate cancer.

Miyake H, Hara I, Yamanaka K, et al.

Prostate. 1999 May; 39(2):123-9.

BACKGROUND: Several investigators have revealed that urokinase-type plasminogen activator (uPA) and its receptor (uPAR) are overexpressed in serum as well as in tumor tissues in patients with various types of cancer. In this study, we examined whether the serum levels of uPA and uPAR could be used as predictors of the progression and prognosis of prostate cancer. METHODS: Serum levels of uPA and uPAR in 54 healthy controls, 62 patients with benign prostatic hypertrophy (BPH), and 72 patients with prostate cancer were measured by a sandwich enzyme immunoassay. RESULTS: The mean serum levels of uPA and uPAR in patients with prostate cancer were significantly higher than those in healthy controls and patients with BPH. Furthermore, the serum uPA and uPAR levels in prostate cancer patients with metastasis were significantly elevated compared with those in patients without metastasis. Among patients who underwent radical prostatectomy, the serum levels of uPA and uPAR in patients with pathologically organ-confined disease were significantly lower than in those with advanced disease. The overall survival rate of prostate cancer patients with elevated serum levels of either uPA or uPAR, or of both, was significantly lower than that of patients with normal serum levels of uPA and uPAR. CONCLUSIONS: The results of this study indicate that the elevation of serum levels of either uPA or uPAR, or of both, could be used as new predictors of progression and prognosis in patients with prostate cancer

Relevance of oxygen in radiation oncology. Mechanisms of action, correlation to low hemoglobin levels.

Molls M, Stadler P, Becker A, et al.

Strahlenther Onkol. 1998 Dec; 174 Suppl 4:13-6.

At the beginning of this century Schwarz (1909) and Holthusen (1921) observed the influence of oxygen on the radiosensitivity of cells. In 1951 Hollaender et al. described that E. coli needed 3-fold higher radiation doses when treated under anoxic conditions compared to normoxic conditions. This led to the evaluation of the oxygen enhancement ratio (OER) for photons (X-rays), neutrons and heavy ions. It was found that the OER for conventional radiation therapy (RT) with photons is much higher (about 3) than the OER for neutron-RT (only 1.5) or heavy ions. According to a hypothesis free radicals which are produced by radiation are fixed in the presence of oxygen. Radicals are interacting with DNA, macromolecules and membranes. The DNA lesion can be followed by cell death. There is some evidence that tumor cells respond to hypoxia with the expression of a variety of genes coding for oxygen regulated proteins such as c-jun, VEGF or p53. Hypoxia also enhances the genetic instability of tumor cells. Oxygen tensions in malignant tumors can be determined under clinical routine conditions by using a computerized polarographic needle electrode system (Eppendorf, Hamburg, Germany). Several studies in the past years showed that tumors are in general more hypoxic than the surrounding normal tissue and that a marked variability of intra- as well as intertumoral pO2 values exist (for review see Vaupel and Hockel 1998). Moreover, it has been shown in different tumor entities that the oxygenation status influences the local control rate and overall survival. Furthermore, the oxygenation status obtained at one site (primary) is significantly related at other sites (lymph node metastases) in patients with squamous cell carcinoma of the head and neck (SCCHN). In addition, there is a significant correlation between hemoglobin level and tumor oxygenation in patients with SCCHN. There is some evidence that the oxygenation status can be improved by the correction of a low hemoglobin level and consequently, the curative chance might rise

Prevalent decrease of the EGF content in the periurethral zone of BPH tissue induced by treatment with finasteride or flutamide.

Monti S, Sciarra F, Adamo MV, et al.

J Androl. 1997 Sep; 18(5):488-94.

The aim of the present investigation is to verify whether treatment with Finasteride or Flutamide influences the regional distribution of testosterone (T), dihydrotestosterone (DHT), and epidermal growth factor (EGF) in benign prostatic hyperplasia (BPH) tissue. Thirty seven BPH patients were studied: 15 untreated, 9 treated with Flutamide (750 mg/day for 2 months), and 13 treated with Finasteride (5 mg/day for 3 months). Testosterone and DHT were evaluated by radioimmunoassay (RIA) after purification of the extracts on celite columns, and EGF was evaluated by RIA after purification on Sep-pak C18 cartridges in total tissue and in periurethral, subcapsular, and intermediate zone. In the untreated group, T, DHT, and EGF of the periurethral region are higher than those of the subcapsular zone (P < 0.01 for T and P < 0.001 for DHT and EGF). In the Flutamide group, DHT is not modified, T is increased (P = "0.045)," and EGF is decreased in total tissue (P < 0.02) and in the periurethral zone (P < 0.01). In the Finasteride group, T is increased (P < 0.001), and DHT and EGF are decreased (P < 0.001), particularly in the periurethral zone. A positive linear correlation between DHT and EGF is observed in the Finasteride and in the untreated groups. In conclusion, in BPH the production of EGF is a DHT-dependent receptor-mediated function. The reduction of this growth factor during both treatments, associated with a fall of DHT in only the Finasteride group, is particularly evident in the periurethral zone. Since Finasteride reduces prostatic volume, mainly of the periurethral zone, we can speculate that DHT is responsible, either directly or indirectly through growth factors such as EGF for the enlargement of this region and thus responsible for urinary obstruction

The contemporary value of pretreatment prostatic acid phosphatase to predict pathological stage and recurrence in radical prostatectomy cases.

Moul JW, Connelly RR, Perahia B, et al.

J Urol. 1998 Mar; 159(3):935-40.

PURPOSE: We examine the clinical prognostic value of the currently available simple and inexpensive immunoenzymatic prostatic acid phosphatase (PAP) assay for the staging and prognosis of radical prostatectomy cases. MATERIALS AND METHODS: Between February 1, 1990 and May 3, 1996 pretreatment PAP was measured in 295 patients who underwent radical prostatectomy. From February 1, 1990 to May 17, 1992 the Hybritech Tandem-E assay was used in 75 cases, from May 18, 1992 to February 28, 1993 the Abbott EIA assay was used in 49 and from March 1, 1993 to May 3, 1996 the Abbott IMx assay was used in 171. PAP assays were analyzed individually and the results were combined with pretreatment prostate specific antigen (PSA) values to assess the ability to predict organ confined prostate cancer and serological recurrence after radical prostatectomy. RESULTS: PAP testing was not of value for predicting organ confined disease or positive margins. However, this test was useful for predicting the first serological PSA recurrence in the 3 periods (77 to 85% correct) and overall (82% correct, p < 0.001, odds ratio 6.06). The Kaplan-Meier disease-free survival rate at 4 years was 78.8% for men with PAP less than 3 ng./ml. and 38.8% for those with PAP 3 ng./ml. or greater, which was significant when pretreatment PSA was less than 10 ng./ml. (p = "0.047)," 10 ng./ml. or greater (p = "0.012)" and overall (p < 0.001). PAP testing added prognostic information to pretreatment PSA values and it was an independent predictor of recurrence. CONCLUSIONS: The widely available and inexpensive PAP assays of the 1990s are predictors of recurrence after radical prostatectomy. They should be included in future studies of prostate cancer recurrence modeling. However, they do not predict pathological stage or margin status

Are dietary influences on the risk of prostate cancer mediated through the insulin-like growth factor system?

Mucci LA, Tamimi R, Lagiou P, et al.

BJU Int. 2001 Jun; 87(9):814-20.

OBJECTIVES: To investigate whether dietary factors that appear to affect the risk of prostate cancer may be similarly associated with serum levels of insulin-like growth factor 1 (IGF-1). Patients and methods In the context of a case-control study, 112 men were admitted to three teaching hospitals in Athens, Greece, for disorders other than cancer. Sociodemographic data and detailed histories of smoking, alcohol and coffee consumption were recorded. A validated food-frequency questionnaire was administered by an interviewer and serological measurements of IGF-1 and its binding protein-3 conducted. RESULTS: IGF-1 declined significantly by almost 25% among men aged >75 years and there was a small reduction in IGF-1 levels with increased alcohol intake, with a mean (95% confidence interval, CI) change of -1.6 (- 2.2 to -0.9)% for an increment of one drink per day. There was no evidence for an effect of either smoking or coffee consumption on IGF-1 level. Among foods, the consumption of cooked tomatoes was substantially and significantly inversely associated with IGF-1 levels, with a mean (95% CI) change of -31.5 (- 49.1 to -7.9)% for an increment of one serving per day. CONCLUSIONS: The strongest known dietary risk factor for prostate cancer (lycopene deficit, as reflected in a reduced intake of cooked tomatoes) and an important endocrine factor in the aetiology of this disease (IGF-1) seem to be related in a way that suggests that at least one, and perhaps more, exogenous factors in the development of prostate cancer may be mediated through the IGF-1 system

Energy intake and prostate tumor growth, angiogenesis, and vascular endothelial growth factor expression.

Mukherjee P, Sotnikov AV, Mangian HJ, et al.

J Natl Cancer Inst. 1999 Mar 17; 91(6):512-23.

BACKGROUND: A sedentary lifestyle coupled with excessive energy intake is speculated to be a factor associated with increased incidence of prostate cancer. We have investigated the effects of energy intake on prostate tumor growth in experimental animals. METHODS: Two transplantable prostate tumor models, i.e., the androgen-dependent Dunning R3327-H adenocarcinoma in rats and the androgen-sensitive LNCaP human carcinoma in severe combined immunodeficient mice, were studied. R3327-H tumor growth and relevant tumor biomarkers (proliferation index, apoptosis [programmed cell death], microvessel density, and vascular endothelial growth factor [VEGF] expression) were compared in ad libitum fed control rats, ad libitum fed castrated rats, and groups restricted in energy intake by 20% or 40%. A second set of experiments involving both tumor models examined tumor growth in ad libitum fed rats or in animals whose energy intake was restricted by 30% using three different methods, i.e., total diet restriction, carbohydrate restriction, or lipid restriction. All P values are two-sided. RESULTS: R3327-H tumors were smaller in energy-restricted or castrated rats than in control rats (P

Lipoxygenase inhibition in prostate cancer.

Myers CE, Ghosh J.

Eur Urol. 1999; 35(5-6):395-8.

Multiple population-based studies show an increased risk of prostate cancer in populations that consume large amounts of animal fat. However, the molecular mechanisms linking dietary fat to prostate cancer biology remain obscure. Animal fats are typically rich sources of arachidonic acid and this fatty acid is converted to a wide range of powerful compounds including leukotrienes, prostaglandins, etc. We have shown that PC3 and LNCaP convert arachidonic acid to the 5-lipoxygenase product, 5-HETE. When the formation of 5-HETE is blocked, human prostate cancer cells enter apoptosis in less than 1 h and are dead within 2 h. Exogenous 5-HETE can rescue these cancer cells. These findings indicate that 5-HETE is a potent survival factor for human prostate cancer cells

Stimulatory effects of insulin and insulin-like growth factor I on migration and tube formation by vascular endothelial cells.

Nakao-Hayashi J, Ito H, Kanayasu T, et al.

Atherosclerosis. 1992 Feb; 92(2-3):141-9.

The effects of insulin and insulin-like growth factor I (IGF-I) on migration, proliferation and tube-forming activity of endothelial cells were investigated, by using bovine carotid artery endothelial cells. Migration was assayed by a filter membrane technique and tube formation was assayed by a quantitative angiogenesis in vitro model which we have recently developed. In this model, endothelial cells are cultured between two layers of type I collagen gel and become organized into tube-like structures which mimic capillaries in vivo ultrastructurally. Insulin (50-1000 microunits/ml) and IGF-I (10-200 ng/ml) significantly stimulated migration of endothelial cells in a dose-dependent manner with a maximal stimulation of 3.0-fold at 1000 microunits/ml for insulin and 3.8-fold at 200 ng/ml for IGF-I (P less than 0.01). Insulin at concentrations up to 1000 microunits/ml and IGF-I up to 100 ng/ml did not affect proliferation of endothelial cells. When insulin or IGF-I was added in culture medium on collagen gels, tube-forming activity of endothelial cells was markedly stimulated. The specific lengths of tubes significantly increased with the increase in insulin concentration from 25 to 100 microunits/ml (P less than 0.01). At 100 microunits/ml, the stimulation was 1.77-fold (P less than 0.01). IGF-I (1-100 ng/ml) also stimulated the elongation of tubes dose-dependently with a maximal stimulation of 1.96-fold at 100 ng/ml (P less than 0.01). Thus, insulin and IGF-I at pathophysiological concentrations stimulate migration and tube-forming activity of endothelial cells, suggesting that these polypeptides may stimulate repair of endothelial injury in cases such as atherosclerosis and may act as a stimulator of angiogenesis

The role of transrectal ultrasound-guided biopsy-based staging, preoperative serum prostate-specific antigen, and biopsy Gleason score in prediction of final pathologic diagnosis in prostate cancer.

Narayan P, Gajendran V, Taylor SP, et al.

Urology. 1995 Aug; 46(2):205-12.

OBJECTIVES. To evaluate the role of ultra sound-guided systematic and lesion-directed biopsies, biopsy gleason score, preoperative serum prostate-specific antigen (PSA) as three objective and reproducible variables to provide a reliable combination in preoperative identification of risk of extraprostatic extension in patients with clinically localized prostate cancer. METHODS. The case records of 813 patients who underwent radical prostatectomy for clinically localized prostate cancer were analyzed. All had multiple systematic biopsies, two to three from each lobe, in addition to lesion-directed biopsies. Additionally, biopsies were done on seminal vesicles (SVs), if abnormal. Based on biopsy results, patients were classified as having stage B1 (T2a-T2b) or B2 (T2c) disease, depending on whether biopsies from one or both lobes were positive and stage C (T3) if there was evidence of SV involvement by biopsy of biopsies from areas of extracapsular extension as seen on transrectal ultrasound (TRUS) were positive. Logistic regression analyses with log likelihood chi-square test was used to define the correlation between individual as well as combination of preoperative variables and pathologic stage. RESULTS. On final pathologic examination, 473 (58%) patients had organ-confined disease, 188 (23%) had extracapsular extension (ECE), with or without positive surgical margins, and 72 (9%) had SV involvement. Eighty (10%) patients had pelvic lymph node metastases. Biopsy-based staging was superior to clinical staging in predicting final pathologic diagnosis. Logistic regression analyses revealed that the combination of biopsy-based stage, preoperative serum PSA, and biopsy Gleason score provided the best prediction of final pathologic stage. Probability plots constructed with these data can provide significant information on risk of extraprostatic extension in individual patients. CONCLUSIONS. This study demonstrates that TRUS-guided systematic biopsy in combination with preoperative serum PSA and biopsy Gleason score may provide a cost-effective approach for management decisions and prognostication in patients with prostate cancer

Transrectal ultrasound guided prostatic nerve blockade eases systematic needle biopsy of the prostate.

Nash PA, Bruce JE, Indudhara R, et al.

J Urol. 1996 Feb; 155(2):607-9.

PURPOSE: We assessed the effect of transrectal ultrasound guided prostatic nerve blockade on the discomfort associated with systematic needle biopsy of the prostate. MATERIALS AND METHODS: A prospective randomized double-blind study was performed of 64 patients requiring systematic biopsy of the prostate. Patients were randomly assigned to receive an injection of 5 ml. 1% lidocaine or 5 ml. saline (0.9% sodium chloride) at the vascular pedicle on 1 side of the prostate only. They were then asked to score the severity of discomfort of the injection and subsequent biopsies on each side. RESULTS: Mean pain scores were significantly lower on the side with than the side without lidocaine injection (1.6 +/- 0.9 versus 2.4 +/- 1.2, p < 0.0001) and not significantly different when saline was injected (2.9 +/- 1.2 versus 3.0 +/- 1.1, p = "0.52)." Pain scores were significantly different when the lidocaine injected side was compared to the saline solution injected side (p < 0.0001) but the difference was not significant between the noninjected sides of the 2 groups (p = "0.076)." Of the patients in the lidocaine group 68% reported that they would prefer to undergo biopsy with the injection compared to only 41% in the placebo group (p = "0.037)." During the study no patient in either group had any adverse effect from the injection. CONCLUSIONS: Transrectal ultrasound guided nerve blockade before prostatic biopsy results in a more comfortable procedure for the patient

Preneoplastic prostate lesions: an opportunity for prostate cancer prevention.

Nelson WG, De Marzo AM, Deweese TL, et al.

Ann N Y Acad Sci. 2001 Dec; 952:135-44.

Environmental factors, especially the diet, play a prominent role in the epidemic of prostate cancer (PCA), in the United States. Many candidate dietary components have been proposed to influence human prostatic carcinogenesis, including fat, calories, fruits and vegetables, anti-oxidants, and various micronutrients, but the specific roles dietary agents play in promoting or preventing PCA remain controversial. We have collected evidence to suggest that GSTP1, the gene encoding the pi-class glutathione S-transferase (GST), may serve a "caretaker" function for prostatic cells. Although GSTP1 can be detected in normal prostatic epithelium, in almost all PCA cases, PCA cells fail to express GSTP1 polypeptides, and lack of GSTP1 expression most often appears to be the result of somatic "CpG island" DNA methylation changes. Loss of GSTP1 function also appears to be characteristic of prostatic epithelial neoplasia (PIN) lesions, thought to represent PCA precursors. We have recently learned that a new candidate early PCA precursor lesion, proliferative inflammatory atrophy (PIA), characterized by proliferating prostatic cells juxtaposed to inflammatory cells, contains epithelial cells that express high levels of GSTP1. These findings have formed the basis for a new model of prostatic carcinogenesis, in which prostatic cells in PIA lesions, subjected to a barrage of inflammatory oxidants, induce GSTP1 expression as a defense against oxidative genome damage. When cells with defective GSTP1 genes appear amongst the PIA cells, such cells become vulnerable to oxidants and electrophiles that inflict genome damage that tends to promote neoplastic transformation to PIN and PCA cells. Subsequently, PIN and PCA cells with defective GSTPI genes remain vulnerable to similar stresses tending to promote malignant progression. This new model for prostatic carcinogenesis has implications for the design of new prostate cancer prevention strategies. Rational prevention approaches might include: (i) restoration of GSTPI expression via treatment with inhibitors of CpG methylation, (ii) compensation for inadequate GSTPI activity via treatment with inducers of general GST activity, and (iii) abrogation of genome-damaging stresses via avoidance of exogenous carcinogens and/or reduction of endogenous carcinogenic (particularly oxidant) stresses

Association between coronary heart disease and cancers of the breast, prostate, and colon.

Neugut AI, Rosenberg DJ, Ahsan H, et al.

Cancer Epidemiol Biomarkers Prev. 1998 Oct; 7(10):869-73.

Coronary heart disease (CHD) and cancers of the breast, prostate, and colon are more common in industrialized countries than in the developing world, and to some degree, these conditions appear to share risk factors. To investigate whether there is an association between these cancers and a prior history of CHD, a hospital-based case-control study was conducted at Columbia-Presbyterian Medical Center in New York. The study was based on 252 breast cancer cases, 256 colorectal cancer cases, and 322 benign surgical controls, all of whom underwent biopsy or surgery between January 1989 and December 1992, and on 319 prostate cancer cases and 189 benign prostatic hypertrophy controls diagnosed between January 1984 and December 1986 (prior to widespread use of prostate-specific antigen screening). Medical records were reviewed on each, focusing on the preoperative anesthesia and surgical clearances. No association was found between a history of CHD and breast or colorectal cancer, but an elevated risk was found for prostate cancer (odds ratio, 2.00; 95% confidence interval, 1.18-3.39), using unconditional logistic regression with adjustment for appropriate confounders. No association was found between cigarette smoking and any of the three cancers. Aspirin use was protective for colorectal cancer (odds ratio, 0.35; 95% confidence interval, 0.17-0.73) but had no association with breast or prostate cancer. The study suggests that individuals with CHD are at elevated risk for prostate cancer but not breast or colorectal cancer. Etiological risk factors associated with CHD should be investigated with regard to prostate cancer. Patients with CHD may represent a high-risk group for prostate cancer and potential future targets for prostate cancer screening interventions

Role of eicosanoids in prostate cancer progression.

Nie D, Che M, Grignon D, et al.

Cancer Metastasis Rev. 2001; 20(3-4):195-206.

Metabolism of arachidonic acid through cyclooxygenase, lipoxygenase, or P450 epoxygenase pathways leads to the formation of various bioactive eicosanoids. In this review, we discuss alterations in expression pattern of eicosanoid-generating enzymes found during prostate tumor progression and expound upon their involvement in tumor cell proliferation, apoptosis, motility, and tumor angiogenesis. The expression of cyclooxygenase-2, 12-lipoxygenase, and 15-lipoxygenase-1 are up-regulated during prostate cancer progression. It has been demonstrated that inhibitors of cyclooxygenase-2, 5-lipoxygenase and 12-lipoxygenase cause tumor cell apoptosis, reduce tumor cell motility and invasiveness, or decrease tumor angiogenesis and growth. The eicosanoid product of 12-lipoxygenase, 12(S)-hydroeicosatetraenoic acid, is found to activate Erkl/2 kinases in LNCaP cells and PKCalpha in rat prostate AT2.1 tumor cells. Overexpression of 12-lipoxygenase and 15-lipoxygenase-1 in prostate cancer cells stimulate prostate tumor angiogenesis and growth, suggesting a facilitative role for 12-lipoxygenase and 15-lipoxygenase-1 in prostate tumor progression. The expression of 15-lipoxygenase-2 is found frequently to be lost during the initiation and progression of prostate tumors. 15(S)-hydroxyeicosatetraenoic acid, the product of 15-lipoxygenase-2, inhibits proliferation and causes apoptosis in human prostate cancer cells, suggesting an inhibitory role for 15-lipoxygenase-2 in prostate tumor progression. The regulation of prostate cancer progression by eicosanoids, in either positive or negative ways, provides an exciting possibility for management of this disease

Why do men refuse or attend population-based screening for prostate cancer?

Nijs HG, Essink-Bot ML, DeKoning HJ, et al.

J Public Health Med. 2000 Sep; 22(3):312-6.

BACKGROUND: The aims of this study were to investigate the motives for refusing or attending population-based screening for prostate cancer, in relation to various background characteristics. METHODS: The present study is part of the European Randomized Study of Screening for Prostate Cancer (ERSPC), and took place in 1995-1996. Men aged 55-75 years were invited using the Rotterdam population registry (100 per cent coverage), of whom 42 per cent gave written informed consent. These men were randomized to receive either determination of prostate specific antigen (PSA), digital rectal examination (DRE), transrectal ultrasound (TRUS) and biopsy on indication (screening group), or no screening (control group). To 626 consecutive men of the screening group a questionnaire was sent before the screening. To 500 randomly selected refusers (no written informed consent) a similar questionnaire was sent, followed by two reminders. In both refusers and attenders we addressed motives, knowledge of prostate cancer, attitudes towards screening, background characteristics and urological complaints (American Urological Association symptom index, AUA7). RESULTS: Response rates for questionnaires were 48 per cent in refusers and 99 per cent in attenders. Main reported motives for refusing were absence of urological complaints (57 per cent) and anticipated pain or discomfort (18 per cent). Main reported motives for attending were personal benefit (82 per cent), contribution to science (49 per cent) and presence of urological complaints (25 per cent). Compared with attenders, refusers were slightly and significantly older, less often married and had a lower level of education; they had less knowledge about prostate cancer and a less positive attitude towards screening; they had worse general health but fewer urological complaints (AUA7 median 2 versus 4, p < 0.001). CONCLUSION: In refusing or attending population-based prostate cancer screening, urological complaints but also knowledge, attitudes and sociodemographic factors seem to play a role. Therefore, the approach of the general population should be carefully considered

[Nerve-sparing radical retropubic prostatectomy. Results of a patient survey].

Noldus J, Michl U, Graefen M, et al.

Urologe A. 2001 Mar; 40(2):102-6.

Improved selection criteria have led to an increasing number of nerve-sparing radical retropubic prostatectomies (RRP) in patients with clinically localized prostate cancer. The results based on patient questionnaires regarding postoperative erectile function are described. Between January 1992 and March 1999, 366 patients (mean age: 62.5 years) underwent uni- or bilateral nerve-sparing RRP at our institution. For evaluation of postoperative patient-reported rates of sexual and erectile function, a questionnaire was used after a follow-up of at least 12 months. Data of five operation periods were analyzed. The results of the unilateral procedure for the five operation periods revealed consistent rates of 13-29% for erections sufficient for intercourse. Bilateral nerve-sparing procedures were almost exclusively performed in periods 3 to 5; only four patients from period 2 underwent the bilateral procedure. The rates of intercourse-sufficient erections were 25% (period 2), 61% (period 3), 50% (period 4), and 52% (period 5), respectively. The results of the unilateral procedure were disappointing. However, the bilateral nerve-sparing method achieved much better results inasmuch as about 50% of the patients reported recovery of erections sufficient for sexual intercourse

Celecoxib as adjunctive therapy for treatment of colorectal cancer.

North GL.

Ann Pharmacother. 2001 Dec; 35(12):1638-43.

OBJECTIVE: To describe the role of celecoxib as adjunctive therapy in the treatment of familial adenomatous polyposis (FAP), an inherited autosomal dominant predisposition syndrome for colorectal cancer. DATA SOURCES: Literature was evaluated through MEDLINE search (1995-March 2000) and through secondary sources, using the search terms celecoxib, cyclooxygenase-2 inhibitors, and familial adenomatous polyps. DATA SYNTHESIS: Observational studies have found a decreased rate of colorectal cancer in people who regularly took aspirin or other nonsteroidal antiinflammatory drugs (NSAIDs). The Food and Drug Administration granted accelerated approval in December 1999 for the NSAID celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, for adjunctive therapy in patients with FAP, based on a six-month, randomized, controlled clinical trial. CONCLUSIONS: Aspirin and other NSAIDs reduce the incidence of colorectal cancer in the general population. Limited clinical studies in patients with FAP using nonaspirin NSAIDs have shown a reduction in polyp burden. A current clinical trial using celecoxib has also shown a reduction in polyp burden in patients with FAP. The long-term clinical impact of using a selective COX-2 inhibitor is not known, since celecoxib has not been studied beyond six months in patients with FAP. By reducing the polyp burden in FAP patients, celecoxib may be useful as adjunctive chemotherapy, in addition to routine endoscopic surveillance and surgery

Correlation of clinical stage, serum prostatic acid phosphatase and preoperative Gleason grade with final pathological stage in 275 patients with clinically localized adenocarcinoma of the prostate.

Oesterling JE, Brendler CB, Epstein JI, et al.

J Urol. 1987 Jul; 138(1):92-8.

The usefulness of clinical stage, serum prostatic acid phosphatase and preoperative Gleason grade in predicting final pathological stage in patients with adenocarcinoma of the prostate remains controversial. To determine the predictive value of these 3 preoperative variables we reviewed 275 patients with clinically localized disease who were treated between April 1982 and February 1986. All patients were examined preoperatively and subsequently were operated upon by 1 urologist. Serum prostatic acid phosphatase was determined in all patients by the Roy method using thymolphthalein monophosphate as the substrate. The Gleason grade of each prostatic biopsy specimen was determined preoperatively by 1 pathologist, who also examined the final pathological specimen with respect to capsular penetration, and seminal vesicle and pelvic lymph node involvement. Using logistic regression analysis with the likelihood ratio chi-square test, clinical stage and Gleason grade had a direct correlation with capsular penetration (p less than 0.0001 and less than 0.0001, respectively), seminal vesicle involvement (p less than 0.0001 and less than 0.0001, respectively) and positive lymph nodes (p less than 0.0001 and less than 0.0002, respectively). Within the normal range of values (0.0 to 0.8 IU/l.) serum prostatic acid phosphatase correlated directly with capsular penetration (p less than 0.003) and seminal vesicle involvement (p less than 0.01) but not with lymph node involvement (p equals 0.08). Again with logistic regression analysis we determined that the best predictors of final pathological stage are not individual variables but models that use combinations of preoperative variables. The models generated are as follows: capsular penetration--serum prostatic acid phosphatase and Gleason grade (p less than 0.00001), seminal vesicle involvement--clinical stage and Gleason grade (p less than 0.00001), and lymph node involvement--clinical stage and Gleason grade (p less than 0.00001). With these models probability plots have been constructed so that the final pathological stage in patients with clinically localized prostatic cancer can be predicted preoperatively

The use of prostate-specific antigen in staging patients with newly diagnosed prostate cancer.

Oesterling JE, Martin SK, Bergstralh EJ, et al.

JAMA. 1993 Jan 6; 269(1):57-60.

OBJECTIVE--To assess the need for obtaining radionuclide bone scans in the staging evaluation of patients with newly diagnosed, untreated prostate cancer. This determination was made on the basis of presenting prostate-specific antigen (PSA) levels. DESIGN--Retrospective review. PARTICIPANTS--The medical records of 2064 consecutive patients with prostate cancer who were evaluated at the Mayo Clinic in Rochester, Minn, from January 1989 through December 1990 were reviewed. Eight hundred fifty-two patients with newly diagnosed, untreated disease and a serum PSA concentration less than 20.0 micrograms/L at presentation comprised the study population. MAIN OUTCOME MEASURE--The rate of false-negative results associated with using the serum PSA concentration to predict bone scan findings. RESULTS--Five hundred sixty-one patients had a serum PSA concentration of 10.0 micrograms/L or less; only three had an abnormal bone scan result, and one had an indeterminate scan result. Of the 467 men whose PSA value was 8.0 micrograms/L or less (two times the upper limit of the reference range), none had bone scan results that were either abnormal or indeterminate. The rate of false-negative results for an abnormal bone scan result was 0% with a serum PSA value of 8.0 micrograms/L or less and 0.5% with a cutoff level of 10.0 micrograms/L. The 95% upper confidence limit for the rate of false-negative results for all PSA cutoff levels less than 20.0 micrograms/L was less than 2%. CONCLUSIONS--For patients with newly diagnosed, untreated prostate cancer, a serum PSA concentration of 10.0 micrograms/L or less, and no skeletal symptoms, a staging radionuclide bone scan does not appear to be necessary. This clinical situation applies to 39% of all patients presenting with newly diagnosed prostate cancer. Since more than 130,000 new cases are diagnosed each year, approximately 50,000 patients are affected annually. If the $600 staging bone scan were eliminated for these patients, a significant economic savings to the health care system in this country would be effected

Preoperative predictors for organ-confined disease in Japanese patients with stage T1c prostate cancer.

Ogawa O, Egawa S, Arai Y, et al.

Int J Urol. 1998 Sep; 5(5):454-8.

BACKGROUND: In order to define the characteristics of patients with clinical stage T1c prostate cancer in Japan, clinicopathologic data obtained from patients treated by radical prostatectomy were reviewed. METHODS: Fifty-four stage T1c cancers were evaluated for tumor volume, Gleason grade, tumor location and pathologic stage from prostatectomy specimens in association with preoperative clinical parameters. RESULTS: The mean tumor volume was 3.94 mL (range, 0.07 to 33.4 mL), and 11 of the 54 tumors had a tumor volume of less than 0.5 mL. Thirty-two tumors (59%) were organ-confined, while 7 (13%) involved the seminal vesicle and/or regional lymph nodes. Multivariate logistic regression analysis of the pretreatment variables, including age, pretreatment PSA level, prostate volume, biopsy grade, and number of cancer-positive cores revealed that the serum PSA level and the number of cancer-positive biopsy cores were independent factors to predict organ-confined tumors (P = 0.036 and 0.044, respectively). For T1c cancer with less than 4 cancer-positive biopsy cores, the sensitivity and specificity for predicting organ-confined tumors were 90% and 70%, with a cut-off value of 17 ng/mL for the serum PSA level. CONCLUSION: The clinicopathologic features of T1c prostate cancer in Japanese patients were similar to those of whites reported elsewhere. Both serum PSA levels and the number of positive biopsy cores may be useful as pretreatment parameters to identify patients with the potential to benefit from radical treatment

Cryosurgery.

Onik G.

Crit Rev Oncol Hematol. 1996 May; 23(1):1-24.

Image-guided prostate cryosurgery: state of the art.

Onik G.

Cancer Control. 2001 Nov; 8(6):522-31.

BACKGROUND: Cryosurgery was first used to treat prostate cancer in the early 1970s but it was not until 1993, when the results from percutaneous ultrasound-guided cryosurgery were published, that the potential advantages of this treatment became apparent. Changes in equipment and techniques have improved the results of cryosurgery, in both tumor control and lower morbidity. METHODS: The author has reviewed data of his own and those of others concerning the changes in techniques employed and outcomes from prostate cryosurgery. RESULTS: Ultrasound-guided percutaneous transperineal placement of the cryoprobes allows monitoring of freezing in real time. Monitoring temperature at critical locations, separating the rectum and prostate by saline injection, and using argon gas rather than liquid nitrogen-based equipment have improved results and lowered complication rates. The technique produces outcomes similar to those obtained with brachytherapy and three-dimensional conformal radiation therapy. CONCLUSIONS: Advantages of cryosurgery include the ability to re-treat patients without added morbidity and to treat salvage postradiation patients with acceptable results and morbidity. The recent demonstration that "nerve-sparing" cryosurgery is possible suggests that cryosurgery may be used more often

Physical activity releases prostate-specific antigen (PSA) from the prostate gland into blood and increases serum PSA concentrations.

Oremek GM, Seiffert UB.

Clin Chem. 1996 May; 42(5):691-5.

Determination of prostate-specific antigen (PSA) is an established tool in detecting prostate cancer. However, the effect of physical activity on the PSA concentration in serum is controversial. We measured serum concentrations of PSA and prostatic acid phosphatase (PAP) in 301 healthy outpatients before and after they performed standardized exercise. Immediately after 15 min of exercise on a bicycle ergometer, their serum PSA concentrations increased by as much as threefold. The increase was age dependent and correlated to the PSA concentration before exercise. This increase was evident in both the free and complexed fractions of PSA. The amount of PSA secreted into blood depends on the volume of the prostate, whereas productivity of the prostate epithelium remains constant or increases slightly with age. We present cutoff values for clinical use. PAP was also increased, but to a lesser extent. The PSA and PAP secretion mechanisms differ. Our data suggest that extensive physical activity should be avoided before blood sampling for diagnostic purposes and, in case of an increase, the PSA concentration should be controlled after an exercise test

Observations on pathology trends in 62,537 prostate biopsies obtained from urology private practices in the United States.

Orozco R, O'Dowd G, Kunnel B, et al.

Urology. 1998 Feb; 51(2):186-95.

OBJECTIVES: To evaluate pathology trends of 62,537 first-time prostate needle-core biopsies submitted by office-based urologists, processed at a single pathology laboratory. METHODS: Prostate biopsy cases obtained over a 2-year period were assessed. Patient information included age, digital rectal examination (DRE) status, and prostate-specific antigen (PSA) serum levels. Biopsy pathology results included the number of tissue samples per case, Gleason score, presence of Gleason grades 4 or 5, percent of biopsy length with evidence of cancer, number of samples with cancer per biopsy, and determination of DNA ploidy status using microspectrophotometry. RESULTS: Adenocarcinoma, suspicious lesions, and isolated high-grade prostatic intraepithelial neoplasia (PIN) were diagnosed in 38.3%, 2.9%, and 4.1% of the biopsies, respectively. For each serum PSA and age range assessed, the positive biopsy rate and incidence of critical pathologic features increased consistently. The average percentage of biopsy length with evidence of tumor, the percentage of cases with Gleason grades 4 or 5, and the percentage of cases with an abnormal DNA ploidy all decreased significantly over the 2-year period (P

The distribution of secondary growths in cancer of the breast. 1889.

Paget S.

Cancer Metastasis Rev. 1989 Aug; 8(2):98-101.

Prevention of spinal bone loss by potassium citrate in cases of calcium urolithiasis.

Pak CY, Peterson RD, Poindexter J.

J Urol. 2002 Jul; 168(1):31-4.

PURPOSE: We determine if potassium citrate treatment stabilizes spinal bone density among patients with recurrent calcium oxalate nephrolithiasis. MATERIALS AND METHODS: We studied a group of 16 men and 5 women with stones taking potassium citrate from 11 to 120 months. They represented all patients from the Stone Clinic who took potassium citrate alone for at least 11 months. L2-L4 bone mineral density data before and after potassium citrate treatment were retrieved retrospectively and analyzed. RESULTS: In the combined group L2-L4 bone mineral density increased significantly by 3.1% over mean duration of 44 months. Z score, corrected for age matched normal values, increased significantly by 3.8%. Urinary pH, citrate and potassium increased significantly during treatment but urinary calcium did not change. CONCLUSIONS: Potassium citrate, a commonly used drug for the prevention of recurrent nephrolithiasis, may avert age dependent bone loss. Spinal bone density increased in most patients when it normally decreases

Periprostatic nerve blockade for transrectal ultrasound guided biopsy of the prostate: a randomized, double-blind, placebo controlled study.

Pareek G, Armenakas NA, Fracchia JA.

J Urol. 2001 Sep; 166(3):894-7.

PURPOSE: We performed a randomized, double-blind, placebo controlled study to assess the safety and efficacy of periprostatic anesthesia administration during prostate biopsy. MATERIALS AND METHODS: From May to November 2000 transrectal ultrasound guided prostate biopsy was performed in 132 consecutive men due to an abnormal digital rectal examination and/or elevated prostate specific antigen. During biopsy 66 patients each were randomly assigned to receive an injection of 1% lidocaine or normal saline. Immediately after biopsy the pain score was recorded independently by patients and the physician using a 10-point linear scale. In addition, patients were given a descriptive questionnaire to be completed at home and mailed back within 2 weeks of biopsy. RESULTS: Mean patient perceived pain scores plus or minus standard deviation of 2.7 +/- 0.21 in the lidocaine and 4.7 +/- 0.26 in the saline groups were significantly different (p

Anastomotic strictures following radical prostatectomy: insights into incidence, effectiveness of intervention, effect on continence, and factors predisposing to occurrence.

Park R, Martin S, Goldberg JD, et al.

Urology. 2001 Apr; 57(4):742-6.

OBJECTIVES: To examine the incidence, effectiveness of intervention, effect on continence, and factors predisposing to the occurrence of anastomotic strictures following radical retropubic prostatectomy. METHODS: Between January 1994 and June 1999, 753 radical retropubic prostatectomies were performed by a single surgeon. Anastomotic strictures were managed by dilatation followed by a self-catheterization regimen. Dilatations were repeated unless more than three dilatations were required over a 9-month interval. A control group representing a randomly selected group of men who did not develop anastomotic strictures was identified. The largest width of the midline vertical abdominal scar was measured. RESULTS: Of the 753 radical retropubic prostatectomies, 36 (4.8%) developed an anastomotic stricture. The mean time interval between the surgical procedure and diagnosis of the stricture was 4.22 months. Of the 26 cases of anastomotic strictures with at least 1-year follow-up, 24 (92.3%) were managed successfully by dilatations alone. No baseline characteristics before surgery were associated with the development of a stricture. The maximal scar width was the only factor that was associated with the development of a stricture in this study. Men with a maximal scar of greater than 10 mm were eight times more likely to develop strictures than men with smaller scars. The percentage of men who required protective pads 1 year following radical retropubic prostatectomy in the control and stricture groups was 12.5% and 46.2%, respectively. CONCLUSIONS: Anastomotic strictures are relatively rare following radical prostatectomy and have a negative effect on the development of continence. Most men are successfully managed with dilatations alone. The development of anastomotic strictures in some men appears to be related to a generalized hypertrophic wound-healing mechanism

Combined use of computed tomography coronary calcium scores and C-reactive protein levels in predicting cardiovascular events in nondiabetic individuals.

Park R, Detrano R, Xiang M, et al.

Circulation. 2002 Oct 15; 106(16):2073-7.

BACKGROUND: The South Bay Heart Watch is a prospective cohort study designed to appraise the value of coronary calcium and risk factors for predicting outcomes in asymptomatic adults. Two factors that may be related to subsequent cardiovascular events are coronary calcium (CAC, a manifestation of subclinical atherosclerosis) and high-sensitivity C-reactive protein (CRP, a measure of chronic inflammation). METHODS AND RESULTS: Between December 1990 and December 1992, 1461 participants without coronary heart disease underwent baseline risk factor screening, computed tomography for CAC, and measurement of CRP. Participants were followed up for 6.4+/-1.3 years. Cox regression analyses were conducted for the 967 nondiabetics with CRP levels < or ="10" mg/L to estimate the risk-factor-adjusted relative risks of CAC and CRP for the occurrence of (1) nonfatal myocardial infarction (MI) or coronary death and (2) any cardiovascular event (MI, coronary death, coronary revascularization, or stroke). CAC was a predictor of both end points (P4.05 mg/L) indicated that there was increasing risk with increasing calcium and CRP. Relative risks for the medium-calcium/low-CRP risk group to high-calcium/high-CRP risk group ranged from 1.8 to 6.1 for MI/coronary death (P=0.003) and 2.8 to 7.5 for any cardiovascular event (P

The use of prostate specific antigen, clinical stage and Gleason score to predict pathological stage in men with localized prostate cancer.

Partin AW, Yoo J, Carter HB, et al.

J Urol. 1993 Jul; 150(1):110-4.

Clinical stage, Gleason score and serum prostate specific antigen (PSA) levels are used separately to predict pathological stage in patients with localized prostate cancer. Because the degree of tumor differentiation has a profound influence on the expression of serum PSA, serum PSA levels alone do not reflect tumor burden accurately. To overcome this obstacle we tested these 3 variables alone and in combinations as predictors of final pathological stage in 703 men with clinically localized prostate cancer at our institution. All patients were assigned a clinical stage by 1 urologist. The Gleason score was determined from preoperative needle biopsy and serum PSA levels were measured on an ambulatory basis. Final pathological stage was determined to be either organ confined, established capsular penetration, seminal vesicle involvement or lymph node involvement. Logistic regression analysis with the likelihood ratio chi-square test determined that serum PSA, Gleason score and clinical stage all predicted final pathological stage well. The results were improved with combinations of the 3 variables (serum PSA, Gleason score and clinical stage) and the combination provided the best separation. From these analyses probability plots and nomograms have been constructed to assist urologists in the preoperative prediction of final pathological stage for patients with clinically localized prostate cancer

Combination of prostate-specific antigen, clinical stage, and Gleason score to predict pathological stage of localized prostate cancer. A multi-institutional update.

Partin AW, Kattan MW, Subong EN, et al.

JAMA. 1997 May 14; 277(18):1445-51.

OBJECTIVE: To combine the clinical data from 3 academic institutions that serve as centers of excellence for the surgical treatment of clinically localized prostate cancer and develop a multi-institutional model combining serum prostate-specific antigen (PSA) level, clinical stage, and Gleason score to predict pathological stage for men with clinically localized prostate cancer. DESIGN: In this update, we have combined clinical and pathological data for a group of 4133 men treated by several surgeons from 3 major academic urologic centers within the United States. Multinomial log-linear regression was performed for the simultaneous prediction of organ-confined disease, isolated capsular penetration, seminal vesicle involvement, or pelvic lymph node involvement. Bootstrap estimates of the predicted probabilities were used to develop nomograms to predict pathological stage. Additional bootstrap analyses were then obtained to validate the performance of the nomograms. PATIENTS AND SETTINGS: A total of 4133 men who had undergone radical retropubic prostatectomy for clinically localized prostate cancer at The Johns Hopkins Hospital (n=3116), Baylor College of Medicine (n=782), and the University of Michigan School of Medicine (n=235) were enrolled into this study. None of the patients had received preoperative hormonal or radiation therapy. OUTCOME MEASURES: Simultaneous prediction of organ-confined disease, isolated capsular penetration, seminal vesicle involvement, or pelvic lymph node involvement using updated nomograms. RESULTS: Prostate-specific antigen level, TNM clinical stage, and Gleason score contributed significantly to the prediction of pathological stage (P

Contemporary update of prostate cancer staging nomograms (Partin Tables) for the new millennium.

Partin AW, Mangold LA, Lamm DM, et al.

Urology. 2001 Dec; 58(6):843-8.

OBJECTIVES: We previously presented nomograms combining preoperative serum prostate-specific antigen (PSA), clinical (TNM) stage, and biopsy Gleason score to provide the likelihood of various final pathologic stages at radical retropubic prostatectomy. The data for the original nomograms were collected from men treated between 1982 and 1996. During the past 10 years, the stage at presentation has shifted, with more men presenting with Stage T1c, Gleason score 5 to 6, and serum PSA levels less than 10.0 ng/mL. In this work, we update the "Partin Tables" with a more contemporary cohort of men treated since 1994 and with revised PSA and Gleason categories. METHODS: Multinomial log-linear regression analysis was used to estimate the likelihood of organ-confined disease, extraprostatic extension, seminal vesicle or lymph nodal status from the preoperative PSA stratified as 0 to 2.5, 2.6 to 4.0, 4.1 to 6.0, 6.1 to 10.0, and greater than 10 ng/mL, clinical (AJCC-TNM, 1992) stage (T1c, T2a, T2b, or T2c), and biopsy Gleason score stratified as 2 to 4, 5 to 6, 3 + 4 = 7, 4 + 3 = 7, or 8 to 10 among 5079 men treated with prostatectomy (without neoadjuvant therapy) between 1994 and 2000 at Johns Hopkins Hospital. The average age was 58 years. RESULTS: In this cohort, more than 60% had T1c, more than 75% had Gleason score of 6, more than 70% had PSA greater than 2.5 and less than 10.0 ng/mL, and more than 60% had organ-confined disease. Nomograms of the robust estimated likelihoods and 95% confidence intervals were developed from 1000 bootstrap analyses. The probability of organ-confined disease improved across the groups, and further stratification of the Gleason score and PSA level allowed better differentiation of individual patients. CONCLUSIONS: These updated "Partin Tables" were generated to reflect the trends in presentation and pathologic stage for men newly diagnosed with clinically localized prostate cancer at our institution. Clinicians can use these nomograms to counsel individual patients and help them make important decisions regarding their disease

Cancer-related behavior of vitamin supplement users.

Patterson RE, Neuhouser ML, White E, et al.

Cancer Epidemiol Biomarkers Prev. 1998 Jan; 7(1):79-81.

Epidemiological studies suggest that certain vitamin supplements may reduce the risk of some cancers. However, observational studies can be compromised by confounding, because supplement use is related to other factors that affect cancer risk. The purpose of this paper is to identify cancer-related behaviors that could confound studies of the associations between vitamin supplement use and cancer risk. Data are from a random digit dial survey to monitor cancer risk behavior in adults in Washington State (n = 1449). Unconditional logistic regression was used to examine whether regular supplement users were more likely to practice other cancer-related behaviors than nonusers, after adjustment for age, education, and smoking. Among women, supplement users were more likely to have had a sigmoidoscopy [odds ratio (OR), 2.3; 95% confidence interval (CI), 1.2-4.5], hemoccult (OR, 2.3; CI, 1.5-3.5), or mammogram (OR, 1.5; CI, 1.0-2.1) in the past 2 years. Among men, supplement users were twice as likely to have had a prostate-specific antigen test (OR, 2.2; CI, 1.3-3.7) and to regularly take aspirin (OR, 1.7; CI, 1.1-2.6). Supplement users were statistically significantly more likely to exercise regularly, eat four or more servings of fruits and vegetables per day, follow a low-fat diet pattern, and believe in a connection between diet and cancer. The association was especially strong for fruits and vegetables (women, OR, 1.9; and CI, 1.3-2.6; men, OR, 2.4; CI, 1.6-3.8). Those investigating the benefits and risks of vitamin and mineral supplements need to be aware of the lifestyle characteristics of supplement users to assess the potential for bias in their studies

A World Waiting to Be Born. Civility Rediscovered.

Peck SM.

1997; Second Edition:50.

Measurement of circulating forms of prostate-specific antigen in whole blood immediately after venipuncture: implications for point-of-care testing.

Piironen T, Nurmi M, Irjala K, et al.

Clin Chem. 2001 Apr; 47(4):703-11.

BACKGROUND: The purpose of this study was to validate the use of whole-blood samples in the determination of circulating forms of prostate-specific antigen (PSA). METHODS: Blood samples of hospitalized prostate cancer and benign prostatic hyperplasia patients were collected and processed to generate whole-blood and serum samples. Three different rapid two-site immunoassays were developed to measure the concentrations of total PSA (PSA-T), free PSA (PSA-F), and PSA-alpha(1)-antichymotrypsin complex (PSA-ACT) to detect in vitro changes in whole-blood samples immediately after venipuncture. The possible influence of muscle movement on the release of PSA from prostate gland was studied in healthy men by measuring the rapid in vitro whole-blood kinetics of PSA forms before and after 15 min of physical exercise on a stationary bicycle. RESULTS: Rapid PSA-T, PSA-F, and PSA-ACT assays were designed using a 10-min sample incubation. No significant changes were detected in the concentrations of PSA-T, PSA-F, and PSA-ACT from the earliest time point of 12-16 min compared with measurements performed up to 4 h after venipuncture. Physical exercise did not influence the concentrations of the circulating forms of PSA. Hematocrit-corrected whole-blood values of PSA-T and PSA-F forms were comparable to the respective serum values. Calculation of the percentage of PSA-F (PSA F/T ratio x 100) was similar irrespective of the sample format used, i.e., whole blood or serum. CONCLUSIONS: We found that immunodetectable PSA forms are likely at steady state immediately after venipuncture, thus enabling the use of anticoagulated whole-blood samples in near-patient settings for point-of-care testing, whereas determinations of PSA (e.g., PSA-T, PSA-F, or PSA-ACT) performed within the time frame of the office visit would provide results equivalent to conventional analyses performed in serum

Radiotherapy for isolated serum prostate specific antigen elevation after prostatectomy for prostate cancer.

Pisansky TM, Kozelsky TF, Myers RP, et al.

J Urol. 2000 Mar; 163(3):845-50.

PURPOSE: Elevated serum prostate specific antigen (PSA) may be the initial and only indication of disease recurrence after prostatectomy for prostate cancer. External beam radiotherapy may be given in this setting in an attempt to eradicate the disease but therapeutic outcomes after this approach require further description. We describe the intermediate term outcome in a large group of patients treated with radiotherapy and identify pre-therapy factors associated with disease outcome. MATERIALS AND METHODS: We retrospectively studied a cohort of 166 consecutive patients treated with radiotherapy between July 1987 and May 1996. The Kaplan-Meier method was used to describe patient outcome for the overall study group, and statistical associations of pre-therapy variables with outcome were sought to identify predictive factors. RESULTS: At a median followup of 52 months 46% (95% confidence interval 38 to 55) of patients were expected to be free of biochemical relapse 5 years after radiotherapy. Multivariate analysis identified pathological classification (seminal vesicle invasion), tumor grade and preradiotherapy serum PSA as independent factors associated with biochemical relapse. Although in 1 of 6 patients a chronic complication was attributed to radiotherapy, it was often mild and self-limited in nature. CONCLUSIONS: In our current series approximately half of the patients treated with radiotherapy for an isolated elevation of serum PSA after prostatectomy were free of biochemical relapse at 5 years of followup. Radiotherapy may be given in this setting with modest long-term morbidity

Relationship of tumor DNA-ploidy to serum prostate-specific antigen doubling time after radiotherapy for prostate cancer.

Pollack A, Zagars GK, el Naggar AK, et al.

Urology. 1994 Nov; 44(5):711-8.

OBJECTIVES: DNA-ploidy is a strong prognostic factor for prostate cancer patients treated with definitive external beam radiotherapy. Using DNA/nuclear protein flow cytometry, three prognostic groups based on DNA-ploidy were identified: from good to poor, these are diploid, near-diploid, and nondiploid tumors. Since recent evidence indicates that the rate at which prostate-specific antigen (PSA) increases in the presence of biochemical failure is predictive of the time to clinical relapse, we examined the relationship between DNA-ploidy and PSA doubling time (PSA-DT). METHODS. Formalin-fixed paraffin-embedded tissues from 76 patients treated at M.D. Anderson Cancer Center with definitive radiotherapy alone were analyzed for ploidy using DNA/nuclear protein flow cytometry. Of these, 24 of the 27 patients with a rising PSA profile had three or more post-treatment PSA values from which the PSA-DTs were calculated. PSA-DTs were estimated using nonlinear regression techniques. RESULTS. The average PSA-DT for the 24 patients in this cohort was 11.3 +/- 10.5 months (+/- SD) with a median of 8.4 months. Diploidy (n = 3) was associated with a PSA-DT of 27.0 +/- 22.8 months, near-diploidy (n = 7) with a PSA-DT of 12.2 +/- 5.7 months, and non-diploidy (n = 14) with a PSA-DT of 7.5 +/- 5.7 months (p = 0.004, Spearman rank test). Stage, grade, and pretreatment PSA, as well as the endpoints of local control, freedom from metastases, and freedom from any relapse, did not correlate significantly with PSA-DT values. However, when patients were subdivided by PSA-DT into those with values 10 months or less (n = 14) and those more than 10 months (n = 10), there was a correlation with 3-year actuarial freedom from relapse: 28% and 74%, respectively (p < 0.01, log-rank). This subdivision of PSA-DT also correlated with DNA-ploidy (p = "0.03," chi-square) and stage (p = "0.04)." CONCLUSIONS. The results show that there is a significant correlation of DNA-ploidy with PSA-DT. Diploidy was associated with the longest PSA-DTs, near-diploidy with intermediate PSA-DTs, and nondiploidy with short PSA-DTs. Patients with short PSA-DTs also had significantly higher actuarial rates of disease relapse at 3 years. These data confirm that PSA-DT is a strong predictor of tumor behavior and that patients who have nondiploid tumors probably require more aggressive, combined modality, treatment

Artificial neural network model to predict biochemical failure after radical prostatectomy.

Porter C, O'Donnell C, Crawford ED, et al.

Mol Urol. 2001; 5(4):159-62.

BACKGROUND: Biochemical failure, defined here as a rise in the serum prostate specific antigen (PSA) concentration to >0.3 ng/mL or the initiation of adjuvant therapy, is thought to be an adverse prognostic factor for men who undergo radical prostatectomy (RP) as definitive treatment for clinically localized cancer of the prostate (CAP). We have developed an artificial neural network (ANN) to predict biochemical failure that may benefit clinicians and patients choosing among the definitive treatment options for CAP. MATERIALS AND METHODS: Clinical and pathologic data from 196 patients who had undergone RP at one institution between 1988 and 1999 were utilized. Twenty-one records were deleted because of missing outcome, Gleason sum, PSA, or clinical stage data. The variables from the 175 remaining records were analyzed for input variable selection using principal component analysis, decision tree analysis, and stepped logistic regression. The selected variables were age, PSA, primary and secondary Gleason grade, and Gleason sum. The records were randomized and split into three bootstrap training and validation sets of 140 records (80%) and 35 records (20%), respectively. RESULTS: Forty-four percent of the patients suffered biochemical failure. The average duration of follow up was 2.5 years (range 0-11.5 years). Forty-two percent of the patients had pathologic evidence of non-organ-confined disease. The average area under the receiver operator characteristic (ROC) curve for the validation sets was 0.75 +/- 0.07. The ANN with the highest area under the ROC curve (0.80) was used for prediction and had a sensitivity of 0.74, a specificity of 0.78, a positive predictive value of 0.71, and a negative predictive value of 0.81. CONCLUSION: These results suggest that ANN models can predict PSA failure using readily available preoperative variables. Such predictive models may offer assistance to patients and physicians deciding on definitive therapy for CaP

Nephrolithiasis and osteoporosis associated with hypophosphatemia caused by mutations in the type 2a sodium-phosphate cotransporter.

Prie D, Huart V, Bakouh N, et al.

N Engl J Med. 2002 Sep 26; 347(13):983-91.

BACKGROUND: Epidemiologic studies suggest that genetic factors confer a predisposition to the formation of renal calcium stones or bone demineralization. Low serum phosphate concentrations due to a decrease in renal phosphate reabsorption have been reported in some patients with these conditions, suggesting that genetic factors leading to a decrease in renal phosphate reabsorption may contribute to them. We hypothesized that mutations in the gene coding for the main renal sodium-phosphate cotransporter (NPT2a) may be present in patients with these disorders. METHODS: We studied 20 patients with urolithiasis or bone demineralization and persistent idiopathic hypophosphatemia associated with a decrease in maximal renal phosphate reabsorption. The coding region of the gene for NPT2a was sequenced in all patients. The functional consequences of the mutations identified were analyzed by expressing the mutated RNA in Xenopus laevis oocytes. RESULTS: Two patients, one with recurrent urolithiasis and one with bone demineralization, were heterozygous for two distinct mutations. One mutation resulted in the substitution of phenylalanine for alanine at position 48, and the other in a substitution of methionine for valine at position 147. Phosphate-induced current and sodium-dependent phosphate uptake were impaired in oocytes expressing the mutant NPT2a. Coinjection of oocytes with wild-type and mutant RNA indicated that the mutant protein had altered function. CONCLUSIONS: Heterozygous mutations in the NPT2a gene may be responsible for hypophosphatemia and urinary phosphate loss in persons with urolithiasis or bone demineralization

A novel translational regulation function for the simian virus 40 large-T antigen gene.

Rajan P, Swaminathan S, Zhu J, et al.

J Virol. 1995 Feb; 69(2):785-95.

Cells use the interferon-induced, double-stranded-RNA-dependent protein kinase PKR as a defense against virus infections. Upon activation, PKR phosphorylates and thereby inactivates the protein synthesis initiation factor eIF-2, resulting in the cessation of protein synthesis. Viruses have evolved various strategies to counteract this cellular defense. In this paper, we show that simian virus 40 (SV40) large-T antigen can antagonize the translational inhibitory effect resulting from the activation of PKR in virus-infected cells. Unlike the situation with other virus-host cell interactions, SV40 large-T antigen does not block the activation of PKR, suggesting that SV40 counteracts the cellular antiviral response mediated by PKR at a step downstream of PKR activation. Mutational analysis of large-T antigen indicates that a domain located between amino acids 400 and 600 of large-T antigen is responsible for this function. These results define a novel translational regulatory function for the SV40 large-T antigen

Expression of bcl-2, p53, and p21 in benign and malignant prostatic tissue before and after radiation therapy.

Rakozy C, Grignon DJ, Sarkar FH, et al.

Mod Pathol. 1998 Sep; 11(9):892-9.

Abnormalities in genes of the apoptotic pathway might contribute to survival in prostatic cancer (PCa) cells after radiation therapy (RT). We investigated the immunohistochemical expression of the products of the p53, p21WAF1, and bcl-2 genes in pre-RT and post-RT biopsy specimens from 38 patients with locally advanced PCa. All of the 38 patients underwent a uniform protocol of RT with or without neoadjuvant hormonal therapy. Immunohistochemical staining for expression of the products of the p53, p21WAF1, and bcl-2 genes was performed on material from pre-RT and post-RT specimens. Sufficient tissue for analysis was available from 25 of the pre-RT and 38 of the post-RT biopsy specimens. In benign prostatic epithelium, RT resulted in expression of p53 (2 [8%] of 25 pre-RT specimens vs. 15 [71%] of 21 post-RT specimens; P < .001) and increased expression of bcl-2 (1 [5%] of 18 pre-RT vs. 18 [86%] of 21 post-RT; P < .001). There was no change in the expression of p21WAF1 (1 [4.5%] of 22 pre-RT vs. 4 [17%] of 23 post-RT; P = "NS)." Post-RT specimens were positive for PCa in 24 (63%) of 38 cases. In the PCa tissue, p53 expression was seen in 10 (42%) of 24 pre-RT and 12 (63%) of 19 post-RT samples (P = "NS)." A significant upregulation of p53 was seen in the subgroup of patients who did not receive neoadjuvant hormonal therapy (9 [82%] of 11 vs. 3 [38%] of 8; P = ".05)." No significant change in p21WAF1 (5 [21%] of 24 vs. 5 [33%] of 15; P = "NS)," or bcl-2 (4 [18%] of 22 vs. 3 [21%] of 14; P = "NS)" expression was detected. There was no significant correlation between immunohistochemical expression of apoptosis-related markers and treatment failure. We concluded that RT induced upregulation of the bcl-2 and p53 gene products in benign prostatic tissue and that this likely reflected a protective mechanism in genetically unaltered epithelium. Increased p53 expression in PCa was only seen in patients without neoadjuvant hormonal treatment, indicating that the cancer cells with abnormal p53 were at least partially protected from RT-induced cell death

Herpes simplex virus 1716, an ICP 34.5 null mutant, is unable to replicate in CV-1 cells due to a translational block that can be overcome by coinfection with SV40.

Randazzo BP, Tal-Singer R, Zabolotny JM, et al.

J Gen Virol. 1997 Dec; 78 ( Pt 12):3333-9.

Herpes simplex virus (HSV) mutants lacking the gene encoding infected cell protein (ICP) 34.5 exhibit an attenuated phenotype in models of pathogenesis and have been used for experimental cancer therapy. Recently it was shown that the HSV ICP 34.5 protein functions to prevent the host cell-induced double-stranded RNA-activated protein kinase (PKR)-dependent translational block that normally occurs during virus infection. We now report that an HSV ICP 34.5 mutant called HSV-1716 is unable to replicate in the simian kidney cell-derived line CV-1, due to a translational block. Moreover, we find that this block can be overcome by simian virus 40 (SV40). This has been shown directly by infecting CV-1 cells with SV40 and HSV-1716 simultaneously, and indirectly via HSV-1716 infection of COS-1 cells (CV-1 cells transformed by an origin-defective mutant of SV40 that codes for wild-type T antigen). The translational block is restored when infections are done in the presence of the phosphatase inhibitor okadaic acid. These results support, but do not directly prove, contentions that HSV ICP 34.5 interacts with the PKR pathway to restore translation in non-permissive cells, and that SV40 large T antigen has a similar functional role, but acts downstream of the site of ICP 34.5 interaction (eIF2alpha) in the pathway. Study of this CV-1/COS-1 system should allow further clarification of the virus-host interactions that underlie the restricted replication of HSV-1 ICP 34.5 gene null mutants

Mutagenic specificity of oxygen radicals produced by human leukemia cells.

Reid TM, Loeb LA.

Cancer Res. 1992 Mar 1; 52(5):1082-6.

An important source of endogenous oxygen radicals are phagocytic cells such as neutrophils and macrophages. The human leukemia cell line HL-60 can be induced to differentiate into a neutrophil-like cell population. Among the properties of these differentiated cells is the ability to produce reactive oxygen species when stimulated by tumor promoters. Mutagenesis induced by HL-60-generated free radicals was assessed using the M13mp2 forward mutation assay. Single-stranded M13mp2 DNA was coincubated with phorbol ester-stimulated HL-60 cells, after which mutations were scored by transfecting the DNA into SOS-induced Escherichia coli. The mutation frequency was increased 6-fold above background in DNA incubated with HL-60 cells. The majority of the mutations were single-base substitutions. However, approximately 6% of the mutations were tandem double substitutions that occurred in runs of adjacent cytidines. Overall, the mutations were clustered at apparent "hot spots," many of which were similar to sites seen using iron to generate oxygen radicals. These results suggest that human cells able to produce oxygen radicals in response to tumor promoters might play a significant role in the generation of tumors

PSA doubling time as a predictor of clinical progression after biochemical failure following radical prostatectomy for prostate cancer.

Roberts SG, Blute ML, Bergstralh EJ, et al.

Mayo Clin Proc. 2001 Jun; 76(6):576-81.

OBJECTIVES: To characterize the clinical progression of disease in men who have undergone prostatectomy for clinically localized prostate cancer and have postoperative biochemical failure (elevated prostate-specific antigen [PSA] level) and to identify predictors of clinical disease progression, including the possible effect of PSA doubling time (PSADT). PATIENTS AND METHODS: Between 1987 and 1993, 2809 patients underwent radical retropubic prostatectomy for clinically localized ( or =0.4 ng/mL) were identified. The PSADT was estimated using log linear regression on all PSA values (excluding those values determined after administration of hormonal therapy) within 15 months after biochemical failure. All patients had regular PSA measurements from the time of surgery through the follow-up period. Systemic progression (SP) was defined as evidence of metastatic disease on a bone scan. Local recurrence (LR) was defined on the basis of digital rectal examination, transrectal ultrasonography, and biopsy. The SP-free survival and LR/SP-free survival (survival free of both LR and SP) after biochemical failure was estimated with use of the Kaplan-Meier method. Patients with prostate cancer treatment after biochemical failure had their follow-up censored from this study at the time of treatment. RESULTS: Postoperative biochemical failure occurred in 879 men (31%). The mean follow-up from time of biochemical failure was 4.7 years (range, 0.5-11 years). The mean time to biochemical failure was 2.9 years (median, 2.4 years). The overall mean SP-free survival from time of biochemical failure was 94% and 91% at 5 and 10 years, respectively. The mean LR/SP-free survival was 64% and 53% at 5 and 10 years, respectively. By using univariate analysis on the 587 patients with PSADT data, significant risk factors for SP were PSADT (P

Dietary fatty acids and prevention of hormone-responsive cancer.

Rose DP.

Proc Soc Exp Biol Med. 1997 Nov; 216(2):224-33.

The results from some, but not all, epidemiological studies indicate that the level of dietary fat intake and the nature of the constituent fatty acids influence both breast and prostate cancer risk, and disease progression. These observations derive support from the use of animal models, which demonstrate that polyunsaturated omega-6 fatty acids stimulate mammary carcinogenesis and tumor growth and metastasis, whereas long-chain omega-3 fatty acids exhibit inhibitory effects. While studies of prostate cancer are less advanced, the available data are in agreement with those designed to evaluate the associations between breast cancer and dietary fatty acids. In both cases, a multiplicity of biological actions of eicosanoids derived from tumor cell arachidonate metabolism appear to elicit responses, both in the tumor itself and in the host cells that subscribe to its microenvironment. This review concludes that clinical intervention trials designed to reduce total fat intake and increase the ratio of omega-3 to omega-6 fatty acids in the diet should be targeted at groups at a relatively high risk for breast or prostate cancer, and also at postsurgically treated cancer patients with the objective of preventing disease recurrence

Particle beam radiation therapy in prostate cancer: is there an advantage?

Rossi CJ, Jr., Slater JD, Reyes-Molyneux N, et al.

Semin Radiat Oncol. 1998 Apr; 8(2):115-23.

Hadron therapy uses heavy particles to deliver therapeutic ionizing energy. Each particle's inherent attributes determine the pattern of energy deposited by its beam, expressed in macro (conformability to a three-dimensional target volume) and micro (radiobiologic properties) distributions. Mass and charge regulate the inherent properties; beam energy provides a controllable, variable characteristic. Generally, heavy charged particles provide superior macrodosimetric properties; heavy particles (charged or not) have microdosimetric characteristics that produce high linear energy transfer (LET). Neutron macrodosimetry is similar to that of photons. Protons and helium ions possess superior macrodosimetric properties, plus microdosimetric characteristics resulting in low LET, yielding beam characteristics that approach the ideal for clinical radiotherapy. Hadron therapy for prostate cancer has been limited by the availability of appropriate treatment facilities. Nonetheless, encouraging results have been obtained. Neutron therapy demonstrated improved overall survival in a multi-institutional randomized trial, and improved local disease control in a subsequent trial. Proton radiation forms the boost component of several conformal dose-escalation studies. A Loma Linda University study demonstrated low treatment-related morbidity despite a prostate dose of 75 CGE; late-morbidity data were superior to published reports from multi-field, conformal photon therapy. A Phase III dose-escalation study of protons for early prostate cancer is proceeding

Harry Potter and the Goblet of Fire.

Rowling JK.

2000; First Edition:723.

Recruitment experience in the first phase of the African American Hereditary Prostate Cancer (AAHPC) study.

Royal C, Baffoe-Bonnie A, Kittles R, et al.

Ann Epidemiol. 2000 Nov; 10(8 Suppl):S68-S77.

The African American Hereditary Prostate Cancer (AAHPC) Study is an ongoing multicenter genetic linkage study organized by Howard University and the National Human Genome Research Institute (NHGRI), with support from the Office for Research on Minority Health and the National Cancer Institute. The goals of the study are to: (i) look for evidence of involvement of chromosome 1q24-25 (HPC1) in African American men with hereditary prostate cancer (HPC) and (ii) conduct a genome-wide search for other loci associated with HPC in African American men. To accomplish these goals, a network has been established including Howard University, the NHGRI, and six Collaborative Recruitment Centers (CRCs). The CRCs are responsible for the identification and enrollment of 100 African American families. To date, 43 families have been enrolled. Recruitment strategies have included mass media campaigns, physician referrals, community health-fairs/prostate cancer screenings, support groups, tumor registries, as well as visits to churches, barber shops, and universities. By far, the most productive recruitment mechanisms have been physician referrals and tumor registries, yielding a total of 35 (81%) families. Approximately 41% (n = 3400) of probands initially contacted by phone or mail expressed interest in participating; the families of 2% of these met the eligibility criteria, and 75% of those families have been enrolled in the study, indicating a 0.5% recruitment yield (ratio of participants to contacts). As the first large-scale genetic linkage study of African Americans, on a common disease, the challenges and successes of the recruitment process for the AAHPC Study should serve to inform future efforts to involve this population in similar studies

Prostate cryoablation: a scientific rationale for future modifications.

Rukstalis DB, Goldknopf JL, Crowley EM, et al.

Urology. 2002 Aug; 60(2 Suppl 1):19-25.

This investigation was designed to identify potential directions for future modification of the percutaneous prostate cryoablation procedure. An analysis of prostate cancer location and volume in radical prostatectomy specimens was performed to evaluate the potential clinical consequences of these proposed modifications. A list of recommendations for improvements in the prostate cryoablation procedure was compiled from informal discussions held with participants in 9 training courses and conferences on prostate cryoablation over 18 months. Subsequently, a population of 112 consecutive, sagittally sectioned whole-mount radical prostatectomy samples was evaluated for prostate cancer volume, number of individual foci, and location to examine the disease-specific outcomes of these proposed modifications. The most common areas for potential alterations in the current cryoablation technique include modifications that would further simplify the procedure, continue to reduce real and perceived toxicity, and augment efficacy. Importantly, modifications designed to reduce treatment side effects could conflict with efforts designed to improve eradication of prostate cancer. Pathologic analysis revealed multifocal cancer in 79.5% of the samples, with 66% of cases exhibiting cancer within 5 mm of the urethra. The median volume of the index cancer was 1.6 cm3, whereas the median volume of the smaller ancillary lesions was 0.3 cm3. Prostate parenchymal-sparing alterations, proposed to reduce incontinence and erectile dysfunction by targeting the index cancer, would likely eradicate clinically significant cancer in 79% of men. The recent enthusiasm for prostate cryoablation as a reasonable minimally invasive treatment option for men with clinically localized cancer is likely to result in modifications of the established surgical technique. Knowledge of the anatomic location and cancer volume within the prostate gland is an important adjunct to planning such alterations. It is possible that parenchymal-sparing modifications to total gland prostate cryoablation can eradicate clinically significant cancer in most men, with a reduction in toxicity and cost

A prospective randomized trial comparing lidocaine and lubricating gel on pain level in patients undergoing transrectal ultrasound prostate biopsy.

Saad F, Sabbagh R, McCormack M, et al.

Can J Urol. 2002 Aug; 9(4):1592-4.

PURPOSE: To compare patient reported pain during TRUS guided biopsies using intrarectal lidocaine gel versus lubricating gel. MATERIALS AND METHODS: From May 2000 to May 2001, 360 men undergoing transrectal prostate biopsy were enrolled in this study. Patients were randomized into two groups. In group 1, 180 patients received 10 cc of 2% intrarectal lidocaine gel (Xylocaine 2% jelly, Astra Pharma Inc.) 5 to 10 minutes before the procedure and in group 2, 180 patients received 10 cc of lubricating gel. No other sedation or analgesia was given. Pain level immediately after the last biopsy was assessed using a 10-point linear visual analog pain scale. RESULTS: The median pain score during transrectal prostate biopsy was 2 (range 0 to 8) and 3 (range 1 to 10) in groups 1 and 2, respectively (p = 0.0001). Only minor complications occurred and complication rates were not significantly different between the groups. CONCLUSION: Rectal administration of lidocaine gel is safe, simple and effective for reducing the pain level associated with transrectal prostate biopsy

Expression of basic fibroblast growth factor and its receptors FGFR1 and FGFR2 in human benign prostatic hyperplasia treated with finasteride.

Saez C, Gonzalez-Baena AC, Japon MA, et al.

Prostate. 1999 Jul 1; 40(2):83-8.

BACKGROUND: The development of benign prostatic hyperplasia (BPH) is an androgen-dependent process which may be mediated by a number of locally produced growth factors. One of these, the basic fibroblast growth factor (bFGF or FGF2), has a mitogenic effect on prostatic stroma. High expression levels of bFGF have been reported in BPH. FGFR1 and FGFR2 receptors, that exhibit affinity for bFGF, have been identified in normal and hyperplastic prostate. Finasteride, a 5alpha-reductase inhibitor, is an effective drug in the treatment of BPH, inducing regressive changes in the prostate of treated patients, even though its mechanisms of action are not yet completely elucidated. This study was designed to assess the effects of finasteride on the expression levels of bFGF, FGFR1, and FGFR2 in patients with BPH. METHODS: The expression levels of bFGF, FGFR1, and FGFR2 in 9 patients with prostatic hyperplasia treated with finasteride were assessed by immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR) analysis of mRNA expression and were compared with those of 9 control patients with untreated BPH. RESULTS: Immunohistochemistry showed strong bFGF immunoreactivity in the prostatic stroma of untreated patients, this being somewhat weaker in the epithelium. In treated patients, epithelial immunoreactivity was practically negative, and a considerable reduction in stromal immunoreactivity was seen. These findings were also confirmed by RT-PCR. FGFR1 showed a weak immunoreactivity in the stroma and in basal epithelial cells. FGFR1 showed a weak immunoreactivity in the stroma and in basal epithelial cells. FGFR2 exhibited strong stromal immunoreactivity, becoming weaker in the basal epithelium. No differences were seen in the expression of both receptors between the groups of treated and untreated patients. CONCLUSIONS: A marked reduction in bFGF levels is seen in BPH treated with finasteride in comparison to untreated BPH. In our opinion, finasteride may act as a negative regulator of bFGF expression, counteracting the role of bFGF in the development of BPH

Gleason score 7 prostate cancer: a heterogeneous entity? Correlation with pathologic parameters and disease-free survival.

Sakr WA, Tefilli MV, Grignon DJ, et al.

Urology. 2000 Nov 1; 56(5):730-4.

OBJECTIVES: Gleason score 7, in different proportions of grades 3 and 4, is the score most frequently assigned to prostate cancer in our radical prostatectomy specimens (RPSs). We correlated the major grade component of score 7 tumors with clinicopathologic parameters and disease-free survival. METHODS: All Gleason score 7 RPSs were classified as having a major grade of 3 or 4 carcinoma. The two groups were compared according to patient age, race, serum prostate-specific antigen (PSA) level, clinical and pathologic stage, tumor volume, and biochemical recurrence. RESULTS: Of the 534 patients analyzed, 356 and 178 had major grade 3 or 4 tumors, respectively. Compared with patients with 3+4 tumors, those with 4+3 had significantly more advanced clinical and pathologic stages, larger tumor volume, higher preoperative PSA levels, and older age and a higher proportion were African American (P

BCL-2 and p53 expression in clinically localized prostate cancer predicts response to external beam radiotherapy.

Scherr DS, Vaughan ED, Jr., Wei J, et al.

J Urol. 1999 Jul; 162(1):12-6.

PURPOSE: Clinicians have long been hampered by the inability to distinguish patients with localized prostate cancer who will and will not respond to radiotherapy. In a significant proportion of patients therapy fails as determined by increasing posttreatment serum prostate specific antigen (PSA). We evaluated the expression of 2 key regulators of apoptosis, bcl-2 and p53, relative to treatment outcomes in patients who received external beam radiotherapy for clinically organ confined carcinoma of the prostate. MATERIALS AND METHODS: Immunohistochemical staining for bcl-2 and p53 on pretreatment needle biopsies was performed in 54 patients who were treated with radiotherapy for localized prostate cancer. Expression was scored using strict criteria. Nadir PSA less than 1 ng./ml. after therapy was considered a successful treatment response. RESULTS: There was a predominance of stage T1c cancer (74%) with a mean Gleason score of 6.9 and an average pretreatment PSA of 25.3 ng./ml. Overall 54% of the patients did not have a nadir PSA of less than 1 ng./ml. Of the bcl-2 positive cases therapy ultimately failed in 85%. Similarly 88% of the patients with p53 positive biopsies had treatment failure and in all with bcl-2 as well as p53 expression radiotherapy failed. Expression of bcl-2 and p53 was an independent prognostic variable for treatment failure with odds ratios (95% confidence interval) of 7.3 and 10.8, respectively. CONCLUSIONS: Expression of bcl-2 and p53 was associated with treatment failure after external beam radiation therapy. These findings suggest that bcl-2 and p53 expression in pretreatment biopsies may be helpful for predicting response to definitive radiotherapy

Value and perspectives of proton radiation therapy for limited stage prostate cancer.

Schulte RW, Slater JD, Rossi CJ, Jr., et al.

Strahlenther Onkol. 2000 Jan; 176(1):3-8.

BACKGROUND: This review article will focus on clinical results and limitations of proton beam irradiation. Possible technological, biological and medical perspectives will be addressed. PATIENTS AND METHODS: A total of 911 patients with limited stage prostate cancer were treated with proton beam irradiation at Loma Linda University between 1991 and 1996. Endpoints of this evaluation were biochemically no evidence of disease survival (bNED) as well as acute and late treatment-related toxicity. RESULTS: The bNED survival rate was 82% at 5 years. Among 870 patients evaluable for late toxicity the following late effects were observed: Grade 3/4: 0%, Grade 2 rectal: 3.5% and bladder: 5.4%. CONCLUSIONS: Despite relatively short follow-up times it seems justified to conclude that proton beam irradiation of prostate cancer can improve bNED rates by 10% and decrease Grade 2 late effects by more than 10%. There were no Grade 3 and 4 late effects

Plasma testosterone and androstenedione after orchiectomy in prostatic adenocarcinoma.

Sciarra F, Sorcini G, Di Silverio F, et al.

Clin Endocrinol (Oxf). 1973 Apr; 2(2):101-9.

The Omega Rx Zone: The Miracle of High-Dose Fish Oil.

Sears B.

2002; First Edition

Familial clustering of breast and prostate cancers and risk of postmenopausal breast cancer.

Sellers TA, Potter JD, Rich SS, et al.

J Natl Cancer Inst. 1994 Dec 21; 86(24):1860-5.

BACKGROUND: Previous studies have suggested that cancers of the breast and prostate cluster in families and that the presence of both diseases in a family may be associated with increased risk of breast cancer. PURPOSE: Our purpose was to evaluate whether 1) prostate cancer aggregates in families with postmenopausal breast cancer, 2) families with cancers of the breast and prostate are the same ones as families with cancers of the breast and ovary, and 3) a family history of prostate cancer is associated with increased risk of postmenopausal breast cancer. METHODS: We analyzed data from a large prospective cohort study of Iowa women that were (at baseline) aged 55-69 years in 1986. At the third follow-up survey in 1992, self-reported data on family history of breast, ovarian, and prostate cancers in parents and siblings were provided by 30,883 women. Additional information was collected to ascertain whether the age-of-onset of breast cancer in mothers or sisters was before or after the age of 45 years. Cancer occurrence was documented using the State Health Registry of Iowa. RESULTS: History of prostate cancer in their father or a brother was reported by 3384 (11.0%) of the women, and a total of 4090 women (13.2%) reported breast cancer in their mother or a sister. A positive family history of both cancers was reported by 556 women, significantly (two-sided P < .001) greater than the 457 women expected if the family histories were independent. The aggregation of breast, prostate, and ovarian cancers was reported by 22 participants, greater than the 2.7 expected (two-sided P < .0001). During 6 years of follow-up, 578 breast cancers were identified in the cohort at risk. Compared with women without a family history of either cancer, women with a family history of breast cancer had a relative risk (RR) of 1.37 (95% confidence interval [CI] = "1.06-1.79)" if the affected relative had onset after the age of 45 years, and an RR of 1.71 (95% CI = "1.13-2.61)" if the affected relative had onset at or before the age of 45. A family history of prostate cancer in the absence of a family history of breast cancer was associated with an RR of 1.19 (95% CI = ".90-1.56)." However, a family history of both breast and prostate cancers was associated with RRs of 2.06 (95% CI = "1.23-3.45)" and 2.35 (95% CI = ".97-5.67)" for breast cancer onset in relatives of greater than 45 and less than or equal to 45 years, respectively. CONCLUSIONS: These observations are concordant with recent reports that suggest a shared familial risk (inherited or environmental) for these hormone-dependent malignancies

CMT-3, a chemically modified tetracycline, inhibits bony metastases and delays the development of paraplegia in a rat model of prostate cancer.

Selzer MG, Zhu B, Block NL, et al.

Ann N Y Acad Sci. 1999 Jun 30; 878:678-82.

Efficacy of one dose fluoroquinolone before prostate biopsy.

Shandera KC, Thibault GP, Deshon GE, Jr.

Urology. 1998 Oct; 52(4):641-3.

OBJECTIVES: To demonstrate the efficacy of a simple preparation for prostate biopsy (PBX) and to determine its potential cost savings. METHODS: One hundred fifty consecutive PBXs were performed using a Fleet enema and a single oral dose (300 mg) of ofloxacin as the pre-PBX preparation. RESULTS: Of the 150 PBXs we performed, only 1 (0.67%) patient developed a urinary tract infection. CONCLUSIONS: A simple and inexpensive pre-PBX preparation proved to be successful in preventing infectious complications and is presented as a potential model for inclusion in clinical pathways for diagnosing adenocarcinoma of the prostate

Preoperative plasma levels of transforming growth factor beta(1) (TGF-beta(1)) strongly predict progression in patients undergoing radical prostatectomy.

Shariat SF, Shalev M, Menesses-Diaz A, et al.

J Clin Oncol. 2001 Jun 1; 19(11):2856-64.

PURPOSE: Elevated local and circulating levels of transforming growth factor beta(1) (TGF-beta(1)) have been associated with prostate cancer invasion and metastasis. We tested the hypothesis that preoperative plasma TGF-beta(1) levels would independently predict cancer stage and prognosis in patients who undergo radical prostatectomy. PATIENTS AND METHODS: The study group consisted of 120 consecutive patients who underwent radical prostatectomy for clinically localized prostate cancer (median follow-up, 53.8 months). Preoperative plasma levels of TGF-beta(1) were measured and correlated with pathologic parameters and clinical outcomes. TGF-beta(1) levels also were measured in 44 healthy men without cancer, in 19 men with prostate cancer metastatic to regional lymph nodes, and in 10 men with prostate cancer metastatic to bone. RESULTS: Plasma TGF-beta(1) levels in patients with lymph node metastases (14.2 +/- 2.6 ng/mL) and bone metastases (15.5 +/- 2.4 ng/mL) were higher than those in radical prostatectomy patients (5.2 +/- 1.3 ng/mL) and healthy subjects (4.5 +/- 1.2 ng/mL) (P

Expression of the interleukin 6 receptor and interleukin 6 in prostate carcinoma cells.

Siegall CB, Schwab G, Nordan RP, et al.

Cancer Res. 1990 Dec 15; 50(24):7786-8.

We have probed for the presence of interleukin 6 (IL6) receptors in prostatic carcinoma cell lines (LNCaP, DU 145, and PC3) by examining their sensitivity to the cytotoxic effects of a chimeric toxin composed of IL6 and Pseudomonas exotoxin (PE). All three cell lines were killed by IL6-PE66(4)Glu, a version of IL6-PE in which the binding domain of native PE has been mutated to debilitate PE binding to its own receptor. This cytotoxic activity confirmed the presence of IL6 receptors on prostatic carcinoma cells. We have measured the number of IL6 receptors found on these cells and have further determined that they secrete IL6. These data provide evidence that IL6 and its receptor may play an important role in human prostate cancer

Nerve growth factor induces the re-expression of functional androgen receptors and p75(NGFR) in the androgen-insensitive prostate cancer cell line DU145.

Sigala S, Tognazzi N, Rizzetti MC, et al.

Eur J Endocrinol. 2002 Sep; 147(3):407-15.

BACKGROUND: One of the paracrine/autocrine factors regulating prostate growth and differentiation is nerve growth factor (NGF). The role of NGF and its receptors in the prostate, however, remains controversial. We have shown that NGF treatment of human prostate cancer cell lines reduced their tumorigenicity, both in vitro and in vivo. OBJECTIVE: To investigate the involvement of NGF as a differentiation factor in prostate cancer cells. DESIGN: We exposed the androgen-independent/androgen receptor (AR)-negative prostate cancer cell line DU145 to NGF to study whether this neurotrophin could revert DU145 cells to a less malignant phenotype. METHODS: DU145 cells were treated with NGF, then ARs and NGF receptor p75(NGFR) expression and telomerase activity were studied. Finally, we investigated whether re-expression of ARs could restore the androgen sensitivity in this cell line. RESULTS AND CONCLUSIONS: NGF treatment induced a reversion of DU145 cells to a less malignant phenotype, characterized by the re-expression of ARs and p75(NGFR) NGF receptors. Re-expression of ARs restored the androgen sensitivity, as suggested by the fact that exposure to dihydrotestosterone stimulated the growth of NGF-treated DU145 cells. This effect was blocked by androgen antagonist drugs, such as hydroxyflutamide and cyproterone acetate, which also induced apoptotic death of NGF-treated cells. The hypothesis that a differentiation pathway is activated by exogenous NGF in DU145 cells is also supported by findings indicating that NGF-treated DU145 cells expressed a low telomerase activity, as a result of a decrease in human telomerase reverse transcriptase transcription

Lifestyle factors and insulin-like growth factor 1 levels among elderly men.

Signorello LB, Kuper H, Lagiou P, et al.

Eur J Cancer Prev. 2000 Jun; 9(3):173-8.

Insulin-like growth factor 1 (IGF-1) is a potentially important determinant of disease; hence epidemiological identification of factors that influence circulating IGF-1 is merited. We therefore analysed data collected in Greece to determine the relationship between anthropometric, lifestyle and dietary variables and serum levels of IGF-1 among elderly men. We identified 51 men with prostate cancer, 50 men with benign prostatic hyperplasia, and 52 apparently healthy elderly men (controls), all matched for age (+/- 1 year). These 153 men provided blood specimens and were interviewed using a validated lifestyle and food frequency questionnaire. We performed multivariate linear regression to identify potential predictors of circulating IGF-1. After controlling for age, body mass index, smoking habits, alcohol drinking and coffee consumption, each 5 cm increase in height predicted a 13.0% increase in IGF-1 (95% CI 0.4-27.2%) among the controls and a 11.3% increase in IGF-1 (95% CI 4.5-18.6%) among the entire study group. None of the investigated dietary factors (total fat, carbohydrate, protein, dairy products, tomatoes, calcium) were strongly related to IGF-1 levels. The positive association between IGF-1 and height integrates the empirical evidence linking IGF-1 and height with prostate cancer risk

Correlations among p53, Her-2/neu, and ras overexpression and aneuploidy by multiparameter flow cytometry in human breast cancer: evidence for a common phenotypic evolutionary pattern in infiltrating ductal carcinomas.

Smith CA, Pollice AA, Gu LP, et al.

Clin Cancer Res. 2000 Jan; 6(1):112-26.

Human solid tumors develop multiple genetic abnormalities that accumulate progressively in individual cells during the course of tumor evolution. We sought to determine whether there are specific sequences of occurrence of these progressive evolutionary changes in human breast cancers by performing correlated cell-by-cell measurements of cell DNA content, p53 protein, Her-2/neu protein, and ras protein by multiparameter flow cytometry in 56 primary tumor samples obtained at surgery. In addition, p53 allelic loss and Her-2/neu gene amplification were determined by fluorescence in situ hybridization in cells from the same samples. We reasoned that if there is a specific order in which genetic changes occur, the same early changes would be found consistently in the cells with the fewest abnormalities. We reasoned further that late-developing abnormalities would not occur alone in individual cells but would almost always be found together with the early changes inherited by the same cells. By these criteria, abnormalities involving p53 generally occurred early in the course of development of invasive breast cancers, whereas ras protein overexpression was found to be a late-occurring phenomenon. Within individual tumors, cellular p53 overexpression was often observed alone in individual cells, whereas ras protein overexpression was rarely observed in the absence of p53 overexpression and/or Her-2/neu overexpression in the same cells. Furthermore, the intracellular level of each abnormally expressed protein was found to increase progressively as new abnormalities were acquired. Infiltrating ductal carcinomas exhibited characteristic phenotypic patterns in which p53 allelic loss and/or p53 protein overexpression, Her-2/neu amplification and/or overexpression, aneuploidy, and ras overexpression accumulated within individual cells. However, this pattern was not a prominent feature of lobular breast cancers. All six lobular breast cancers studied were diploid. p53 allelic loss and/or early p53 overexpression, and late ras cooverexpression in the same cells were less common in lobular breast cancers than in infiltrating ductal carcinomas. Although Her-21neu overexpression was a common finding in lobular breast cancers, Her-2/neu amplification was not observed in these tumors

Low bone mineral density in hormone-naive men with prostate carcinoma.

Smith MR, McGovern FJ, Fallon MA, et al.

Cancer. 2001 Jun 15; 91(12):2238-45.

BACKGROUND: The objective of this study was to determine the prevalence of low bone mineral density in men with prostate carcinoma and no history of androgen-deprivation therapy. METHODS: The authors conducted a cross-sectional study in 41 hormone-naive men with locally advanced, lymph node positive, or recurrent prostate carcinoma and no radiographic evidence of bone metastases. Bone mineral density of the total hip, posterior-anterior (PA) lumbar spine, and lateral lumbar spine was determined by dual-energy X-ray absorptiometry (DXA) using a densitometer. Trabecular bone mineral density of the lumbar spine was determined by quantitative computed tomography (QCT). Bone mineral density results were expressed in standard deviation units relative to young adult men (T score) and relative to age-matched men (Z score). RESULTS: Fourteen of 41 men (34%; 95% confidence interval [95% CI], 20-51%) had T scores < -1.0 at one or more skeletal sites by DXA, 12 of 41 men (29%; 95% CI, 16-42%) had T scores between -1.0 and -2.5, and 2 of 41 men (5%; 95% CI, 1-17%) had T scores < -2.5. Thirty-nine of 41 men (95%; 95% CI, 83-99%) had T scores < -1.0 by QCT, 13 of 41 men (31%; 95% CI 18-48%) had T scores between -1.0 and -2.5, and 26 of 41 men (63%; 95% CI, 47-78%) had T scores < -2.5. T scores for trabecular bone mineral density of the lumbar spine were significantly lower than T scores for either the total hip (P < 0.001) or the PA lumbar spine (P < 0.001). The mean Z score for trabecular bone mineral density of the lumbar spine was -0.7 +/- 0.9. Hypogonadism, hypovitaminosis D, and dietary calcium intakes below the Recommended Daily Allowance were observed in 20%, and 17%, and 59% of study participants, respectively. CONCLUSIONS: Many hormone-naive men with prostate carcinoma have low bone mineral density. QCT is a more sensitive method than DXA for diagnosing low bone mineral density in this patient population. Trabecular bone mineral density is lower than expected for age and risk factors for osteoporosis are common

Periprostatic local anesthesia before ultrasound guided prostate biopsy.

Soloway MS, Obek C.

J Urol. 2000 Jan; 163(1):172-3.

PURPOSE: We assessed the morbidity and benefit of periprostatic local anesthesia administered before ultrasound guided prostate biopsy. MATERIALS AND METHODS: After placing the transrectal ultrasound probe and visualizing the prostate 50 consecutive patients received local anesthesia before prostate biopsies. RESULTS: There was no morbidity associated with the infiltration of local anesthesia into the periprostatic neurovascular plexus. Only 1 patient had discomfort during prostate biopsies, and 10 patients who previously underwent biopsies without anesthesia commented favorably on the dramatic difference. CONCLUSIONS: Many patients have pain during transrectal ultrasound guided biopsies of the prostate and few clinicians provide a periprostatic nerve block before this procedure. A periprostatic nerve block administered before the biopsies dramatically decreases discomfort. We urge all urologists to attempt this procedure, and we are confident that they will adopt it as part of their practice

Vascular endothelial growth factor is up-regulated in vitro and in vivo by androgens.

Sordello S, Bertrand N, Plouet J.

Biochem Biophys Res Commun. 1998 Oct 9; 251(1):287-90.

Evidence from pathophysiological studies support the concept that embryonic development, tumor progression, and hormonally-regulated tissue masses such as adult prostate and corpus luteum are angiogenesis-dependent. We examined if the prostatic expression of vascular endothelial growth factor (VEGF), the major regulator of normal and pathological angiogenesis, was regulated by testosterone. Northern blot of VEGF messenger ribonucleic acid (mRNA) extracted from a human immortalized epithelial prostatic cell line (PNT1) showed that dihydrotestosterone (DHT) up-regulated VEGF mRNA at a level comparable to that observed upon exposure to growth factors. Polymerase chain reaction of reverse transcribed mRNA demonstrated that the ratio of the two splice variants encoding the 121 and 165 isoforms of VEGF were not affected by DHT. VEGF biological activity, measured in the conditioned medium by radio receptor assay, was increased by DHT. Injection of testosterone in adult rats induced a transient increase of the ventral lobe weight and the specific activity of prostatic VEGF, leading to a 7-fold increase in the prostate content of VEGF

High-sensitivity C-reactive protein in the prediction of coronary events in patients with premature coronary artery disease.

Speidl WS, Graf S, Hornykewycz S, et al.

Am Heart J. 2002 Sep; 144(3):449-55.

BACKGROUND AND METHODS: Inflammation plays an important role in the initiation and progression of atherosclerosis and in the pathogenesis of acute cardiovascular events. Recent studies have indicated a possible association between C-reactive protein (CRP) and the clinical outcome of coronary artery disease (CAD). We studied prospectively in a group of 125 patients with premature CAD whether plasma levels of CRP as measured with a high-sensitivity assay predict risk for future coronary events. All patients had stable CAD at time of blood sampling but had originally been seen with unstable angina or myocardial infarction. The mean follow-up time after blood collection was 54 months, and death, myocardial infarction, need for coronary revascularization, or admission to hospital with angina pectoris were defined as clinical end points. RESULTS: Patients in the highest tertile of CRP levels had a >3.8-fold risk (risk ratio 3.82, 95% CI 1.19-12.17) for death, myocardial infarction, or need for coronary revascularization compared with the patients in the first tertile. The relative risk for patients in the second tertile was 3.5-fold higher (95% CI 1.04-11.56). CRP levels in the third tertile independently predicted risk after adjustment for lipids and other clinical risk factors. CONCLUSION: In patients with clinically stable conditions who have a positive history for acute coronary syndromes before age 50 years, plasma levels of CRP higher than 1.6 mg/L are predictors of future coronary events and therefore indicate the role of underlying chronic inflammation for the clinical course of CAD. Accordingly, reference limits for prediction of risk in CAD have to be lower in this specific patient group than in middle-aged or elderly patients

STAT3 mediates IL-6-induced neuroendocrine differentiation in prostate cancer cells.

Spiotto MT, Chung TD.

Prostate. 2000 Feb 15; 42(3):186-95.

BACKGROUND: In the human prostate cancer cell line LNCaP, interleukin (IL)-6 has been shown to regulate both growth and neuroendocrine (NE) differentiation. We recently observed that IL-6 mediated growth arrest in LNCaP by activating STAT 3. Since differentiation and growth arrest are often associated processes, we investigated whether STAT3 also mediated NE differentiation in this prostate cancer cell line. METHODS: We treated previously characterized clones LNCaP-neo (neomycin-resistant LNCaP) and LNCaP-SF (LNCaP-STAT3 dominant negative mutant) with IL-6 and screened for NE differentiation by observing morphological changes and immunoblotting for two NE markers, neuron-specific enolase (NSE) and chromogranin A (ChA). To characterize further the role of STAT3 in growth arrest and differentiation, we transfected a wild-type STAT3 vector into PC-3 cells and generated a subclone PC-3-S3. In this clone, we assessed differentiation by observing morphological changes and determined growth responses by cell counting and clonogenic assays. RESULTS: We observed that IL-6 induced formation of neurite extensions, morphologic features associated with NE differentiation, and enhanced expression of neuronal markers ChA and NSE in LNCaP-neo cells. In contrast, LNCaP-SF, possessing a dominant negative mutant form of STAT3, exhibited no characteristics of IL-6 induced NE differentiation. Furthermore, expression of a constitutively phosphorylated wild-type STAT3 in PC-3 cells inhibited growth and induced the formation of neurite extensions and NSE expression. CONCLUSIONS: These results indicate that STAT3 is a mediator of both NE differentiation and growth inhibition in LNCaP and PC-3, suggesting a connection between growth inhibition and NE differentiation in prostate cancer

Chemical composition and potential health effects of prunes: a functional food?

Stacewicz-Sapuntzakis M, Bowen PE, Hussain EA, et al.

Crit Rev Food Sci Nutr. 2001 May; 41(4):251-86.

Prunes are dried plums, fruits of Prunus domestica L., cultivated and propagated since ancient times. Most dried prunes are produced from cultivar d'Agen, especially in California and France, where the cultivar originated. After harvest, prune-making plums are dehydrated in hot air at 85 to 90 degrees C for 18 h, then further processed into prune juice, puree, or other prune products. This extensive literature review summarizes the current knowledge of chemical composition of prunes and their biological effects on human health. Because of their sweet flavor and well-known mild laxative effect, prunes are considered to be an epitome of functional foods, but the understanding of their mode of action is still unclear. Dried prunes contain approximately 6.1 g of dietary fiber per 100 g, while prune juice is devoid of fiber due to filtration before bottling. The laxative action of both prune and prune juice could be explained by their high sorbitol content (14.7 and 6.1 g/100 g, respectively). Prunes are good source of energy in the form of simple sugars, but do not mediate a rapid rise in blood sugar concentration, possibly because of high fiber, fructose, and sorbitol content. Prunes contain large amounts of phenolic compounds (184 mg/100 g), mainly as neochlorogenic and chlorogenic acids, which may aid in the laxative action and delay glucose absorption. Phenolic compounds in prunes had been found to inhibit human LDL oxidation in vitro, and thus might serve as preventive agents against chronic diseases, such as heart disease and cancer. Additionally, high potassium content of prunes (745 mg/100 g) might be beneficial for cardiovascular health. Dried prunes are an important source of boron, which is postulated to play a role in prevention of osteoporosis. A serving of prunes (100 g) fulfills the daily requirement for boron (2 to 3 mg). More research is needed to assess the levels of carotenoids and other phytochemicals present in prunes to ensure correct labeling and accuracy of food composition tables in order to support dietary recommendations or health claims

Influence of the hypoxic subvolume on the survival of patients with head and neck cancer.

Stadler P, Becker A, Feldmann HJ, et al.

Int J Radiat Oncol Biol Phys. 1999 Jul 1; 44(4):749-54.

PURPOSE: Tumor hypoxia is regarded as an important factor influencing radiation response, disease-free, and overall survival of patients with squamous cell carcinoma of the head and neck (SCCHN). This study was performed to reevaluate the prognostic significance of the "classical oxygenation parameters" hypoxic fraction (percentage of pO2 values < 5 mmHg or < 2.5 mmHg, respectively) and median pO2, and to determine the influence of a new radiobiological factor. This factor was termed the "hypoxic subvolume" (HSV) and was defined as percentage of pO2-values below 5 mmHg multiplied by the total tumor volume. The rationale of this parameter was to quantify approximately the amount of hypoxic tissue which should be correlated to the number of hypoxic cells in the tumor. It is obvious that a tumor of 100 cm3 with a hypoxic fraction of 20% (HSV = "20" cm3) contains more hypoxic cells than a tumor of 1 cm3 with a hypoxic fraction of 50% (HSV = "0.5" cm3). METHODS AND MATERIALS: Pretreatment pO2 was assessed in 59 patients with SCCHN with the Eppendorf histograph, and pretreatment volume was determined by ultrasonography (lymphnode metastases) and computer tomography (primaries). All patients were referred to our departments for radiotherapy (n = "27," median dose 70 Gy) or radiochemotherapy (n = "32;" 5-FU, mitomycin C, median dose 70 Gy), respectively. All parameters were evaluated using the Kaplan-Meier analysis, and significance was assumed at a p-value of < 0.05 (log-rank test, Cox-Mantel). A multivariate analysis was performed to control for confounding factors. The median follow-up was 233 days. At the time of the evaluation, 34 of the 59 patients were dead. RESULTS: In univariate analyses, the hypoxic fraction (pO2 < 5 mmHg, PO2 < 2.5 mmHg [p < 0.05]), the hemoglobin concentration (p < 0.05), and the hypoxic subvolume (p < 0.01) were of prognostic significance for overall survival. In multivariate analysis, the hemoglobin concentration and the hypoxic subvolume (p = "0.01)" were significant prognosticators. We found no significant correlation between tumor volume or median pO2 and overall survival. No clear correlation was found between tumor volume and hypoxic fraction. CONCLUSION: These data suggest that the total amount of hypoxic tissue, as determined by the hypoxic subvolume, influences the prognosis of patients suffering from SCCHN. In addition, our data confirm the statements of previous studies that low pretherapy pO2-values indicate a worse prognosis

Combination of symptom score, flow rate and prostate volume for predicting bladder outflow obstruction in men with lower urinary tract symptoms.

Steele GS, Sullivan MP, Sleep DJ, et al.

J Urol. 2000 Aug; 164(2):344-8.

PURPOSE: The severity of lower urinary tract symptoms associated with benign prostatic enlargement correlates poorly with bladder outlet obstruction. Since urodynamic studies are presumed to be relatively complex, invasive and not cost-effective, they are not routinely performed by physicians treating men with lower urinary tract symptoms. As a result, a large number of patients are treated for bladder outlet obstruction when in fact obstruction may not be present. Since other noninvasive methods have not been effective for predicting bladder outlet obstruction, we investigated whether a combination of prostate volume, uroflowmetry and the American Urological Association (AUA) symptom index would be reliable for predicting this condition. MATERIALS AND METHODS: We prospectively evaluated 204 men with a mean age plus or minus standard deviation of 66.7 +/- 7.5 years who presented with lower urinary tract symptoms. Each patient completed an AUA symptom index questionnaire and underwent uroflowmetry, post-void residual urine volume measurement, pressure flow study and transrectal ultrasound of the prostate to estimate prostatic volume. We constructed receiver operating characteristics curves using various threshold values for maximum urine flow and prostate volume. Threshold values for maximum urine flow and prostate volume were used alone and combined with the AUA symptom index for predicting bladder outlet obstruction. We selected a cutoff value for maximum urine flow of 10 or less ml. per second and prostate volume of 40 gm. or greater, and used these values with an AUA symptom index of greater than 20 to predict bladder outlet obstruction in the group overall. RESULTS: Differences in the mean symptom index score in men with and without bladder outlet obstruction were not statistically significant. There was no obstruction in 19%, 28.9% and 35% of those with severe, moderate and mild symptoms, respectively. The selected cutoff values of maximum urine flow, prostate volume and symptom score combined correctly predicted obstruction in all 39 patients. Therefore, our combination of cutoff values proved to be highly accurate for predicting bladder outlet obstruction. Sensitivity, specificity, and positive and negative predictive values were 26%, 100%, 100% and 32%, respectively. CONCLUSIONS: Our study showed that combining the AUA symptom index, maximum urine flow and prostate volume reliably predicted bladder outlet obstruction in a small subset of patients only. Although bladder outlet obstruction was correctly predicted by our threshold values of AUA symptom index, maximum urine flow and prostate volume in only 39 men (26%) with obstruction, these patients represent a substantial group in any large urological practice treating male lower urinary tract symptoms

An artificial neural network considerably improves the diagnostic power of percent free prostate-specific antigen in prostate cancer diagnosis: results of a 5-year investigation.

Stephan C, Jung K, Cammann H, et al.

Int J Cancer. 2002 May 20; 99(3):466-73.

Our study was performed to evaluate the diagnostic usefulness of %fPSA alone and combined with an ANN at different PSA concentration ranges, including the low range 2-4 ng/ml, to improve the risk assessment of prostate cancer. A total of 928 men with prostate cancer and BPH without any pretreatment of the prostate in the PSA range 2-20 ng/ml were enrolled in the study between 1996 and 2001. An ANN with input data of PSA, %fPSA, patient's age, prostate volume and DRE status was developed to calculate the individual's risk before performing a prostate biopsy within the different PSA ranges 2-4, 4.1-10 and 10.1-20 ng/ml. ROC analysis and cut-off calculations were used to estimate the diagnostic improvement of %fPSA and ANN in comparison to PSA. At the 90% sensitivity level, %fPSA and ANN performed better than PSA in all ranges, enhancing the specificity by 15-28% and 32-44%, respectively. For the low PSA range 2-4 ng/mL, we recommend a first-time biopsy at an ANN specificity level of 90%. For PSA 4-10 ng/mL, we recommend a first-time biopsy based on the ANN at the 90% sensitivity level. Use of an ANN enhances the %fPSA performance to further reduce the number of unnecessary biopsies within the PSA range 2-10 ng/ml

Multicenter evaluation of an artificial neural network to increase the prostate cancer detection rate and reduce unnecessary biopsies.

Stephan C, Cammann H, Semjonow A, et al.

Clin Chem. 2002 Aug; 48(8):1279-87.

BACKGROUND: The percentage of free prostate-specific antigen (%fPSA) has been shown to improve specificity for the diagnosis of prostate cancer (PCa) over total PSA (tPSA). A multicenter study was performed to evaluate the diagnostic value of a %fPSA-based artificial neural network (ANN) in men with tPSA concentrations between 2 and 20 microg/L for detecting patients with increased risk of a positive prostate biopsy for cancer. METHODS: We enrolled 1188 men from six different hospitals with PCa or benign prostates between 1996 and 2001. We used a newly developed ANN with input data of tPSA, %fPSA, patient age, prostate volume, and digital rectal examination (DRE) status to calculate the risk for the presence of PCa within different tPSA ranges (2-4, 4.1-10, 2-10, 10.1-20, and 2-20 microg/L) at the 90% and 95% specificity or sensitivity cutoffs, depending on the tPSA concentration. ROC analysis and cutoff calculations were used to estimate the diagnostic improvement of the ANN compared with %fPSA alone. RESULTS: In the low tPSA range (2-4 microg/L), the ANN detected 72% and 65% of cancers at specificities of 90% or 95%, respectively. At 4-10 microg/L tPSA, the ANN detected 90% and 95% of cancers with specificities of 62% and 41%, respectively. Use of the ANN with 2-10 microg/L tPSA enhanced the specificity of %fPSA by 20-22%, thus reducing the number of unnecessary biopsies. CONCLUSIONS: Enhanced accuracy of PCa detection over that obtained using %fPSA alone can be achieved with a %fPSA-based ANN that also includes clinical information from DRE and prostate volume measurements

Utility of PSA doubling time in follow-up of untreated patients with localized prostate cancer.

Stephenson AJ, Aprikian AG, Souhami L, et al.

Urology. 2002 May; 59(5):652-6.

OBJECTIVES: To evaluate the prostate-specific antigen (PSA) changes and the ability of PSA doubling time (PSADT) to predict disease progression in untreated patients with clinically localized prostate cancer. METHODS: A total of 104 patients with localized prostate cancer were followed up expectantly with serial PSA measurements and digital rectal examination (DRE). PSADT was calculated by linear regression analysis for the 94 patients who had a minimum of three PSA measurements and 12 months of follow-up. The median follow-up was 33 months. Of the 94 patients, 45 underwent repeat prostate biopsy to evaluate whether tumor progression occurred during the observation period. RESULTS: Twenty-seven percent of patients had rapid PSADTs (less than 48 months). Only the presence of palpable disease on DRE correlated with a PSADT of less than 48 months (P

Vascular endothelial growth factor expression and tumor angiogenesis are regulated by androgens in hormone responsive human prostate carcinoma: evidence for androgen dependent destabilization of vascular endothelial growth factor transcripts.

Stewart RJ, Panigrahy D, Flynn E, et al.

J Urol. 2001 Feb; 165(2):688-93.

PURPOSE: The hormonally regulated growth of some human carcinomas represents an important therapeutic target. We report that androgens modulate the angiogenic activity of hormone responsive human prostate cancer. MATERIALS AND METHODS: To define further the critical mechanisms underlying hormone responsiveness we examined the angiogenic mediator, vascular endothelial growth factor messenger (m) RNA and protein in response to androgens in vitro as well as the angiogenic response of xenografts of human prostate cancer after androgen withdrawal in vivo. RESULTS: In vitro androgen deprivation of LnCaP prostate cancer cells led to decreased vascular endothelial growth factor mRNA and protein expression as well as a 5-fold destabilization in vascular endothelial growth factor mRNA transcripts. In addition, androgen withdrawal inhibited the hypoxic induction of vascular endothelial growth factor mRNA. In mice bearing LnCaP tumors castration resulted in a rapid decrease in mRNA expression and markedly reduced tumor neovascularization. CONCLUSIONS: These findings implicate sex steroids as an important stimulus for vascular endothelial growth factor regulation in hormone sensitive tumors and demonstrate the reversal of neovascularization after hormone withdrawal as an early event in the tumor response to therapy

Exploiting tumor-specific defects in the interferon pathway with a previously unknown oncolytic virus.

Stojdl DF, Lichty B, Knowles S, et al.

Nat Med. 2000 Jul; 6(7):821-5.

Interferons are circulating factors that bind to cell surface receptors, activating a signaling cascade, ultimately leading to both an antiviral response and an induction of growth inhibitory and/or apoptotic signals in normal and tumor cells. Attempts to exploit the ability of interferons to limit the growth of tumors in patients has met with limited results because of cancer-specific mutations of gene products in the interferon pathway. Although interferon-non-responsive cancer cells may have acquired a growth/survival advantage over their normal counterparts, they may have simultaneously compromised their antiviral response. To test this, we used vesicular stomatitis virus (VSV), an enveloped, negative-sense RNA virus exquisitely sensitive to treatment with interferon. VSV rapidly replicated in and selectively killed a variety of human tumor cell lines even in the presence of doses of interferon that completely protected normal human primary cell cultures. A single intratumoral injection of VSV was effective in reducing the tumor burden of nude mice bearing subcutaneous human melanoma xenografts. Our results support the use of VSV as a replication-competent oncolytic virus and demonstrate a new strategy for the treatment of interferon non-responsive tumors

Intermittent androgen deprivation in prostate cancer patients: factors predictive of prolonged time off therapy.

Strum SB, Scholz MC, McDermed JE.

Oncologist. 2000; 5(1):45-52.

OBJECTIVES: We hypothesize that prostate cancer (PC) patients who achieve and maintain an undetectable prostate-specific antigen (UD-PSA) on androgen deprivation therapy (ADT) have a predominantly androgen-dependent cancer cell population sensitive to apoptosis that allows for a prolonged time off ADT. This study summarizes patient- and treatment-related factors associated with a prolonged time off ADT in patients electing intermittent androgen deprivation (IAD). METHODS: Hormone-naive patients with PC were treated with ADT using an antiandrogen and a luteinizing-hormone-releasing hormone-agonist. Of 255 consecutive patients, 216 (85%) achieved a UD-PSA ( or = 5.0 ng/ml. Forty-one patients received finasteride as part of IAD induction and as maintenance off therapy; these patients are excluded from the current study and are the focus of another publication. The remaining 52 patients are assessable for response being either in the off-phase of IAD > or = 1 year or having restarted IAD. RESULTS: In the first IAD cycle, the median duration of the on-phase of IAD was 16 months (mean 19.0 months, range 3.6-71 months), and the median off-phase duration was 15.5 months (mean 24.1 months, range 3.2-87+ months). In 28 patients who maintained a UD-PSA for > or = 1 year, their median off-phase duration was 29 months (mean 35.8 months, range 7.8-87+ months), with nine (32%) still off IAD after a median follow-up of 62 months. Significant (p or = 1 year (p = 0.010), PSA-only recurrence after local therapy (p = 0.039), and reaching a testosterone level > or = 150 ng/dl in > or = 4 months off ADT (p = 0.041). After a median of 66 months of follow-up, only one (2%) patient developed androgen-independent PC. CONCLUSIONS: Hormone-naive patients who achieve and maintain a UD-PSA for at least one year during ADT may initiate IAD and anticipate a prolonged off-phase duration. Attainment of a UD-PSA on ADT may serve as an in vivo sensitivity test of a patient's tumor cell population, and allow for better selection of those best suited for IAD

Apoptosis and bcl-2 expression in prostate cancer: significance in clinical outcome after brachytherapy.

Szostak MJ, Kaur P, Amin P, et al.

J Urol. 2001 Jun; 165(6 Pt 1):2126-30.

PURPOSE: Radiation induced apoptosis of prostate cancer cells may have therapeutic and prognostic significance in patients treated with radiotherapy. We determined whether the ability of prostate tumor cells to undergo apoptosis has potential value for predicting the clinical response of patients with prostate cancer to brachytherapy. MATERIALS AND METHODS: A total of 76 patients with clinical stages T1 to 2 disease who were not receiving adjuvant therapy underwent transperineal implantation with 125iodine or 103palladium seeds and biopsy 7 to 23 months (median 12) after therapy. Nonresponders were classified using the American Society for Therapeutic Radiology and Oncology criteria. The apoptotic index was analyzed using the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling assay in archived biopsy specimens from 76 treated and 19 matched pretreatment control patients. Serial sections of prostatic tumors were also evaluated for the expression of bax and bcl-2 proteins (apoptosis regulators) by immunohistochemical testing. RESULTS: A significant increase in the apoptotic index was detected in post-brachytherapy compared with pretreatment prostate specimens (3.1% versus 2%, p

Investigation on serum neurone-specific enolase in prostate cancer diagnosis and monitoring: comparative study of a multiple tumor marker assay.

Tarle M, Rados N.

Prostate. 1991; 19(1):23-33.

A quadruple tumor marker serotest assay (neurone-specific enolase, NSE, prostate-specific antigen, PSA, prostatic acid phosphatase, PAP, and carcino-embryonic antigen, CEA) was performed on sera from both 63 patients with untreated prostate cancer and 135 patients treated with orchiectomy, flutamide, diethylstilbestrol (DES), cyproterone acetate (CPA), and Estracyt. In untreated patients with local tumor elevated blood NSE concentrations were found more frequently (10/35, 28.6%) than in untreated subjects with disseminated disease (3/28, 10.7%). Elevated NSE values were measured more frequently in nonresponders to therapy 10/46 (21.7%), than in responders during prostate cancer partial remission (2/89, 2.2%). In none of NSE-positive neoplasms a small cell prostate cancer has been histologically detected. Many of NSE-positive tumors are also closely associated with elevated blood CEA values. The applied anticancer drugs were inefficient in the normalization of neither one from the pair of elevated NSE and CEA concentrations (regardless of the numerical values of the other two markers, PSA and PAP), but their values were found to decline occasionally only after surgical treatment. In patients with raised PSA, PAP, and CEA levels but with a normal NSE value, the application of the same treatment strategies was in the most of subjects sufficient to provoke either temporary or even lasting tumor response to therapy. Hence, it appears that the assessment of the NSE serotest, despite its minimal value in the overall tumor staging and monitoring, might furnish the decision-making step related to the treatment of aggressive prostate cancer with an additional and powerful tool

A more objective staging of advanced prostate cancer--routine recognition of malignant endocrine structures: the assessment of serum TPS, PSA, and NSE values.

Tarle M, Frkovic-Grazio S, Kraljic I, et al.

Prostate. 1994; 24(3):143-8.

Bone scans, serum tissue-specific polypeptide antigen (TPS), prostate specific antigen (PSA), and neuron-specific enolase (NSE) were assessed in a total of 80 hormonally treated prostate cancer patients. Thirty-nine patients were free of osseous lesions; in 8 subjects, 3 or fewer scintigraphic hot spots were found; in 29 patients, more than 3 bone lesions were recorded. In 3 patients, a partial contribution of endocrine cell cancer structures was found, while in one patient, a homogeneous small cell carcinoma was detected at autopsy. Measurement of the serum PSA test showed a clear-cut rise from stage D0 subjects to stage D2 patients, with a small number of bone lesions (> or = 3). However, a relative decrease in the mean PSA level was measured with further progression in a number of hot spots in bone (> 3). Androgen threshold that is critical for the induction of the PSA (and PAP) expression seems to differ markedly in various cell subpopulations that arise during adenocarcinoma dedifferentiation. This fact explains not only the rise in serum PSA in the majority of progressive and previously castrated subjects after an initial period of hormonal responsiveness, but also a relative decline of androgen-dependent PSA expression with further tumor progression. Localized disease was accompanied with normal or just slightly elevated TPS concentration. In metastatic tumors, serum TPS values revealed a steady increase with the progression in bone. These data seem to reflect not only an increase in tumor proliferation rate with progressively transformed genome, but also the rise in the number of proliferating cells. The presence of nonepithelial transformed tumor structures, such as small cell cancer within a bulk of adenocarcinoma, reduces or normalizes numerical serotests values of both TPS and PSA even during tumor progression. The extent of such decline depends upon the bulk of the endocrine component. The assessment of the above parameters, especially when associated with elevated plasma NSE concentrations, may help in distinguishing an advanced adenocarcinoma with and without elements of malignant neuroendocrine structures. The proposed approach, modified by applying corresponding organ-specific markers, may be checked for its possible general use in staging protocols of various heterogeneous tumors

Effect of thermal variables on frozen human primary prostatic adenocarcinoma cells.

Tatsutani K, Rubinsky B, Onik G, et al.

Urology. 1996 Sep; 48(3):441-7.

OBJECTIVES: Recent advances in imaging technology and cryotechnology have rekindled interest in prostate cryosurgery. Cryosurgery, however, cannot be applied precisely without knowing how the thermal variables used during the procedure affect tissue destruction. The goal of this article is to provide quantitative values for the relationship between thermal variables during freezing and the destruction of human primary prostatic adenocarcinoma cells. METHODS: Human primary prostatic adenocarcinoma cells were frozen with controlled thermal parameters, using a directional solidification apparatus. Cell viability was determined after thawing, using trypan blue and a two-dye fluorescent test and correlated to the thermal variables used during freezing. RESULTS: Human primary prostatic adenocarcinoma cells are damaged by intracellular chemical damage when frozen with cooling rates lower than 5 degrees C/min and by intracellular ice formation when frozen with cooling rates higher than 25 degrees C/min. A double freeze/thaw cycle is required to ensure complete cell destruction at high subzero temperatures, which must be lower than -40 degrees C for the low cooling rates and lower than -19 degrees C for the higher cooling rate. CONCLUSIONS: Haphazard freezing does not necessarily destroy tissue during cryosurgery; however, quantitative data on the relation between thermal variables and frozen cell destruction can provide the means for performing cryosurgery more precisely and with greater control over the outcome of the procedure

Ejaculation increases the serum prostate-specific antigen concentration.

Tchetgen MB, Song JT, Strawderman M, et al.

Urology. 1996 Apr; 47(4):511-6.

OBJECTIVES: To determine the effect of ejaculation on the serum prostate-specific antigen (PSA) concentration in men at risk for developing prostate cancer. METHODS: A prospective, community-based study was conducted in which 64 men, aged 49 to 79 years, underwent a serum PSA determination immediately before ejaculation (baseline) and at 1 hour, 6 hours, and 24 hours following ejaculation. The serum PSA also was measured 48 hours and 1 week after ejaculation if the concentration had not returned to the baseline value by the previous time interval. All subjects abstained from ejaculation for a minimum of 7 days prior to the study and until the PSA concentration returned to the baseline level. Absolute and relative change in serum PSA concentration, as well as the time to return to baseline PSA concentration following ejaculation, were assessed. RESULTS: The serum PSA concentration increased following ejaculation in 87% of the subjects. The mean baseline PSA was 1.8 ng/mL (median, 0.7 ng/mL). The mean absolute PSA change +/- standard deviation 1 hour, 6 hours, 24 hours, and 48 hours after ejaculation was 0.8 +/- 1.32 ng/mL, 0.3 +/- 0.66 ng/mL, 0.2 +/- 0.33 ng/mL, and 0.4 +/- 0.40 ng/mL, respectively. The mean relative PSA change +/- standard error 1 hour, 6 hours, 24 hours, and 48 hours after ejaculation was 41 +/- 4%, 9 +/- 1.5%, 8 +/- 1.3%, and 10 +/- 2.3%, respectively. The absolute and relative changes in PSA concentration noted 1 hour, 6 hours, and 24 hours after ejaculation were statistically significant (P = 0.0001). A strong correlation was observed between absolute change in PSA and baseline serum PSA, at each time interval (1 hour: r = 0.68, 6 hours: r = 0.77, 24 hours: r = 0.70; P < 0.0001) after ejaculation. Similarly, a significant correlation was noted between absolute change in PSA and patient age at each time interval (1 hour: r = "0.37," 6 hours: r = "0.38;" P = "0.002," 24 hours: r = "0.55;" P < 0.0001). Ninety-two percent of subjects returned to baseline by 24 hours (95% confidence interval (Cl) = "83%" to 97%), whereas 97% of subjects returned to baseline by 48 hours (95% Cl = "89%" to 99%). CONCLUSIONS: Ejaculation causes a significant increase in the serum PSA concentration in men between 49 and 79 years of age that may persist for up to 48 hours. This change appears to correlate with age and baseline PSA. It is recommended that men abstain from ejaculation for 48 hours prior to having a serum PSA determination

Predictive modeling techniques in prostate cancer.

Tewari A, Porter C, Peabody J, et al.

Mol Urol. 2001; 5(4):147-52.

A number of new predictive modeling techniques have emerged in the past several years. These methods can be used independently or in combination with traditional modeling techniques to produce useful tools for the management of prostate cancer. Investigators should be aware of these techniques and avail themselves of their potentially useful properties. This review outlines selected predictive methods that can be used to develop models that may be useful to patients and clinicians for prostate cancer management

Genetic adaptive neural network to predict biochemical failure after radical prostatectomy: a multi-institutional study.

Tewari A, Issa M, El Galley R, et al.

Mol Urol. 2001; 5(4):163-9.

BACKGROUND AND PURPOSE: Despite many new procedures, radical prostatectomy remains one of the commonest methods of treating clinically localized prostate cancer. Both from the physician's and the patient's point of view, it is important to have objective estimation of the likelihood of recurrence, which forms the foundation for treatment selection for an individual patient. Currently, it is difficult to predict the probability of biochemical recurrence (rising serum prostate specific antigen [PSA] concentration) in an individual patient, and approximately 30% of the patients do experience recurrence. Tools predicting the recurrence will be of immense practical utility in the treatment selection and planning follow up. We have utilized preoperative parameters through a computer based genetic adaptive neural network model to predict recurrence in such patients, which can help primary care physicians and urologists in making management recommendations. PATIENTS AND METHODS: Fourteen hundred patients who underwent radical prostatectomy at participating institutions form the subjects of this study. Demographic data such as age, race, preoperative PSA, systemic biopsy based staging and Gleason scores were used to construct a neural network model. This model simulated the functioning of a trained human mind and learned from the database. Once trained, it was used to predict the outcomes in new patients. RESULTS: The patients in this comprehensive database were representative of the average prostate cancer patients as seen in USA. Their mean age was 68.4 years, the mean PSA concentration before surgery was 11.6 ng/mL, and 67% patients had a Gleason sum of 5 to 7. The mean length of follow-up was 41.5 months. Eighty percent of the cancers were clinical stage T2 and 5% T3. In our series, 64% of patients had pathologically organ-confined cancer, 33% positive margins, and 14% had seminal vesicle invasion. Lymph node positive patients were not included in this series. Progression as judged by serum PSA was noted in 30.6%. With entry of a few routinely used parameters, the model could correctly predict recurrence in 76% of the patients in the validation set. The area under the curve was 0.831. The sensitivity was 85%, the specificity 74%, the positive predictive value 77%, and the negative predictive value of 83%. CONCLUSION: It was possible to predict PSA recurrence with a high accuracy (76%). Physicians desiring objective treatment counseling can use this model, and significant cost savings are anticipated because of appropriate treatment selection and patient-specific follow-up protocols. This technology can be extended to other treatments such as watchful waiting, external-beam radiation, and brachytherapy

The Lives of a Cell.

Thomas L.

1978; Second Edition

Identifying the predictors of acute urinary retention following magnetic-resonance-guided prostate brachytherapy.

Thomas MD, Cormack R, Tempany CM, et al.

Int J Radiat Oncol Biol Phys. 2000 Jul 1; 47(4):905-8.

PURPOSE: Larger prostate gland volumes have been associated with long-term urinary morbidity in prostate interstitial radiation therapy utilizing ultrasound image guidance technique. This study was performed to identify the clinical and technical predictors of acute urinary retention following magnetic-resonance (MR)-guided prostate interstitial brachytherapy. METHODS AND MATERIALS: Fifty patients underwent MR-guided prostate brachytherapy between December 1997 and March 1999. Patient selection was limited to men with stage T1cNXM0 disease, PSA of less than10 ng/mL, biopsy Gleason score not more than 3 + 4, and endorectal coil MR stage T2 disease. Dosimetry plans were developed in the operating room and (125)Iodine sources were implanted using MR real-time guidance. The peripheral zone (PZ) of the prostate gland was defined as the clinical target volume (CTV) and the minimum prescribed dose to the CTV was 137 Gy. The volumes of the PZ, transition zone (TZ), and total prostate gland volume were also determined by MR. Individual source strength ranged from 0.35 to 0.54 microGym(2)/h (NIST 99, median 0.46 microGym(2)/h) and the total implanted activity ranged from 17.0 to 43.1 mCi (median, 28.1 mCi) using 43-120 seeds (median, 79). The seeds were placed using MR-compatible biopsy needles (14-28, median, 19). RESULTS: The ability of clinical (MR defined prostate, PZ, and TZ volumes) and technical (number of catheters, number of seeds implanted, and total activity) factors to predict AUR for 50 men undergoing MR-guided prostate interstitial brachytherapy were evaluated using univariable and logistic regression multivariable analyses. Six men (12%) experienced AUR within 24 h after removal of the Foley catheter subsequent to prostate brachytherapy. The total number of seeds (p = 0.05), MR determined prostate volume (p < 0.01), and the MR-determined TZ volume (p < 0.01) were significant predictors of AUR on univariable analysis. Utilizing a multivariable logistic regression analysis, the TZ volume was the only significant predictor of AUR (p /= 50 cc), it was also self-limiting

The relation between bone mineral density, insulin-like growth factor I, lipoprotein (a), body composition, and muscle strength in adolescent males.

Thorsen K, Nordstrom P, Lorentzon R, et al.

J Clin Endocrinol Metab. 1999 Sep; 84(9):3025-9.

Osteoporosis is the most common metabolic bone disease. A low peak bone mass is regarded a risk factor for osteoporosis. Heredity, physical activity, and nutrition are regarded important measures for the observed variance in peak bone mass. Lp(a) lipoprotein is a well-known risk factor for atherosclerosis. Serum insulin-like growth factor I (IGF-I) has been found to be increased in males with early cardiovascular disease. In this study, we evaluated the association between bone mass, body constitution, muscle strength, Lp(a), and IGF-I in 47 Caucasian male adolescents (mean age, 16.9 yr). Bone mineral density (BMD) and body composition were measured by dual x-ray absorptiometry, muscle strength of thigh using an isokinetic dynamometer, IGF-I by RIA, and Lp(a) by enzyme-linked immunosorbent assay. IGF-I was only associated with Lp(a) (r = 0.38, P < 0.01). Lp(a) was related to total body (r = "0.40," P < 0.01), skull (r = "0.45," P < 0.01), and femoral neck BMD (r = "0.44," P < 0.01). Lp(a) was also related to fat mass (r = "0.34," P < 0.05) and muscle strength (r = "0.30-0.42," P < 0.05). After multiple regression and principal component (PC) analysis, the so-called PC body size (weight, fat mass, lean body mass, and muscle strength) was the most significant predictor of BMD (beta = "0.28-0.51," P < 0.05-0.01), followed by the so-called PC physical activity (beta = "0.28-0.38," P < 0.05-0.01, weight-bearing locations). However, the PC analysis confirmed that Lp(a) was an independent predictor of total body, skull, and femoral neck BMD (beta = "0.33-0.36," P < 0.01). The present investigation confirms that BMD, body size, and muscle strength are closely related and that the level of physical activity is a major determinant of BMD. However, the positive relation of Lp(a), a major risk factor for cardiovascular disease, to BMD has not previously been described. The importance of this observation has to be further investigated

Induction of cyclo-oxygenase-2 mRNA by prostaglandin E2 in human prostatic carcinoma cells.

Tjandrawinata RR, Dahiya R, Hughes-Fulford M.

Br J Cancer. 1997; 75(8):1111-8.

Prostaglandins are synthesized from arachidonic acid by the enzyme cyclo-oxygenase. There are two isoforms of cyclooxygenases: COX-1 (a constitutive form) and COX-2 (an inducible form). COX-2 has recently been categorized as an immediate-early gene and is associated with cellular growth and differentiation. The purpose of this study was to investigate the effects of exogenous dimethylprostaglandin E2 (dmPGE2) on prostate cancer cell growth. Results of these experiments demonstrate that administration of dmPGE2 to growing PC-3 cells significantly increased cellular proliferation (as measured by the cell number), total DNA content and endogenous PGE2 concentration. DmPGE2 also increased the steady-state mRNA levels of its own inducible synthesizing enzyme, COX-2, as well as cellular growth to levels similar to those seen with fetal calf serum and phorbol ester. The same results were observed in other human cancer cell types, such as the androgen-dependent LNCaP cells, breast cancer MDA-MB-134 cells and human colorectal carcinoma DiFi cells. In PC-3 cells, the dmPGE2 regulation of the COX-2 mRNA levels was both time dependent, with maximum stimulation seen 2 h after addition, and dose dependent on dmPGE2 concentration, with maximum stimulation seen at 5 microg ml(-1). The non-steroidal anti-inflammatory drug flurbiprofen (5 microM), in the presence of exogenous dmPGE2, inhibited the up-regulation of COX-2 mRNA and PC-3 cell growth. Taken together, these data suggest that PGE2 has a specific role in the maintenance of human cancer cell growth and that the activation of COX-2 expression depends primarily upon newly synthesized PGE2, perhaps resulting from changes in local cellular PGE2 concentrations

[Screening techniques].

Tremollieres F, Pouilles JM, Ribot C.

Presse Med. 2002 Apr 20; 31(15):694-8.

WOMEN "AT RISK": Assessment of the risk of osteoporosis in a woman approaching the menopause relies essentially on the evaluation of her bone mass and the study of a certain number of clinical criteria. The principle osteoporosis risk markers are age, past personal and family history of fractures due to bone fragility, low body weight, past history of early menopause and all the affections corresponding classically to "secondary" osteoporosis. OSTEODENSITOMETRY: Densitometric measurement is the corner stone of this assessment, since any decrease of 1 in the standard deviation of bone density corresponds to a two-fold greater risk of fracture. This relationship has led to a new densitometric definition of osteoporosis, based on a decrease of more than 2.5 standard deviations compared with the median value of a young adult (t-score < -2.5). THE INTEREST OF BIOCHEMICAL MARKERS: The interest of bone remodeling biochemical markers has not been clearly defined. Combined with densitometric measurements, they may permit the assessment of the level of bone remodeling and hence estimate bone loss, which is one of the determinant factors of fracture risk

Bone mineral density at the hip predicts mortality in elderly men.

Trivedi DP, Khaw KT.

Osteoporos Int. 2001; 12(4):259-65.

Low bone density as assessed by calcaneal ultrasound has been associated with mortality in elderly men and women. We examined the relationship between bone density measured at the hip and all cause and cardiovascular mortality in elderly men. Men aged 65-76 years from the general community were recruited from general practices in Cambridge between 1991 and 1995. At baseline survey, data collection included health questionnaires, measures of anthropometry and cardiovascular risk factors, as well as bone mineral density (BMD) measured using dual energy X-ray absorptiometry. All men have been followed up for vital status up to December 1999. BMD was significantly inversely related to mortality from all causes and cardiovascular disease, with decreasing rates with increasing bone density quartile, and an approximate halving of risk between the bottom and top quartile (p < 0.002, test for trend all causes and p < 0.025, test for trend for cardiovascular deaths). In multivariate analyses using the Cox proportional hazards model, an increase of 1 standard deviation (0.144 g/cm2) in total hip bone density was significantly associated with an age-adjusted 0.77 relative risk (95% CI 0.66-0.91) for all-cause mortality and 0.76 relative risk (95% CI 0.62-0.93) for cardiovascular disease mortality. The association remained significant after adjusting for age, body mass index, cigarette smoking status, serum cholesterol, systolic blood pressure, past history of heart attack, stroke or cancer and other lifestyle factors which included use of alcohol, physical activity and general health status. Low bone density at the hip is thus a strong and independent predictor of all-cause and cardiovascular mortality in older men

Effect of selenium in combination with Adriamycin or Taxol on several different cancer cells.

Vadgama JV, Wu Y, Shen D, et al.

Anticancer Res. 2000 May; 20(3A):1391-414.

The anti-neoplastic properties of an Selenium compound were studied in vitro on several tumor cell lines: Breast (MCF-7, MCF-10, SKBR-3, BCAP37), Lung (RH2), Prostate (LNCap and PC-3), Colon (T84, Caco-2), Small Intestine (HCF8), and Liver (HepG2). We also examined additive or synergistic effect of Selenium in combination with standard anti-cancer drugs, Adriamycin (Doxorubicin) and Taxol. The effect of Selenium was assessed by apoptosis; DNA synthesis; growth rate by MTT assay; uptake of amino acid MeAIB by System A; and morphological changes. Our results demonstrate that MCF-7 and SKBR-3 showed increase in apoptosis as measured by DNA fragmentation and increase in "rounded" cells and membrane "blebbing", decrease in MeAIB uptake, and decrease in DNA synthesis. These changes were Selenium dose dependent with optimal inhibition at Selenium concentration between 4 and 40 ng/ml after 72 hrs of treatment. Similar observations were made with RH2, HCF8, Caco-2, and HepG2 cells. In contrast, LNCap, PC-3, and T-84 were not significantly affected by Selenium. However, addition of Adriamycin or Taxol in combination with Selenium caused small but significant inhibition of prostate cancer cells LNCap and PC-3. Addition of chemotherapeutic agents either Taxol or Doxorubicin with Selenium caused further inhibition of MCF-7, SKBR-3, RH2, HCF8, and HepG2 cells. In conclusion, Selenium has a significant anti-neoplastic effect on breast, lung, liver, and small intestinal tumor cells. Supplementation of Selenium enhanced chemotherapeutic effect of Taxol and Doxorubicin in these cells beyond that seen with the chemotherapeutic drugs used alone. These in vitro studies on several cancer cell lines suggest a potential benefit of Selenium-enhancement of anticancer effects other systems, and therefore offer further relevance to clinical trials efforts

Liquid chromatography-mass spectrometry of cis- and all-trans-lycopene in human serum and prostate tissue after dietary supplementation with tomato sauce.

van Breemen RB, Xu X, Viana MA, et al.

J Agric Food Chem. 2002 Apr 10; 50(8):2214-9.

Several epidemiological studies suggest a lower incidence of prostate cancer in men who routinely consume tomato products. Tomatoes are the primary dietary source of lycopene, which is among the most potent antioxidants of the carotenoids. Men with clinical stage T1 or T2 prostate adenocarcinoma were recruited (n = 32) and consumed tomato sauce based pasta dishes for 3 weeks (equivalent to 30 mg of lycopene per day) before radical prostectomy. Prostate tissue from needle biopsy just before intervention and prostectomy after supplementation from a subset of 11 subjects was evaluated for both total lycopene and lycopene geometrical isomer ratios. A gradient HPLC system using a C(18) column with UV-vis absorbance detection was used to measure total lycopene. Because the absorbance detector was insufficiently sensitive, HPLC with a C(30) column and positive ion atmospheric pressure chemical ionization mass spectrometric (LC-MS) detection was developed as a new assay to measure the ratio of lycopene cis/trans isomers in these samples. The limit of detection of the LC-MS method was determined to be 0.93 pmol of lycopene on-column, and a linear response was obtained over 3 orders of magnitude. Total lycopene in serum increased 2.0-fold from 35.6 to 69.9 microg/dL (from 0.664 to 1.30 microM) as a result of dietary supplementation with tomato sauce, whereas total lycopene in prostate tissue increased 3.0-fold from 0.196 to 0.582 ng/mg of tissue (from 0.365 to 1.09 pmol/mg). all-trans-Lycopene and at least 14 cis-isomer peaks were detected in prostate tissue and serum. The mean proportion of all-trans-lycopene in prostate tissue was approximately 12.4% of total lycopene before supplementation but increased to 22.7% after dietary intervention with tomato sauce. In serum there was only a 2.8% but statistically significant increase in the proportion of all-trans-lycopene after intervention. These results indicate that short-term supplementation with tomato sauce containing primarily all-trans-lycopene (83% of total lycopene) results in substantial increases in total lycopene in serum and prostate and a substantial increase in all-trans-lycopene in prostate but relatively less in serum

Selenium modulation of cell proliferation and cell cycle biomarkers in human prostate carcinoma cell lines.

Venkateswaran V, Klotz LH, Fleshner NE.

Cancer Res. 2002 May 1; 62(9):2540-5.

Prostate cancer (PCA) is the most common histological malignancy and the second leading cause of cancer deaths among North American men. There has been considerable interest in the chemopreventative properties of selenium. In this study, we assessed whether selenium inhibits cell growth and associated cell cycle regulatory proteins. Human PCA cells (LNCaP, PC3, PC3-AR2, and PC3-M) were incubated with and without selenium (Seleno-DL-methionine, 150 microM) for 24, 48, and 72 h. Cells were fixed and stained with propidium iodide for flow cytometry analysis. In parallel experiments, total protein was extracted, immunoprecipitated with cyclin E antibody, and analyzed by Western blot for the expression of cell cycle markers. Treatment with selenium caused G1 arrest and an 80% reduction in the S phase of LNCaP with no effect on PC3. However, PC3 cells transfected with the androgen receptor (PC3-AR2) exhibited a G2/M arrest and a marked reduction (57%) in the S phase during cell cycle progression. In the analysis of cell cycle regulatory molecules, selenium-treated cells demonstrated a significant induction of cyclin-dependent kinase inhibitors Cip1/p21 and Kip1/p27. These data suggest that selenium possesses strong antiproliferative properties in regard to human PCA. This effect appears to be dependent on the presence of a functioning androgen receptor. This provides a theoretical basis for Phase III studies of selenium in PCA prevention

The dynamics of prostate specific antigen in hormone refractory prostate carcinoma: an analysis of cancer and leukemia group B study 9181 of megestrol acetate.

Vollmer RT, Dawson NA, Vogelzang NJ.

Cancer. 1998 Nov 1; 83(9):1989-94.

BACKGROUND: Although many physicians measure serum prostate specific antigen (PSA) during the follow-up of patients with hormone refractory prostate carcinoma (HRPC), little has been done to formalize the determination of how these serial values of PSA impact on prognosis. To understand HRPC fully, make decisions about choices of treatment as well as about clinical research on treatments for HRPC patients, and design appropriate measures of PSA response, it seems that first it would be necessary to understand how these serial measures of PSA relate to survival. The purpose of this study was to determine how repeated measurements of PSA impact on the probability of imminent death for patients with HRPC. METHODS: One hundred forty-eight men with HRPC were enrolled in Cancer and Leukemia Group B Study 9181, in which they were treated with either a low dose (160 mg/day) or a high dose (640 mg/day) of megestrol acetate (MA). Because preliminary data analysis indicated that these treatments had no effect on survival, the authors pooled the data to analyze the overall dynamics of PSA and survival during the follow-up period. The authors attempted to correlate initial and monthly PSA measurements, which were mandated by the study protocol, with the probability of death at any time during follow-up. For statistical analysis, the Cox proportional hazards model and the general linear model were used. In addition to the level of PSA, the authors used the relative velocity of PSA, which was defined as (dy/dt)/y, with "y" symbolizing serum PSA and "t" symbolizing time. RESULTS: Both log(PSA) and the average relative velocity of PSA (rva) were significantly correlated with survival time (P=0.0001 and P=0.0008, respectively), and the analysis performed with the Cox proportional hazards model yielded the following formula for a PSA hazard score: PSA hazard score =0.251*(log(PSA) - mean log(PSA)) + 24.5*(rva - mean rva) This hazard score tended to be higher for patients who were about to die. For example, there was a close correlation between the hazard score and the probability of death as the next observed event. Furthermore, the hazard score provided a dynamic measure of how PSA was affected by treatment. CONCLUSIONS: The average relative velocity of PSA has been identified by the authors as a new measure of the dynamics of PSA in HRPC. It can be determined from sequential values of PSA. This average, together with the log(PSA), are significantly related to the probability of imminent death

The dynamics of prostate specific antigen during watchful waiting of prostate carcinoma: a study of 94 Japanese men.

Vollmer RT, Egawa S, Kuwao S, et al.

Cancer. 2002 Mar 15; 94(6):1692-8.

BACKGROUND: For the moment, there is uncertainty about the usefulness of early treatment of localized prostate carcinoma, uncertainty about whether some patients with early cancer can be managed expectantly, and uncertainty about how such patients might be recognized. METHODS: The authors studied serial values of prostate specific antigen (PSA) in 94 Japanese men with diagnosed prostate carcinoma and who were managed by watchful waiting. Their median follow-up duration was 32 months (range, 1.6-118). The authors used a log-linear model to fit the values of PSA over time, and then they used the Cox survival model to relate the intercept (PSA amplitude) and slope (relative velocity) to observed local or systemic outcomes that were independent of PSA. RESULTS: The authors found that the log-linear model fit the serial values of PSA during watchful waiting very well. Prostate specific antigen amplitude related significantly to T classification (P = 0.0006), but not to grade (P > 0.2), and the relative velocity related significantly to both T classification (P = 0.009) and to grade (P = 0.02). Although the T classification, histologic grade, and log(PSA) at diagnosis were associated significantly with time to outcome, the combination of amplitude and relative velocity provided more information. These 2 PSA parameters resulted in a higher model likelihood ratio, and their individual P values in the Cox model were 0.0005 and 0.005, respectively. With these two in the Cox model, T classification, grade, log(PSA), and PSA doubling time provided no further significant information. CONCLUSIONS: A log-linear model seems to fit serial measurements of PSA during watchful waiting, and preliminary results suggest that both the amplitude and the relative velocity relate closely to clinical outcomes

The impact of degenerative conditions in the spine on bone mineral density and fracture risk prediction.

von der RP, Hansen MA, Overgaard K, et al.

Osteoporos Int. 1996; 6(1):43-9.

We examined the impact of degenerative conditions in the spine (osteophytosis and endplate sclerosis) and aortic calcification in the lumbar region on bone mineral content/density (BMC/BMD) measured in the spine and forearm by absorptiometry and on fracture risk prediction. The radiographs of 387 healthy postmenopausal women, aged 68-72 years, were assessed in masked fashion for the presence of osteophytosis, endplate sclerosis and aortic calcification in the region from L2 to L4. Vertebral deformities/fractures were assessed by different definitions. Osteophytes larger than 3 mm and in numbers of 3 or more resulted in a significantly (12%) higher spinal bone mass (p < 0.001). Endplate sclerosis had a similar effect (p < 0.001). In subjects with both degenerative conditions the BMC/BMD in the spine and forearm were significantly higher than in unaffected women (19% in the spine, 10% in the forearm; p < 0.001). The spinal BMD values were significantly lower in fractured women if both degenerative conditions were absent (p < 0.001), whereas fractured and unfractured women had similar values if degenerative conditions were present. Degenerative conditions did not alter the ability of forearm BMC to discriminate vertebral or peripheral fractures. Receiver operating characteristic (ROC) curves (true positive fraction versus false positive fraction) were generated for BMD of the lumbar spine and BMC of the forearm with regard to the discrimination between women with vertebral and peripheral fractures and healthy premenopausal women. The ROC curves for women without degenerative conditions were consistently above the curves for women affected by osteophytosis and endplate sclerosis in the lumbar spine (p < 0.001). In conclusion, osteophytes and endplate sclerosis have a considerable influence on spinal bone mass measurements in elderly postmenopausal women and affect the diagnostic ability of spinal scans to discriminate osteoporotic women. Our data suggest that in elderly women, unless the spine is radiologically clear of degenerative conditions, a peripheral measurement procedure should be considered an alternative for assessment of bone mineral content/density

[A comparison of two noninvasive measurement methods for determining central osteoporosis taking into consideration the ash content].

von Stremple A, Prokopp M, Flindt C.

Aktuelle Radiol. 1993 Jan; 3(1):31-6.

Two noninvasive methods for measuring bone mineral density are compared (DE-QCT; DEXA). Accuracy was determined by ash weight and real bone density. 40 human cadaver spines (D5, D11, L3, L5) were examined. There was significant high correlation between DE-QCT and real bone density (r = 0.9, alpha or = 0.05) in the cases with osteoporotic and none osteoporotic vertebra. DE-QCT seems to be a valuable method for measuring central bone mineral density

Transperineal brachytherapy in patients with large prostate glands.

Wang H, Wallner K, Sutlief S, et al.

Int J Cancer. 2000 Aug 20; 90(4):199-205.

The purpose of this study is to help clarify the use of prostate size as a selection factor for prostate brachytherapy. From 1997 to 1998, 33 patients with a TRUS-based prostate volume greater than 50 cc were treated at the University of Washington by I-125 (144 Gy) or Pd-103 (115 Gy) implantation for prostatic carcinoma. These 33 patients comprised 7% of the total implants performed. Each patient underwent a preimplant TRUS study in the lithotomy position, taking serial axial images of the prostate at 0.5 cm intervals from the base of the gland to the apex. The contours on the preimplant TRUS images were used to calculate the prostate volumes reported here. Only one patient received supplemental external beam irradiation prior to implantation. Twelve patients were treated with neoadjuvant androgen ablation prior to implantation. The prostate volumes quoted here are those taken after hormonal downsizing. Postimplant axial CT images were digitized to calculate the CT-based target coverage. Preimplant urinary obstructive symptoms were quantified by the criteria of the American Urologic Association. Each patient was contacted at the time of this article preparation to update postimplant morbidity information. In all cases, at least 80% of the postimplant volume was covered, despite a median implant-related volume increase of 15%. Five of the 33 patients' postimplant CT scans showed some degree of incomplete target coverage of the anterior/lateral prostate margin. There was no clear association between inadequate anterior/lateral coverage and the degree of interference. Twelve of the 33 patients developed acute postimplant urinary retention, all occurring within 24 hr of implantation. Within this group of 33 patients with a large prostate volume, there was no relationship between the likelihood of acute or chronic urinary retention and preimplant prostate size or obstructive symptoms. Patients who developed postimplant retention lasting more than one week were generally managed by intermittent self-catheterization. By one month, 85% of patients were catheter-free. Based on the data reported here, we are more inclined to accept patients with a large prostate for implantation without insisting on preimplant size reduction. Int. J. Cancer (Radiat. Oncol. Invest.) 90, 199-205 (2000)

Down-regulation of prostate-specific antigen expression by finasteride through inhibition of complex formation between androgen receptor and steroid receptor-binding consensus in the promoter of the PSA gene in LNCaP cells.

Wang LG, Liu XM, Kreis W, et al.

Cancer Res. 1997 Feb 15; 57(4):714-9.

As a specific competitive inhibitor of 5alpha-reductase, an intracellular enzyme that converts testosterone to dihydrotestosterone, finasteride is being extensively used for the treatment of benign prostatic hyperplasia and in experimental settings for prostate cancer. In this study, we showed that finasteride markedly inhibited prostate-specific antigen (PSA) secretion and expression. The promoter of the PSA gene contains several well-known cis-regulatory elements. Among them, steroid receptor-binding consensus (SRBC) has been identified as a functional androgen-responsive element. Our previous study showed that PSA was not only present in conditioned medium of the PSA-positive LNCaP cells but was also detectable in small amounts in PSA-negative cell lines, PC-3 and DU-145 (L. G. Wang et al., Oncol. Rep., 3: 911-917, 1996). A strong correlation between binding of nuclear factors to SRBC and the level of PSA present in the conditioned medium and cell extracts was found in these three cell lines, whereas no such correlation with binding was obtained using Sp1 oligonucleotide as a probe. Binding of LNCaP cell nuclear proteins to SRBC was diminished when the cells were exposed to 25 microM finasteride, at which concentration 50% of both PSA mRNA and protein were inhibited. As a major component of DNA-protein complexes, the level of androgen receptor was dramatically decreased in the cells treated with finasteride. Our data indicate that inhibition of complex formation between SRBC and nuclear proteins due to the remarkable decrease in the level of androgen receptor plays a key role in the down-regulation of PSA gene expression by finasteride in LNCaP cells

Decreased growth of established human prostate LNCaP tumors in nude mice fed a low-fat diet.

Wang Y, Corr JG, Thaler HT, et al.

J Natl Cancer Inst. 1995 Oct 4; 87(19):1456-62.

BACKGROUND: Geographic variation in the incidence of clinically detected prostate cancer is considerable, with a 120-fold greater incidence in the United States than in China. The incidence of latent prostate cancer, however, shows little variation worldwide, with approximately 30% of men older than age 50 years having microfocal disease (determined by autopsy). Some epidemiologic studies have suggested that a high intake of dietary fat may constitute a risk factor for the development of advanced prostate cancer. PURPOSE: We studied the influence of dietary fat content on the growth of tumors established in athymic nude mice with androgen-sensitive, human prostatic adenocarcinoma cells (LNCaP cells). We also investigated whether manipulation of dietary fat content altered prostate-specific antigen (PSA) production by these tumors. METHODS: Tumors were induced in nude mice by subcutaneous injection of 10(6) LNCaP cells. Both the American Type Culture Collection (ATCC) LNCaP cell line and a more androgen-responsive subline derived from it (i.e., the Harris LNCaP cell line) were used. Mice were fed a 40.5-kcal% fat diet at the time of tumor cell injection. Three weeks later, after measurable tumors were formed, the animals were assigned to receive diets with one of the following fat contents: 40.5, 30.8, 21.2, 11.6, or 2.3 kcal% fat. Food intake, animal weights, and tumor volumes were recorded weekly; serum PSA and testosterone levels were measured at the termination of the study. Post hoc multiple comparisons were made using the Student-Newman-Keuls procedure. Two-sided tests of statistical significance were used to evaluate pairwise comparisons. RESULTS: Tumor growth rates, final tumor weights, and ratios of final tumor weights to animal weights were substantially greater in groups that continued to receive a 40.5-kcal% fat diet than in groups whose diets were changed to 2.3 kcal%, 11.6 kcal%, or 21.2 kcal% fat (all P values < .04). Comparison of these parameters among the 2.3-kcal%, 11.6-kcal%, and 21.2-kcal% dietary fat groups did not reveal any statistically significant differences. No statistically significant differences were noted in total ingested calories, animal weight gain, serum testosterone levels, or histopathologic characteristics of the tumors among the tested dietary groups. Serum PSA levels were highest in the 40.5-kcal% fat group and lowest in the 2.3-kcal% fat group (evaluated only for ATCC LNCaP cells; P < .05). CONCLUSIONS: Reduction of dietary fat substantially slows the growth of tumors established from human prostatic adenocarcinoma cells in a murine xenograft model. A positive association persists between tumor volumes and serum PSA levels even after extreme modification of dietary fat content

Dietary ratio of (n-6)/(n-3) polyunsaturated fatty acids alters the fatty acid composition of bone compartments and biomarkers of bone formation in rats.

Watkins BA, Li Y, Allen KG, et al.

J Nutr. 2000 Sep; 130(9):2274-84.

The effects of dietary polyunsaturated fatty acids (PUFA) on ex vivo bone prostaglandin E(2) (PGE(2)) production and bone formation rate were evaluated in rats. Weanling male Sprague-Dawley rats were fed AIN-93G diet containing 70 g/kg of added fat for 42 d. The dietary lipid treatments were formulated with safflower oil and menhaden oil to provide the following ratios of (n-6)/(n-3) fatty acids: 23.8 (SMI), 9.8 (SMII), 2.6 (SMIII), and 1.2 (SMIV). Ex vivo PGE(2) production in liver homogenates and bone organ cultures (right femur and tibia) were significantly lower in rats fed diets with a lower dietary ratio of (n-6)/(n-3) fatty acids than in those fed diets with a higher dietary ratio. Regression analysis revealed a significant positive correlation between bone PGE(2) and the ratio of arachidonic acid (AA)/eicosapentaenoic acid (EPA), but significant negative correlations between bone formation rate and either the ratio of AA/EPA or PGE(2) in bone. Activities of serum alkaline phosphatase isoenzymes, including the bone-specific isoenzyme (BALP), were greater in rats fed a diet high in (n-3) or a low ratio of (n-6)/(n-3), further supporting the positive action of (n-3) fatty acids on bone formation. These results demonstrated that the dietary ratio of (n-6)/(n-3) modulates bone PGE(2) production and the activity of serum BALP in growing rats

Complications of ultrasound-guided transperineal prostate biopsy. A prospective study.

Webb JA, Shanmuganathan K, McLean A.

Br J Urol. 1993 Nov; 72(5 Pt 2):775-7.

A prospective study of the complications of transperineal prostate biopsy was undertaken in 171 patients; 150 (88%) returned a questionnaire 1 week after biopsy. The incidence of serious complications was low, with 1 patient requiring admission for presumed septicaemia and another developing acute retention of urine. Many patients had minor complications, with 42% having haematuria, 13% haemospermia and 31% pain. Only 18% needed analgesia following biopsy. Since transperineal prostate biopsy has such a low incidence of infective complications, we suggest that it should be considered in frail or elderly patients in whom septicaemia may be especially hazardous

Prostate-specific antigen, a serine protease, facilitates human prostate cancer cell invasion.

Webber MM, Waghray A, Bello D.

Clin Cancer Res. 1995 Oct; 1(10):1089-94.

Human prostatic epithelial cells constitutively secrete prostate-specific antigen (PSA), a kallikrein-like serine protease, which is a normal component of the seminal plasma. PSA is currently used as a specific diagnostic marker for the early detection of prostate cancer. We demonstrate that PSA degrades extracellular matrix glycoproteins fibronectin and laminin and, thus, may facilitate invasion by prostate cancer cells. Blocking PSA proteolytic activity with PSA-specific mAb results in a dose-dependent decrease in vitro in the invasion of the reconstituted basement membrane Matrigel by LNCaP human prostate carcinoma cells which secrete high levels of PSA. A novel PSA-SDS-PAGE zymography method for the detection of matrix degrading ability of PSA is also described. We propose that: (a) because of the dysplastic cellular disorganization in early neoplastic lesions called prostatic intraepithelial neoplasia (PIN), PSA may be secreted not only at the luminal end but also, abnormally, at the cell-basement membrane interface, causing matrix degradation and facilitating invasion; and (b) PSA, along with urokinase, another serine protease secreted by prostatic epithelium, may be involved in the proteolytic cascade during prostate cancer invasion and metastasis. The discovery of the extracellular matrix degrading ability of PSA not only makes it a marker for early detection but also a target for prevention and intervention in prostate cancer

Urokinase-mediated extracellular matrix degradation by human prostatic carcinoma cells and its inhibition by retinoic acid.

Webber MM, Waghray A.

Clin Cancer Res. 1995 Jul; 1(7):755-61.

Both normal and malignant prostatic epithelial cells in culture secrete urokinase-type plasminogen activator (u-PA) into the culture medium. u-PA has been shown to have a direct association with invasive and metastatic potential of many types of cancers. We propose that prostate cancer has the intrinsic ability to invade and metastasize because of its inherent ability to secrete the serine protease u-PA. We further propose that in prostate cancer, u-PA is the key enzyme which occupies a place at the apex of the proteolytic cascade and initiates the degradative process. Subsequently, collagenases are recruited after activation of procolla-genases by another serine protease plasmin formed by the activation of plasminogen by u-PA. Extracellular proteolysis involving plasmin can cause massive degradation of the extracellular matrix. We show that u-PA alone can use fibronectin as a substrate and degrade it, but u-PA alone did not degrade laminin. Serum-free conditioned medium from DU-145 human prostatic carcinoma cells has the ability to degrade both fibronectin and laminin. However, treatment of cultures with 1 microM all-trans retinoic acid (RA) for 48 h reduced the ability of serum-free conditioned medium to cause u-PA-mediated degradation of fibronectin and laminin. Thus, RA had a protective effect on these extracellular matrix glycoproteins. Treatment of cells with RA also decreased their ability to invade Matrigel in the in vitro invasion assay in a dose-dependent manner. RA at the 0.5, 1, and 10 microM level reduced invasion to 65.7%, 46.7%, and 34.3% of control, respectively. RA reduced extracellular proteolysis and thus inhibited extracellular matrix degradation and invasion. These results may also explain one mechanism by which retinoids inhibit invasion and metastasis in vitro and in vivo. These studies have important translational value in the chemoprevention of progression of prostatic intraepithelial neoplasia to invasive carcinoma

Cytokine variations in patients with hormone treated prostate cancer.

Wise GJ, Marella VK, Talluri G, et al.

J Urol. 2000 Sep; 164(3 Pt 1):722-5.

PURPOSE: We evaluated the immunological response in patients with hormone sensitive and refractory prostate cancer, and untreated benign prostatic hyperplasia (BPH). MATERIALS AND METHODS: Serum levels of pro-inflammatory and anti-inflammatory cytokines were measured by enzyme-linked immunosorbent assay in 3 groups of patients. The groups included 18 men with a mean age of 79 years who had hormone sensitive prostate cancer, mean prostate specific antigen (PSA) plus or minus standard deviation 1.03 +/- 2.65 ng./ml. and a mean of 35 months of treatment, 10 with a mean age of 86 years who had hormone refractory prostate cancer, mean PSA 27.52 +/- 42.23 ng./ml. and a mean of 42 months of treatment, and 19 with a mean age of 73 years who had BPH and mean PSA 3.37 +/- 2.47 ng./ml. Results were compared with those in 10 age matched, disease-free controls. In the hormone sensitive group PSA regressed to normal and there was clinical evidence of a response to hormone ablation therapy, including orchiectomy, luteinizing hormone releasing hormone analogue and androgen blockade. Hormone refractory cases had elevated PSA and/or clinical evidence of disease progression. RESULTS: Levels of the anti-inflammatory cytokines interleukin (IL)-4, IL-6 and IL-10 were significantly elevated in the hormone refractory group compared with values in the hormone sensitive group (p = 0.02, 0.01 and 0.0001, respectively). Abnormal anti-inflammatory cytokines in hormone resistant cases correlated with elevated PSA, while in the BPH group there was no significant difference from controls. Pro-inflammatory cytokines in the hormone sensitive and resistant groups were not significantly different from those in controls. CONCLUSIONS: Our study indicates that in hormone refractory prostate cancer a high level of the anti-inflammatory cytokines IL-4, IL-6 and IL-10 develops that is directly associated with elevated PSA. Changes in the level of anti-inflammatory cytokines when androgen independent cells exist may have an important role in the selection of a subset of hormone insensitive cells. These criteria may be used as a prognostic marker for the response to hormone ablation therapy in men with prostate cancer

Long-term alpha-tocopherol supplementation is associated with lower serum vascular endothelial growth factor levels.

Woodson K, Triantos S, Hartman T, et al.

Anticancer Res. 2002 Jan; 22(1A):375-8.

BACKGROUND: We previously reported that daily supplementation with alpha-tocopherol reduced prostate cancer risk in a large, randomized trial, the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. One potential mechanism explaining this is that alpha-tocopherol inhibited tumor angiogenesis, an effect demonstrated in animal models. PATIENTS AND METHODS: We evaluated whether long-term supplementation with alpha-tocopherol modified serum vascular endothelial growth factor (VEGF) levels, a cytokine integrally involved in angiogenesis, in men who were not diagnosed with cancer and had baseline and follow-up blood available. One hundred of these men who received alpha-tocopherol (50 mg daily) were randomly selected and matched on age, study center and time between blood draws to 100 men who received placebo (median follow-up 3.7 years). VEGF levels were measured by enzyme-linked immunosorbent assay. The effect of alpha-tocopherol supplementation on serum VEGF was evaluated using a matched-paired t-test for differences in the change in VEGF over the intervention period between groups. RESULTS: There was an 11% reduction in VEGF levels in the alpha-tocopherol group as compared with a 10% increase in the placebo group (p=0.03). CONCLUSION: Our findings suggest that one of the mechanisms behind the inhibition of prostate carcinogenesis by alpha-tocopherol in the ATBC Study may have been through reduced VEGF concentrations and the suppression of tumor angiogenesis and therefore growth

Hypoxia as a target for combined modality treatments.

Wouters BG, Weppler SA, Koritzinsky M, et al.

Eur J Cancer. 2002 Jan; 38(2):240-57.

There is overwhelming evidence that solid human tumours grow within a unique micro-environment. This environment is characterised by an abnormal vasculature, which leads to an insufficient supply of oxygen and nutrients to the tumour cells. These characteristics of the environment limit the effectiveness of both radiotherapy and chemotherapy. Measurement of the oxygenation status of human tumours has unequivocally demonstrated the importance of this parameter on patient prognosis. Tumour hypoxia has been shown to be an independent prognostic indicator of poor outcome in prostate, head and neck and cervical cancers. Recent laboratory and clinical data have shown that hypoxia is also associated with a more malignant phenotype, affecting genomic stability, apoptosis, angiogenesis and metastasis. Several years ago, scientists realised that the unique properties within the tumour micro-environment could provide the basis for tumour-specific therapies. Efforts that are underway to develop therapies that exploit the tumour micro-environment can be categorised into three groups. The first includes agents that exploit the environmental changes that occur within the micro-environment such as hypoxia and reduced pH. This includes bioreductive drugs that are specifically toxic to hypoxic cells, as well as hypoxia-specific gene delivery systems. The second category includes therapies designed to exploit the unique properties of the tumour vasculature and include both angiogenesis inhibitors and vascular targeting agents. The final category includes agents that exploit the molecular and cellular responses to hypoxia. For example, many genes are induced by hypoxia and promoter elements from these genes can be used for the selective expression of therapeutic proteins in hypoxic tumour cells. An overview of the various properties ascribed to tumour hypoxia and the current efforts underway to exploit hypoxia for improving cancer treatment will be discussed

COX-2 inhibitors in cancer treatment and prevention, a recent development.

Xu XC.

Anticancer Drugs. 2002 Feb; 13(2):127-37.

Epidemiological and experimental studies have demonstrated the effect of non-steroidal anti-inflammatory drugs (NSAIDs) in the prevention of human cancers. NSAIDs block endogenous prostaglandin synthesis through inhibition of cyclooxygenase (COX) enzymatic activity. COX-2, a key isoenzyme in conversion of arachidonic acid to prostaglandins, is inducible by various agents such as growth factors and tumor promoters, and is frequently overexpressed in various tumors. The contribution of COX-2 to carcinogenesis and the malignant phenotype of tumor cells has been thought to be related to its abilities to (i) increase production of prostaglandins, (ii) convert procarcinogens to carcinogens, (iii) inhibit apoptosis, (iv) promote angiogenesis, (v) modulate inflammation and immune function, and (vi) increase tumor cell invasiveness, although some studies indicated that NSAIDs have COX-2-independent effects. A number of clinical trials using COX-2 inhibitors are in progress, and the results from these studies will increase our understanding of COX-2 inhibition in both cancer treatment and prevention. The combination of COX-2 inhibitors with radiation or other anti-cancer or cancer prevention drugs may reduce their side effects in future cancer prevention and treatment. Recent progress in the treatment and prevention of cancers of the colon, esophagus, lung, bladder, breast and prostate with NSAIDs, especially COX-2 inhibitors, is also discussed

Alendronate inhibits osteopontin expression enhanced by parathyroid hormone-related peptide (PTHrP) in the rat kidney.

Yasui T, Fujita K, Sasaki S, et al.

Urol Res. 1998; 26(5):355-60.

It has been reported that osteopontin (OPN) plays an important role during urolithiasis as well as bone formation. Generation of stones in the urinary tract may be associated with osteoporosis and bisphosphonates are potent inhibitors of bone resorption, being used with effect in the management of bone disease. We therefore investigated the relationship between alendronate, a bisphosphonate derivative, and OPN expression in the kidney. Alendronate was administered to rats made hypercalcemic by treatment with parathyroid hormone-related peptide (PTHrP). The renal expression of OPN was then evaluated at both protein and mRNA levels. OPN expression was enhanced in the distal tubular cells of hypercalcemic rats and was decreased by alendronate. The observed inhibition of OPN expression suggests an ability of alendronate and other bisphosphonates to act as inhibitors of stone formation in the urinary tract

Kinetics of serum prostate-specific antigen after external beam radiation for clinically localized prostate cancer.

Zagars GK, Pollack A.

Radiother Oncol. 1997 Sep; 44(3):213-21.

BACKGROUND AND PURPOSE: To determine the kinetics of serum prostate-specific antigen (PSA) after radiation therapy of localized prostate cancer and to evaluate whether such kinetics provide prognostic information. MATERIALS AND METHODS: Eight hundred forty-one men with serial PSA determinations who underwent external beam radiation without androgen ablation were analyzed to determine postradiation PSA kinetic parameters (half-life and doubling time) and to correlate these parameters with disease outcome. Non-linear regression techniques were used to determine half-lives and doubling times. RESULTS: The postradiation serum PSA data fitted well to first order kinetic models. The median PSA half-life was 1.6 months (range 0.5-9.2 months). There was no correlation between half-life and T-stage or Gleason grade. A significant but quantitatively weak correlation was present between the pretreatment PSA level and half-life; lower pretreatment levels were associated with longer half-lives. Half-life did not correlate with disease outcome whether the endpoint was local recurrence, distant metastasis or rising PSA. In 263 men with a rising postradiation PSA profile the median PSA doubling time was 12.2 months (range 0.8-80.2 months). Faster doubling times were significantly associated with higher T-stage, higher Gleason grade and higher pretreatment PSA levels. Thus, patients with initially adverse disease developed faster rising PSA values after treatment than patients with less adverse disease. The most striking correlation was between rapid doubling time and the likelihood of metastatic relapse. Patients who developed metastases had a median PSA doubling time of 4.2 months compared to a median doubling time of 11.7 months in patients who developed local recurrence. Overall, patients with a PSA doubling time of less than 8 months had a 7-year actuarial metastatic rate of 54%, while patients with a PSA doubling time exceeding 8 months had only a 7% metastatic rate. Particularly ominous was the combination of a doubling time shorter than 8 months which began to rise within the first year; by 3 years 50% of these men had metastases and all were actuarially projected to develop such relapse by 6.5 years. CONCLUSIONS: Overall, the clinical utility of postradiation serum PSA kinetics was small. There were no discernible uses for PSA half-life. In patients with a rising PSA profile the faster the kinetics the more adverse the disease. Doubling times shorter than 8 months, especially if the rise begins in the first year, predict for metastatic relapse. However, in the absence of decisively useful treatment for metastatic prostate cancer the virtues of the early detection of metastases remain unclear

Predictors of improved outcome for patients with localized prostate cancer treated with neoadjuvant androgen ablation therapy and three-dimensional conformal radiotherapy.

Zelefsky MJ, Lyass O, Fuks Z, et al.

J Clin Oncol. 1998 Oct; 16(10):3380-5.

PURPOSE: To identify prognostic variables that predict for improved biochemical and local control outcome in patients with localized prostatic cancer treated with neoadjuvant androgen deprivation (NAAD) and three-dimensional conformal radiotherapy (3D-CRT). MATERIALS AND METHODS: Between 1989 and 1995, 213 patients with localized prostate cancer were treated with a 3-month course of NAAD that consisted of leuprolide acetate and flutamide before 3D-CRT. The purpose of NAAD in these patients was to reduce the preradiotherapy target volume so as to decrease the dose delivered to adjacent normal tissues and thereby minimize the risk of morbidity from high-dose radiotherapy. The median pretreatment prostate-specific antigen (PSA) level was 15.3 ng/mL (range, 1 to 560 ng/mL). The median 3D-CRT dose was 75.6 Gy (range, 64.8 to 81 Gy), and the median follow-up time was 3 years (range, 1 to 7 years). RESULTS: The significant predictors for improved outcome as identified in a multivariate analysis included pretreatment PSA level < or = "10.0" ng/mL(P < .00), NAAD-induced preradiotherapy PSA nadir < or = "0.5" ng/mL (P < .001), and clinical stage < or = "T2c" (P < .04). The 5-year PSA relapse-free survival rates were 93%, 60%, and 40% for patients with pretreatment PSA levels < or = "10" ng/mL, 10 to 20 ng/mL, and greater than 20 ng/mL, respectively (P < .001). Patients with preradiotherapy nadir levels < or = "0.5" ng/mL after 3 months of NAAD experienced a 5-year PSA relapse-free survival rate of 74%, as compared with 40% for patients with higher nadir levels (P < .001). The incidence of a positive biopsy among 34 patients pretreated with androgen ablation was 12%, as compared with 39% for 117 patients treated with 3D-CRT alone who underwent a biopsy (P < .001). CONCLUSION: For patients treated with NAAD and high-dose 3D-CRT, pretreatment PSA, preradiotherapy PSA nadir response, and clinical stage are important predictors of biochemical outcome. Patients with NAAD-induced PSA nadir levels greater than 0.5 ng/mL before radiotherapy are more likely to develop biochemical failure and may benefit from more aggressive therapies

Vitamin E succinate inhibits the function of androgen receptor and the expression of prostate-specific antigen in prostate cancer cells.

Zhang Y, Ni J, Messing EM, et al.

Proc Natl Acad Sci U S A. 2002 May 28; 99(11):7408-13.

Although epidemiological evidence indicates that a daily supplement of vitamin E may reduce the risk of prostate cancer, the detailed mechanism underlying this effect remains unclear. Here we demonstrate that alpha-tocopheryl succinate (VES) can suppress the expression of prostate-specific antigen (PSA), a marker for the progression of prostate cancer. VES can also suppress androgen receptor (AR) expression by means of transcriptional and posttranscriptional modulation, but not ligand binding, nuclear translocation, or AR dimerization. This VES-mediated inhibition of AR is selective because VES does not repress the expression of other nuclear receptors. Cell growth studies further show that VES inhibits the growth of prostate cancer LNCaP cells. In contrast, hydroxyflutamide (HF), an antiandrogen currently used to treat prostate cancer patients, only slightly inhibits LNCaP cell growth. Interestingly, simultaneous addition of HF and VES results in a more significant inhibition of LNCaP cell growth. Moreover, selenomethionine (SM), a prostate cancer treatment adjuvant, shows an inhibitory effect on LNCaP cell growth, yet has no effect on the AR/PSA pathway. Together, our data indicate that VES may suppress androgen/AR-mediated cell growth and PSA expression by inhibiting AR expression at both the transcription and translation levels. This previously undescribed mechanism may explain how VES inhibits the growth of prostate cancer cells and help us to establish new therapeutic concepts for the prevention and treatment of prostate cancer

Significant inhibition by the flavonoid antioxidant silymarin against 12-O-tetradecanoylphorbol 13-acetate-caused modulation of antioxidant and inflammatory enzymes, and cyclooxygenase 2 and interleukin-1alpha expression in SENCAR mouse epidermis: implications in the prevention of stage I tumor promotion.

Zhao J, Sharma Y, Agarwal R.

Mol Carcinog. 1999 Dec; 26(4):321-33.

The flavonoid antioxidant silymarin is used clinically in Europe and Asia for the treatment of liver diseases and is sold in the United States and Europe as a dietary supplement. Recently we showed that silymarin possesses exceptionally high cancer-preventive effects in different mouse skin carcinogenesis models and affords strong anticancer effects in human skin, cervical, prostate, and breast carcinoma cells. More recently, we showed that the anti-tumor-promoting effect of silymarin is primarily targeted against stage I tumor promotion in mouse skin (Cancer Res 1999;59:622-632). Based on this recent study, in this report, further investigations were made to identify and define the biochemical and molecular mechanisms of silymarin's effect during stage I tumor promotion in mouse skin. A single topical application of silymarin at 3-, 6-, and 9-mg doses onto SENCAR mouse skin followed 30 min later with 12-O-tetradecanoylphorbol 13-acetate (TPA) at a 3-microg dose resulted in a 76-95% inhibition (P < 0.001) of TPA-caused skin edema. Similarly, these doses of silymarin also showed 39-90%, 29-85%, and 15-67% protection (P < 0.05 or 0.001), against TPA-caused depletion of epidermal superoxide dismutase, catalase, and glutathione peroxidase activity, respectively. Pretreatment of mice with silymarin also produced highly significant inhibition of TPA-caused induction of epidermal lipid peroxidation (47-66% inhibition, P < 0.001) and myeloperoxidase activity (56-100% inhibition, P < 0.001). In additional studies assessing the effect of silymarin on arachidonic acid metabolism pathways involving lipoxygenase and cyclooxygenase (COX), similar doses of silymarin showed highly significant inhibition of TPA-caused induction of epidermal lipoxygenase (49-77% inhibition, P < 0.001) and COX (35-64% inhibition, P < 0.01 or 0.001) activity. Western immunoblot analysis showed that the observed effect of silymarin on COX activity was due to inhibition of TPA-inducible COX-2 with no change in constitutive COX-1 protein levels. In other studies, silymarin also showed dose-dependent inhibition of TPA-caused induction of epidermal interleukin 1alpha (IL-1alpha) protein (39-72% inhibition, P < 0.005 or 0.001) and mRNA expression. Taken together, the results from these biochemical and molecular studies further substantiate our recent observation of silymarin's anti-tumor-promoting effects primarily at stage I tumor promotion. Furthermore, the observed inhibitory effects of silymarin on COX-2 and IL-1alpha should be further explored to develop preventive strategies against those cancers in which these molecular targets play one of the causative roles, such as non-melanoma skin, colon, and breast cancers in humans

Impact of different variables on the outcome of patients with clinically confined prostate carcinoma: prediction of pathologic stage and biochemical failure using an artificial neural network.

Ziada AM, Lisle TC, Snow PB, et al.

Cancer. 2001 Apr 15; 91(8 Suppl):1653-60.

BACKGROUND: The advent of advanced computing techniques has provided the opportunity to analyze clinical data using artificial intelligence techniques. This study was designed to determine whether a neural network could be developed using preoperative prognostic indicators to predict the pathologic stage and time of biochemical failure for patients who undergo radical prostatectomy. METHODS: The preoperative information included TNM stage, prostate size, prostate specific antigen (PSA) level, biopsy results (Gleason score and percentage of positive biopsy), as well as patient age. All 309 patients underwent radical prostatectomy at the University of Colorado Health Sciences Center. The data from all patients were used to train a multilayer perceptron artificial neural network. The failure rate was defined as a rise in the PSA level > 0.2 ng/mL. The biochemical failure rate in the data base used was 14.2%. Univariate and multivariate analyses were performed to validate the results. RESULTS: The neural network statistics for the validation set showed a sensitivity and specificity of 79% and 81%, respectively, for the prediction of pathologic stage with an overall accuracy of 80% compared with an overall accuracy of 67% using the multivariate regression analysis. The sensitivity and specificity for the prediction of failure were 67% and 85%, respectively, demonstrating a high confidence in predicting failure. The overall accuracy rates for the artificial neural network and the multivariate analysis were similar. CONCLUSIONS: Neural networks can offer a convenient vehicle for clinicians to assess the preoperative risk of disease progression for patients who are about to undergo radical prostatectomy. Continued investigation of this approach with larger data sets seems warranted

Prostate cryoablation using direct transperineal placement of ultrathin probes through a 17-gauge brachytherapy template-technique and preliminary results.

Zisman A, Pantuck AJ, Cohen JK, et al.

Urology. 2001 Dec; 58(6):988-93.

OBJECTIVES: To describe a new surgical approach to third-generation cryoablation of the prostate and present our preliminary results. METHODS: The technique is detailed and demonstrated in a Web-based video- clip tutorial. Ninety-two men underwent prostate cryoablation (71 primary ablations, 19 salvage procedures, and 2 repeated cryoablations), using direct transperineal placement of ultrathin probes through a 17-gauge brachytherapy template. RESULTS: No fistulous or major complications were observed. Eight patients (8.3%) had minor complications. In 36 patients, the follow-up period was long enough to permit nadir prostate-specific antigen (PSA) evaluation. In 31 (86%), the nadir PSA was 0.5 ng/mL or less. In 5 patients, the nadir PSA was greater than 0.5 ng/mL. The workup revealed systemic failure in 3 patients and inadequate eradication of the prostate gland in 2 patients. In 18 (86%) of 21 androgen-ablation-naive patients, the nadir PSA was 0.5 ng/mL or less. Nine (43%) had an undetectable nadir PSA and 3 had a nadir PSA of greater than 0.5 ng/mL. CONCLUSIONS: A modified, less-invasive approach to cryoablation of the prostate is presented. The preliminary results do not show an increased rate of complications compared with other published series. The clinical outcome data are preliminary. Longer follow-up data are required to draw conclusions concerning efficacy