Multimodal Biomarkers That Predict the Presence of Gleason Pattern 4: Potential Impact for Active Surveillance.

PURPOSE: Latent grade group ≥2 prostate cancer can impact the performance of active surveillance protocols. To date, molecular biomarkers for active surveillance have relied solely on RNA or protein. We trained and independently validated multimodal (mRNA abundance, DNA methylation, and/or DNA copy number) biomarkers that more accurately separate grade group 1 from grade group ≥2 cancers. MATERIALS AND METHODS: Low- and intermediate-risk prostate cancer patients were assigned to training (n=333) and validation (n=202) cohorts. We profiled the abundance of 342 mRNAs, 100 DNA copy number alteration loci, and 14 hypermethylation sites at 2 locations per tumor. Using the training cohort with cross-validation, we evaluated methods for training classifiers of pathological grade group ≥2 in centrally reviewed radical prostatectomies. We trained 2 distinct classifiers, PRONTO-e and PRONTO-m, and validated them in an independent radical prostatectomy cohort. RESULTS: PRONTO-e comprises 353 mRNA and copy number alteration features. PRONTO-m includes 94 clinical, mRNAs, copy number alterations, and methylation features at 14 and 12 loci, respectively. In independent validation, PRONTO-e and PRONTO-m predicted grade group ≥2 with respective true-positive rates of 0.81 and 0.76, and false-positive rates of 0.43 and 0.26. Both classifiers were resistant to sampling error and identified more upgrading cases than a well-validated presurgical risk calculator, CAPRA (Cancer of the Prostate Risk Assessment; P < .001). CONCLUSIONS: Two grade group classifiers with superior accuracy were developed by incorporating RNA and DNA features and validated in an independent cohort. Upon further validation in biopsy samples, classifiers with these performance characteristics could refine selection of men for active surveillance, extending their treatment-free survival and intervals between surveillance.

Treatment patterns and trends in patients dying of prostate cancer in Quebec: a population-based study.

INTRODUCTION: Since just after the year 2000 in Quebec, the management of metastatic castration-resistant prostate cancer (mcrpc) has evolved considerably, with the inclusion of docetaxel-based chemotherapy, bone-targeted therapies (zoledronic acid and denosumab), and more recently, abiraterone, enzalutamide, and cabazitaxel for docetaxel-refractory patients. In the present study, we aimed to analyze contemporary mcrpc management patterns and therapy utilization trends in Quebec. METHODS: The study cohort consisted of patients dying of prostate cancer (pca) between January 2001 and December 2013, selected from Quebec public health care insurance databases. Patient selection was based on death from a pca-related cause or therapy used according to the Canadian Urological Association guidelines on mcrpc management. Treatments included chemotherapy (mitoxantrone before 2005 and docetaxel after 2005), abiraterone, bone-targeted therapy (zoledronic acid or denosumab, or both), and palliative radiation therapy (rt). During the study period, neither enzalutamide nor cabazitaxel was publicly reimbursed in Quebec, and as a result, no capture of their use was possible for this study. Multivariate logistic regression was used to identify factors associated with the probability of receiving chemotherapy, bone-targeted therapies, and palliative rt before death from pca. RESULTS: Overall, the database search identified 3106 patients who died of pca between January 2001 and December 2013. Median age of death was 78 years. Of those 3106 patients, just 2568 (83%) received mcrpc-specific treatments: chemotherapy, abiraterone, palliative rt, or bone-targeted therapy; the other 17% of the patients were managed solely with maximum androgen blockade (androgen deprivation therapy plus anti-androgens) despite a record of pca-related death. Logistic regression analyses indicate that patients dying after 2005 were more likely to have received chemotherapy [odds ratio (or): 1.51; 95% ci: 1.22 to 1.85] and bone-targeted therapy (or: 1.97; 95% ci: 1.64 to 2.37). Age was a significant predictor for the use of chemotherapy, bone-targeted therapy, and palliative rt (ors in the range 0.96-0.98, p < 0.05). CONCLUSIONS: Patient age seems to be a strong determinant in the of selection mcrpc therapy, affecting the probability of the use of chemotherapy, bone-targeted therapy, or palliative rt. Although chemotherapy is still used only in a small percentage of patients, the introduction of new therapies-such as bone-targeted therapy, docetaxel, and abiraterone-affected treatment selection over time. The availability of enzalutamide since February 2014 will likely produce additional changes in mcrpc management.

Urologist referral delay and its impact on survival after radical cystectomy for bladder cancer.

BACKGROUND: Evidence shows that wait times before bladder cancer surgery have been increasing, and wait time can negatively affect survival. We aimed to determine if a long delay caused by an indirect referral before a first urologist visit affects the survival of patients undergoing radical cystectomy for bladder cancer. METHODS: We analyzed data from 1271 patients who underwent surgery for bladder cancer during the decade 2000-2009. The cohort was obtained by linking two administrative databases in the province of Quebec. Patients were considered to have been directly referred to a urologist if they had 5 or fewer visits with a general practitioner before their first urologist visit; otherwise, they were considered to have been indirectly referred. The effect on survival after surgery of a longer delay before a first urologist visit was assessed using Cox regression models. RESULTS: Median referral delay for the study population was 30 days (56 days for women, 23 days for men; p < 0.0001). Indirect referral was observed for 49% of women and 33% of men. Compared with patients who were directly referred, those who were indirectly referred after first symptoms of bladder cancer experienced poorer survival (hazard ratio: 1.29; 95% confidence interval: 1.10 to 1.52). Women who were indirectly referred had a significant 47% greater risk of death after radical cystectomy. Men who were indirectly referred also experienced decreased survival (adjusted hazard ratio: 1.25; 95% confidence interval: 1.03 to 1.51). CONCLUSIONS: Patients indirectly referred to a urologist had an increased risk of mortality after surgery. Compared with men, women had longer wait times and poorer survival.

An open-label, phase 2 trial of bicalutamide dose escalation from 50 mg to 150 mg in men with CAB and castration resistance. A Canadian Urology Research Consortium Study.

BACKGROUND: Bicalutamide is a widely used, relatively non-toxic anti-androgen, particularly when used in combination with androgen deprivation. In men on combined androgen blockade (CAB), the typical dose is 50 mg per day. For men receiving monotherapy with bicalutamide anti-androgen, the dose is 150 mg per day. The objective was to determine the PSA response rate to increasing bicalutamide to 150 mg per day in men who develop castrate-resistant prostate cancer (CRPC) on CAB with goserelin acetate and bicalutamide 50 mg per day. METHODS: A national, multicentre, phase 2, open-label study in men on CAB with a rising PSA>2.0. The primary end point of the trial was PSA response at 12 months, defined as a decline by 50% or more compared with baseline value. Partial response was defined as a PSA decline of 10-49%. Secondary end points were duration of PSA response, change in slope of serum PSA, change in ratio of free PSA: total PSA at 3 months, 6 months and 12 months as compared with baseline; duration of the bicalutamide withdrawal response after discontinuation; the rate of cardiovascular events; and toxicity. The study was initially planned to accrue 100 patients, but was closed early due to diminishing accrual. RESULTS: Sixty-four patients were accrued; 61 patients received trial treatment and constituted the intention-to-treat (ITT) cohort. 70% were M0. Among 59 evaluable ITT patients, 13 (22%) patients had a >50% PSA decline, 5 (8%) had a decline between 10 and 50%, 4 (7%) had stabilization and 37 (63%) had PSA progression. The median duration was 3.7 months (95% confidence interval of 0.92-6.21 months). CONCLUSION: In patients with early biochemical failure on CAB with bicalutamide 50 mg, an increase in dose to 150 mg of bicalutamide resulted in a PSA response of ⩾ 50% in 22% of patients. Toxicity was mild. Bicalutamide dose intensification may benefit a subset of patients with CRPC. We believe this relatively inexpensive approach warrants further evaluation.

Direct cost for initial management of prostate cancer: a systematic review.

BACKGROUND: Prostate cancer (pca) is the most common non-skin cancer among men in Canada and other Western countries. Increased prevalence and higher cost of newer treatments have led to a significant rise in the economic burden of pca. The objectives of the present study were to systematically review the literature on direct costs for the initial management of pca, and to examine the methodologic considerations across studies. METHODS: Bibliographic databases were systematically searched for peer-reviewed articles in English. Studies were reviewed for methodologic considerations and mean direct cost of active surveillance or watchful waiting (as/ww) and initial treatments. Direct cost was standardized to 2011 Canadian dollars. RESULTS: After a review of abstracts and full-text papers, seventeen articles met the eligibility criteria and were included in the review. Studies were published during 1992-2010. The studies reported on health care systems in the United States, France, the United Kingdom, German, Italy, and Spain. Our review identified a lack of methodologic consensus, leading to variation in direct costs between studies. Nevertheless, results indicate a significant direct cost of pca treatments. CONCLUSIONS: The existing literature lacks methodologically rigorous studies on the direct costs of pca treatments specific to publicly funded health care systems. Additional studies are required to appreciate the direct costs of newer treatments and the impact of their adoption on the growing economic burden of pca management.

Differences in prostate cancer detection between Canadian and Saudi populations

Few studies have addressed racial differences in prostate cancer (PCa) detection between Western and Arabian countries, although PCa has a significantly lower prevalence in Arabic populations compared to Western populations. Therefore, an explanation of this difference is lacking. Serum prostate-specific antigen (PSA) is a valuable marker used to select patients who should undergo prostate biopsies, although the manner in which it is used may require adjustments based on the ethnic population in question. We investigated racial differences in the PCa detection rate between Canadian and Saudi populations. A retrospective analysis was performed of data collected prospectively over 5 consecutive years in urology clinics at the McGill University Health Center (MUHC) and King Saud University Hospital (KSUH). Men who had high (>4'ng/mL) or rising PSA levels and a negative digital rectal examination were eligible. A total of 1403 Canadian and 414 Saudi patients were evaluated for the study; 717 and 158 men, median age 64 and 68 years, were included in the MUHC and KSUH cohorts, respectively, P<0.0001). Median serum PSA, prostate volume, and PSA density values were 6.1'ng/mL, 47.3 g, and 0.12'ng·mL−1·g−1, respectively, for MUHC patients and 5.2'ng/mL, 64.5'g, and 0.08'ng·mL−1·g−1, respectively, for KSUH patients (P<0.0001, t-test followed by one-way ANOVA). In addition, the KSUH group had a significantly lower PCa detection rate among patients younger than 60 years of age and with PSA values <10'ng/mL.

Differences in prostate cancer detection between Canadian and Saudi populations.

Few studies have addressed racial differences in prostate cancer (PCa) detection between Western and Arabian countries, although PCa has a significantly lower prevalence in Arabic populations compared to Western populations. Therefore, an explanation of this difference is lacking. Serum prostate-specific antigen (PSA) is a valuable marker used to select patients who should undergo prostate biopsies, although the manner in which it is used may require adjustments based on the ethnic population in question. We investigated racial differences in the PCa detection rate between Canadian and Saudi populations. A retrospective analysis was performed of data collected prospectively over 5 consecutive years in urology clinics at the McGill University Health Center (MUHC) and King Saud University Hospital (KSUH). Men who had high (>4'ng/mL) or rising PSA levels and a negative digital rectal examination were eligible. A total of 1403 Canadian and 414 Saudi patients were evaluated for the study; 717 and 158 men, median age 64 and 68 years, were included in the MUHC and KSUH cohorts, respectively, P<0.0001). Median serum PSA, prostate volume, and PSA density values were 6.1'ng/mL, 47.3 g, and 0.12'ng · mL(-1) · g(-1), respectively, for MUHC patients and 5.2'ng/mL, 64.5'g, and 0.08'ng · mL(-1) · g(-1), respectively, for KSUH patients (P<0.0001, t-test followed by one-way ANOVA). In addition, the KSUH group had a significantly lower PCa detection rate among patients younger than 60 years of age and with PSA values <10'ng/mL.

Relationship between initial PSA density with future PSA kinetics and repeat biopsies in men with prostate cancer on active surveillance.

The objective of our study is to examine the correlation between PSA density (PSAd) at the time of diagnosis with PSA velocity (PSAV), PSA doubling time and tumour progression, on repeat biopsy, in men with prostate cancer on active surveillance. Data from 102 patients with clinically localized prostate cancer on active surveillance in the period between 1992 and 2007, who had the necessary parameters available, were collected. PSAd was calculated and correlated with PSAV, PSA doubling time (PSADT), Gleason score at diagnosis and local progression on repeated biopsies. PSAV was 0.64 and 1.31 ng ml(-1) per year (P = 0.02), PSADT of 192 and 113 months (P = 0.4) for PSAd below and above 0.15, respectively. The rate of detecting high Gleason score (≥ 7) at diagnosis was 6 and 23% for PSAd below and above 0.15, respectively. A total of 101 patients underwent at least a second biopsy and the incidence of upgrading was 10 and 31% for PSAd below and above 0.15, respectively (P = 0.001). Although low PSAd is an accepted measure for suggesting insignificant prostate cancer, our study expands its role to indicate that PSAd < 0.15 may be an additional clinical parameter that may suggest indolent disease, as measured by future PSAV and repeat biopsy over time.

Preventing bone complications in advanced prostate cancer.

The diagnosis and treatment of prostate cancer have steadily been improving since the late 1980s. However, clinicians still confront a large group of men developing disease metastatic to bone. Adequate control of bone complications plays a fundamental role in achieving control of symptoms and quality of life in this group. Androgen deprivation therapy, the standard treatment for advanced prostate cancer, increases the risk of various complications, including bone disease. This review addresses the prevention of bone complications related not only to prostate cancer metastases but also to impaired bone integrity caused by androgen deprivation therapy.

Outcome of surgical treatment of patients with upper versus lower urinary tract urothelial carcinoma: stage-by-stage comparison.

OBJECTIVES: It remains controversial whether we can apply similar principles in the management of upper urinary tract urothelial carcinoma (UUT-UC) based on the behavior of bladder urothelial carcinoma (B-UC). We sought to assess whether UUT-UC and B-UC have similar biology and performed a stage-by-stage comparative analysis of outcome between the 2 groups. METHODS: A retrospective review was performed on patients who underwent nephroureterectomy for UUT-UC and radical cystectomy for B-UC from 1991 to 2006. Standard variables were collected and recurrence-free and overall survival (OS) rates were calculated. RESULTS: 280 patients with a median age of 69 years were included (99 UUT-UC treated via nephroureterectomy and 181 B-UC treated via radical cystectomy). Median follow-up was 29 months. None received neoadjuvant chemotherapy. Patients with UUT-UC presented less commonly with invasive disease compared to those with B-UC (44 vs. 77% were >pT2). Overall, 5-year OS for the B-UC group was significantly lower than for the UUT-UC group (60.8 vs. 74.5%, p = 0.02). However, when patients were stratified by stage (>pT2), patients with B-UC had similar OS compared to those with UUT-UC (54.6 vs. 60.8%, p = 0.74). CONCLUSION: Invasive UUT-UC appears to have similar tumor biology compared to B-UC. Whether we can safely extrapolate on the benefit of neoadjuvant and adjuvant strategies to patients with UUT-UC requires further investigation.

Vascular targeted photodynamic therapy with palladium-bacteriopheophorbide photosensitizer for recurrent prostate cancer following definitive radiation therapy: assessment of safety and treatment response.

PURPOSE: Tookad is a novel intravascular photosensitizer. When activated by 763 nm light, it destroys tumors by damaging their blood supply. It then clears rapidly from the circulatory system. To our knowledge we report the first application of Tookad vascular targeted photodynamic therapy in humans. We assessed the safety, pharmacokinetics and preliminary treatment response as a salvage procedure after external beam radiation therapy. MATERIALS AND METHODS: Patients received escalating drug doses of 0.1 to 2 mg/kg at a fixed light dose of 100 J/cm or escalated light doses of 230 and 360 J/cm at the 2 mg/kg dose. Four optical fibers were placed transperineally in the prostate, including 2 for light delivery and 2 for light dosimetry. Treatment response was assessed primarily by hypovascular lesion formation on contrast enhanced magnetic resonance imaging and transrectal ultrasound guided biopsies targeting areas of lesion formation and secondarily by serum prostate specific antigen changes. RESULTS: Tookad vascular targeted photodynamic therapy was technically feasible. The plasma drug concentration was negligible by 2 hours after infusion. In the drug escalation arm 3 of 6 patients responded, as seen on magnetic resonance imaging, including 1 at 1 mg/kg and 2 at 2 mg/kg. The light dose escalation demonstrated an increasing volume of effect with 2 of 3 patients in the first light escalation cohort responding and all 6 responding at the highest light dose with lesions encompassing up to 70% of the peripheral zone. There were no serious adverse events, and continence and potency were maintained. CONCLUSIONS: Tookad vascular targeted photodynamic therapy salvage therapy is safe and well tolerated. Lesion formation is strongly drug and light dose dependent. Early histological and magnetic resonance imaging responses highlight the clinical potential of Tookad vascular targeted photodynamic therapy to manage post-external beam radiation therapy recurrence.

Androgen receptor CAG repeat length contraction in diseased and non-diseased prostatic tissues.

To investigate contraction of CAG repeats within the androgen receptor gene (AR) as shorter CAG repeats have been implicated as a possible risk factor in prostate cancer (PCa). AR CAG repeat lengths were analyzed in DNA from microdissected diseased prostates, leukocytes from matched peripheral blood, and control non-diseased prostates. Consistently, all prostatic tissues, whether from benign or cancerous areas of diseased prostates, or from control prostates, showed multiple AR CAG repeat contractions. Germline DNA from blood leukocytes had single CAG repeat lengths in the normal range. AR CAG repeat length contraction may be involved in prostate carcinogenesis and may precede the pathological process.

Whole-mount prostate sections reveal differential endoglin expression in stromal, epithelial, and endothelial cells with the development of prostate cancer.

Endoglin is a nonsignaling receptor for transforming growth factor that contributes to the action of this growth factor in diverse cell types. It may also exhibit a function of its own. Endoglin levels vary with disease states and is a marker of new blood vessels. We studied endoglin expression in whole-mount prostate sections from 64 patients with localized prostate cancer, assessing reactivity in the epithelium, the stroma, and blood vessels. Cells in normal/benign acini were negative but significantly immunoreactive (P<0.001) in both prostatic intraepithelial neoplasia (PIN; 52% of cases) and malignant areas (77% of cases). In tumors, this involved less than 25% of malignant cells in 59% of specimens. The endoglin-stained stroma was detected mainly in areas surrounding PIN acini and tumors. Endoglin antibodies detected more microvessels than von Willebrand Factor antibodies in all prostatic areas (P<0.01). In addition, the number of microvessels increased with the development of cancer and correlated with Gleason score (P<0.01). Changes in endoglin expression in PIN and malignant cells, the surrounding stroma, and related blood vessels, suggest that endoglin function may be altered in prostate cancer.

Comparative evaluation of various prostate specific antigen ratios for the early detection of prostate cancer.

OBJECTIVE: To compare the performance of various ratios using total prostate specific antigen (PSA), complexed PSA (cPSA) and free PSA (fPSA) in the early detection of prostate cancer. PATIENTS AND METHODS: The study included 535 consecutive patients evaluated at a prostate cancer detection clinic between January 1998 and October 1999. Patients had blood samples drawn before transrectal ultrasonography and prostate biopsy to measure PSA, cPSA and fPSA. Receiver operating characteristic (ROC) curves (sensitivity vs 1 - specificity) were used to evaluate the performance of PSA, cPSA, f/tPSA, cPSA/tPSA, fPSA/cPSA, tPSA/prostate volume (PV), fPSA/PV, and cPSA/PV. The areas under the curve (AUC) were calculated for each ratio. The performance of each ratio over all patients or in those with a tPSA of 4-6 or 4-10 ng/mL were evaluated. RESULTS: Of the 535 patients, 204 (38%) had biopsy-confirmed prostate cancer. The AUC obtained with tPSA alone was 0.64; when measured for all patients the cPSA/PV (0.78), PSA/PV (0.77), f/tPSA (0.76) and fPSA/cPSA (0.75) performed better than tPSA alone. Furthermore, in patients with a tPSA of 4-10 ng/mL, tPSA/PV (0.72), cPSA/PV (0.71), f/tPSA (0.69), fPSA/cPSA (0.69) and cPSA/tPSA (0.62) performed better than tPSA alone (0.52). Finally, in patients with a tPSA of 4-6 ng/mL, PSA/PV and cPSA/PV performed better than the other ratios. CONCLUSIONS: The use of PSA ratios gives a higher sensitivity and specificity for detecting prostate cancer than the use of tPSA alone.

Prostate cancer and use of nonsteroidal anti-inflammatory drugs: systematic review and meta-analysis.

Animal and laboratory studies suggest that regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce prostate cancer risk. To assess this association, we conducted a systematic review and meta-analysis of observational studies published before January 2003. We derived summary odds ratios (ORs) using both fixed and random effects models and performed subgroup analyses to explore the possible sources of heterogeneity between combined studies. We identified 12 reports (five retrospective and seven prospective studies). Most studies of aspirin use reported inverse associations, but only two were statistically significant. The summary OR for the association between aspirin use and prostate cancer was 0.9 (95% confidence interval: 0.82-0.99; test of homogeneity P=0.32), and varied from 1.0 for retrospective studies to 0.85 for prospective studies. Studies that measured exposure to a mixture of NSAIDs were less consistent. These results indicate an inverse association between aspirin use and prostate cancer risk. The current epidemiological evidence and, in particular, the strong and consistent laboratory evidence underline the need for additional epidemiological studies to confirm the direction and magnitude of the association.

Natural history of renal masses followed expectantly.

PURPOSE: An increasing number of incidental renal masses have been detected with increasing use of ultrasonography, computerized tomography and magnetic resonance imaging. We investigated the natural history of incidentally detected renal masses. MATERIALS AND METHODS: A total of 24 patients were included in this retrospective analysis. Average patient age was 68.3 years (range 29 to 83). The 16 males and 8 females were followed with abdominal imaging for a mean and median followup of 31.6 and 24 months, respectively (range 8 to 86). Patients elected to be observed because of age, poor medical condition or the presence of a mass in a solitary kidney. The majority of patients (22 of 24) were asymptomatic at diagnosis. Two patients were followed with bilateral renal masses, and 2 with T3b tumors. Of the 20 patients with incidental solitary renal masses, 6 were at the upper pole, 9 were mid polar and 5 lower pole. Mean maximum diameter of lesions was 3.3 cm (median 2.7, range 0.9 to 10). Growth rate was calculated based on diameter and tumor volume. RESULTS: Of the 24 patients only 5 demonstrated tumor growth during the surveillance period. No metastasis developed in any patients. Mean tumor growth rate observed in the 5 patients was 0.49 cm per year or 7.3 cc per year. Of the 24 patients 4 underwent surgery after surveillance because of apparent tumor growth or per patient request. Pathology revealed renal cell carcinoma in all 4. CONCLUSIONS: Tumor growth of renal masses is often limited. Most of our patients did not demonstrate significant growth when followed expectantly. Without tumor growth the risk of metastasis seems limited.

Serum insulin-like growth factor (IGF)-1 and IGF-binding protein-3 do not correlate with Gleason score or quantity of prostate cancer in biopsy samples.

OBJECTIVE: To examine the relationship of serum insulin-like growth factor (IGF)-1 and IGF binding protein-3 (IGFBP-3) with histological cancer characteristics in men undergoing transrectal ultrasonography (TRUS)-guided biopsy. PATIENTS AND METHODS: Patients (652), with either an elevated serum prostate-specific antigen level or an abnormal digital rectal examination, were initially evaluated by TRUS and sextant prostatic needle biopsy. Blood was drawn before biopsy, serum extracted and stored frozen until IGF-1 and IGFBP-3 were measured. In all, 241 patients had prostate cancer (37%) and were included in this study. The number of positive biopsies, the volume of tumour in each positive biopsy and the Gleason score were recorded. RESULTS: Of the 241 patients, 37 had five or six positive biopsies (from six), 128 had two to four and 76 had one. Serum IGF-1 did not correlate with the number of positive biopsies, with means of 176.7, 178.3 and 164.4 ng/mL, respectively (P = 0.3), while the mean IGFBP-3 was 2695, 2795 and 2572 ng/mL, respectively (P = 0.09). The additive percentiles of tumour volume in positive biopsies were assessed for each patient but serum IGF-1 and IGFBP-3 did not correlate (P = 0.7 and 0.9, respectively). In all, 92 patients had a Gleason score of < 7, 80 a score of 7 and 69 a score of > 7; the mean (sd) IGF-1 levels for the three groups were 181 (39), 174.6 (35) and 176 (26) ng/mL, and the mean IGFBP-3 2798 (240), 2735 (284) and 2647 (221) ng/mL, respectively, none of the differences being statistically significant. CONCLUSIONS: Serum IGF-1 and IGFBP-3 do not correlate with quantity of cancer or Gleason score in biopsy samples from patients with prostate cancer.

Vascular endothelial growth factor and signaling in the prostate: more than angiogenesis.

In cloning tyrosine kinase genes in dog prostate cells, a fragment of the vascular endothelial growth factor (VEGF) receptor 1 or Flt-1 was sequenced. To test for a functional protein, Flt-1 antibodies were used to probe immunoprecipitated tyrosine phosphorylated proteins. Western blotting revealed a major 170-180 kDa band and a few bands below 116 kDa in dog prostate and human prostatic carcinoma PC-3 cells, with higher levels in PC-3. Similar results were obtained with human placental membranes used as a source of Flt-1. That the major Flt-1 tyrosine phosphorylated protein was likely VEGF-R1 and part of VEGF signaling pathways was shown by enhanced level of only this protein when PC-3 cells were exposed to VEGF. Accordingly specific cell surface receptor complexes, displaced by VEGF but not EGF and compatible with Flt-1 in size, were revealed by chemical cross-linking after 125I-VEGF binding. Similarly to the prostatic neuroproduct, gastrin-releasing peptide/bombesin, VEGF directly triggered the tyrosine phosphorylation of focal adhesion kinase and stimulated PC-3 cell motility. The titration of prostate tissue sections with VEGF-A antibodies revealed a confined staining in chromogranin A and/or serotonin positive neuroendocrine (NE) cells, including in primary tumors and lymph node metastases. Given that NE differentiation is associated with advanced disease, that NE cells are a significant source of VEGF in prostatic tumors, and that VEGF directly act on prostate cancer cells in vitro, VEGF-A may be more than angiogenic in prostate cancer and hence favor progression by affecting tumor cells.

Comparative evaluation of total PSA, free/total PSA, and complexed PSA in prostate cancer detection.

OBJECTIVES: To compare the performance of prostate-specific antigen (PSA), the free/total PSA (F/T PSA) ratio, and complexed PSA (cPSA) in prostate cancer detection. METHODS: Five hundred thirty-five patients evaluated at the UROMED prostate cancer detection clinic had total PSA, free PSA, and cPSA measured before undergoing transrectal ultrasonography and sextant prostate biopsies. A direct comparison was performed between the different PSA assays to evaluate their ability to detect prostate cancer. RESULTS: Of the 535 patients evaluated, 38.1% had prostate cancer detected. The mean age of the entire population was 63.6 years (range 35 to 86). Abnormal digital rectal examination findings were present in 33.4% of the patients. The mean and median values of PSA and cPSA were significantly higher and the F/T PSA ratio was lower in patients with prostate cancer. The F/T PSA ratio performed better than either cPSA or total PSA. A higher specificity was observed with the F/T PSA ratio than with cPSA using either the entire patient population or subsets of patients with PSA levels between 4.0 and 10 ng/mL or 4.0 to 6.0 ng/mL. CONCLUSIONS: The use of the F/T PSA ratio offers improved prostate cancer detection compared with either cPSA or total PSA.