Effect of nonsteroidal antiandrogen monotherapy versus castration therapy on neuroendocrine differentiation in prostate carcinoma

Objectives. To determine whether the ad ministration of the nonsteroidal antiandrogen bicalutamide reduces the risk of an increase in chromogranin A (CgA) levels in patients with prostate cancer who experienced biochemical failure after radical retropubic prostatectomy (RRP) compared with pharmacologic castration therapy. It has been hypothesized that continuous androgen suppression for the treatment of prostate cancer results in hyperactivation of neuroendocrine cells and an increase in CgA levels. Methods. Forty-eight patients with pT3pN0M0 prostate cancer and biochemical (prostate-specific antigen) progression after RRP were randomized to bicalutamide monotherapy or pharmacologic castration. The serum levels of CgA and prostate-specific antigen were measured at 1, 3, 6, 12, 18, and 24 months of therapy. The changes in serum CgA levels were compared for patients who successfully responded to the first 24 months of therapy. Results. In both treatment groups, a statistically significant trend was noted for CgA levels to increase from baseline to 24 months. This trend was lower in the bicalutamide group (slope = 0.60, 95% confidence interval 0.28 to 0.92; P = 0.004) than in the castration group (slope = 0.29, 95% confidence interval 0.08 to 0.50; P = 0.01). Conclusions. The results of this study provide the first evidence to show that in patients with prostate cancer undergoing hormonal therapy, nonsteroidal antiandrogen monotherapy produces a significantly lower increase in serum CgA compared with castration

Antiandrogen monotherapy: Recommendations for the treatment of prostate cancer

Objective: The concept of antiandrogens as monotherapy for the treatment of prostate cancer is discussed. Methods: Both Medline and Current Contents were used to identify studies on antiandrogen monotherapy in prostate cancer. We tried to analyze this database critically to establish whether or not there is evidence for using this monotherapy. Results: In particular, bicalutamide in monotherapy has been compared with castration in large international trials. Results show that antiandrogen monotherapy is inferior to castration in patients with metastatic tumour but the difference in median survival is limited. In locally advanced M0 prostate cancer bicalutamide 150 mg monotherapy seems equivalent to castration in terms of overall survival and time to progression. Analysis of quality of life showed that there is evidence of some benefits from bicalutamide when compared to castration in both sexual interest and physical capacity. Conclusion: Antiandrogens in monotherapy can be effective and well tolerated. However, more research is needed because none of the available compounds have definitively been proven to be equivalent to castration

Can the intraprostatic concentration of epidermal growth factor influence the variance of serum prostate specific antigen levels in patients with benign prostatic hyperplasia?

Purpose: Except for prostate volume, little is known about the factors influencing serum prostate specific antigen (PSA) levels. Considering that dihydrotestosterone and epidermal growth factor are regulators of the proliferation and differentiation in the epithelial component of human prostate tissue and that PSA is produced only by the epithelial cells of the gland, studies were performed on patients with a histological diagnosis of benign prostatic hyperplasia (BPH) to establish whether a significant association exists between the intraprostatic concentration of dihydrotestosterone or epidermal growth factor and serum PSA levels. Materials and Methods: A total of 20 patients with BPH who had not been previously treated were part of a larger study on the correlation among PSA, prostate volume and age, and were evaluated according to the algorithm in the guidelines of the international consultation on BPH. All men underwent open suprapubic prostatectomy to enucleate the entire adenoma and in each case sections were made in the periurethral, subcapsular and intermediate zones of the BPH tissue. Dihydrotestosterone and epidermal growth factor concentrations were evaluated by radioimmunoassay in the periurethral zone and in total BPH tissue. Results: In these 20 patients with BPH serum PSA levels were significantly associated with epidermal growth factor but not with dihydrotestosterone concentrations in total BPH tissue (r = 0.7762, p = 0.00002836 and r = 0.3923, p = 0.0956307, respectively). A stronger association was found between PSA levels and the periurethral concentration of epidermal growth factor and dihydrotestosterone (r = 0.8117, p = 0.000005 and r = 0.5656, p = 0.0098326, respectively). On the contrary, epidermal growth factor and dihydrotestosterone were not significantly associated with prostate volume (p = 0.957415 and p = 0.531439, respectively). Conclusions: To our knowledge this study is the first report in the literature to demonstrate an association between serum PSA, and dihydrotestosterone and epidermal growth factor levels, particularly in the periurethral zone of human BPH tissue. These data suggest the importance of epidermal growth factor and dihydrotestosterone in influencing serum PSA levels

New anti-angiogenic targeted therapy in advanced renal cell carcinoma (RCC): Current status and future prospects

Objectives: To address the rationale for anti-angiogenic targeted therapies in advanced RCC. Methods: We reviewed the international recent literature, using Pubmed search. Results: RCC is genetically linked to factors regulating angiogenesis, in particular vascular endothelial growth factor (VEGF). Sunitinib is a multitarget receptor tyrosine-kinase (TK) inhibitor, acting on VEGF receptor (VEGFR) and platelet-derived growth factor receptors (PDGFR). Sorafenib is an oral multikinase inhibitor (VEGFR and PDGFR) showing also inhibitors effect on the Raf system. Phase I trials showed no life threatening toxicities relates to these agents. Phase II and phase III trials showed that these antiangiogenic agents are effective in the treatment of advanced RCC, mainly in cytokine refractory metastatic RCC. Survival benefits exist in particular when advanced RCC patients undergo cytoreductive nephrectomies before the initiation of the systemic therapy. To better use this kind of targeted therapy in advanced RCC, different points must be developed: the identification of clinical characteristic of RCC able to predict outcomes and responses to therapy; differences among different compounds; advantages of combination or sequential therapies. Conlusions: Targeted therapy with Sunitinib and Sorafenib has been approved to FDA and is revolutioning how we clinically approach advanced RCC. © 2008 Bentham Science Publishers Ltd

Histopathological aspects of transitional cell carcinoma of the bladder: Analysis of 20 years experience

Background: In this study we used histopathological examinations performed over a 20-year period to describe the characteristics of newly diagnosed transitional cell carcinoma (TCC) of the bladder in relation to patient age, and to verify changes in the TCC over different periods of observation or in relation to patient age. Methods: We reviewed all histopathological examinations performed from January 1979 to December 1998 in patients undergoing surgery who were newly diagnosed with TCC of the bladder. All examinations were performed by the same pathologist and reviewed by two pathologists. In each case analyzed, we evaluated T classification of the tumor, histological grade, size, localization, growth type, multiplicity and carcinoma in situ (CIS). Results: The study population included 3113 men and 620 women. The mean patient age was 66.31 +/- 10.84 years. A high percentage of Ta (52.2%) and T1 (27.7%) tumors were found. The number of cases observed and, in particular, the percentage of Ta tumors increased significantly and progressively from the first (1979-1983 = 376 cases; Ta = 37.8%) to the last (1994-1998 = 1732 cases; Ta = 56.3%) period of observation (P < 0.001). A significant difference in the distribution of histological grade and T classification in the different age decades was apparent (P < 0.001); in particular, for G1 and Ta tumors there was a trend to decrease, whereas for G3, T1 and T2 tumors there was a tendency to increase with age decades. Conclusion: In our analysis, age of patient and the period of examination significantly influenced different pathological characteristics of newly diagnosed TCC of the bladder

RELATIONSHIP AMONG SYMPTOMS SCORE,PROSTATE VOLUME AND URINARY FLOW RATES IN 543 PATIENTS WITH AND WIHTOUT BPH

BACKGROUND. Studies on the relationship among symptom score, urinary flow rate, and prostate volume in men with lower urinary tract symptoms (LUTS) continue to be of great interest. METHODS. A total of 2,418 men, aged 30-86 years, agreed to participate in an interview and to complete a questionnaire regarding voiding patterns. All subjects answering positively to one or more of the questions were submitted to a diagnostic assessment, based on the algorithm outlined by the guidelines of the International Consultation on Benign Prostatic Hyperplasia (BPH). Five hundred forty-three out of the 2,418 participants (22.45%) were evaluated. At the end of the diagnostic evaluation, 400 men with LUTS but without concomitant conditions (except BPH) known to interfere with normal voiding were selected. Descriptive statistics were used to characterize age, symptom score (International Prostate Symptom Score), prostate volume, and urinary flow rate distribution in these patients. Correlations among the aforementioned parameters were evaluated by means of a multivariate, multiple linear regression and logistic regression model. RESULTS. As reported in other studies, only weak or modest correlations were found. Moreover, the 400 cases were classified according to four age decades. The decrease in peak and mean flow rate per decade of age was similar (0.5 and 0.4 ml/sec); the increase in prostate volume and in total symptom score per decade was 3.3 cc and 0.6, respectively. In patients less than 50 years old, most of the correlations were stronger than those observed in the entire population of 400 men (age and prostate volume, c.c. 0.2864; age and peak flow rate, c.c. -0.2689; age and mean flow rate, c.c. -0.3034). However, symptom score continued to be weakly correlated with age and prostate volume (c.c. 0.0498 and 0.1966, respectively). In the last part of the study, men were assigned to different treatment strategies. Patients who were assigned to surgical treatment had higher prostate volume and IPSS and lower urinary flow rate than those assigned to nonsurgical treatment. CONCLUSIONS. We believe that the reason for the weak statistical association frequently reported in the literature is mainly the urology clinic-based population from which the patient samples were drawn. Data emerging from this analysis support the hypothesis that age is one of the principal factors influencing the relationship among symptom score, urinary flow rate, and prostate volume. (C) 1998 Wiley-Liss, Inc

Reduced intraoperative bleeding during transurethral resection of the prostate: Evaluation of finasteride, vascular endothelial growth factor, and CD34

Finasteride is an antiandrogen that inhibits 5-α- reductase, an enzyme that converts testosterone to dihydrotestosterone. Finasteride significantly reduces intraoperative bleeding when 10 mg/d is administered for 60 days before transurethral resection of the prostate. Our double-blind, randomized, placebo-controlled study evaluated 200 patients with benign prostatic hyperplasia who underwent transurethral resection of the prostate. We compared a placebo group (n = 100) with a group (n = 100) administered 5 mg of finasteride twice a day for 8 weeks. We intended to demonstrate the mechanisms and effects of finasteride compared with those of vascular endothelial growth factor, and to evaluate CD34, an immunohistochemical marker of blood vessel density in the prostate. Our results indicated a lower average microvascular density and vascular endothelial growth factor index for hypertrophic prostate in the finasteride group than in the placebo group

Variation in chromogranin A serum levels during intermittent versus continuous androgen deprivation therapy for prostate adenocarcinoma

OBJECTIVES. It has been hypothesized that continuous androgen-suppression therapy produces hyperactivation of neuroendocrine (NE) cells and an increase in chromogranin A (CgA) in prostate carcinoma (PC). The aim of this study was to verify whether the intermittent administration of androgen deprivation (IAD) reduces the risk of CgA increase in PC cases treated with complete androgen deprivation (CAD). MATERIALS AND METHODS. We analyzed changes in serum CgA levels in patients with PC who successfully responded to the first 24 months of IAD versus continuous CAD therapy. Two different populations were analyzed: Type 1 = pT3pN0M0 prostate cancers with biochemical (PSA) progression after RRP; Type 2 = metastatic PC directly submitted to CAD. Cases in Type I and Type 2 population were randomly assigned to IAD versus continuous CAD therapy. Forty cases each in Type 1 and Type 2 population were included in the analysis. At 1, 3, 6,12,18,24 months of IAD versus continuous therapy, serum levels of CgA compared to PSA levels were analyzed. RESULTS. In population Type 1 and Type 2, in the group of cases continuously treated with CAD (Group 2), there was a significant trend to increase for CgA levels from baseline to 24 months of therapy. On the contrary, no significant variations were found in cases treated with IAD (Group 1). Either in population Type 1 or Type 2, at 12- and 24-month follow-up, mean and median serum levels of CgA were significantly (P < 0.005) lower in Group 1 than in Group 2. CONCLUSIONS. The present study represents the first evidence in the literature that the intermittent administration of CAD therapy significantly reduces the increase in serum CgA levels during CAD therapy. (C) 2003 Wiley-Liss, Inc

COMPLETE RESPONSE TO THE COMBINATION THERAPY WITH ANDROGEN BLOCKADE AND SOMATOSTATIN ANALOGUE IN A PATIENT WITH ADVANCED PROSTATE CANCER: MAGNETIC RESONANCE IMAGING WITH 1H-SPECTROSCOPY: Part 2

Serum prostate-specific antigen and chromogranin A levels steadily decreased over a 12-mo follow-up period, at which time the patient is alive without disease progression and with a complete objective and symptomatic response

Effect of bone proteins on human prostate cancer cell lines in vitro

BACKGROUND Despite the high incidence and serious consequences of skeletal metastasis in prostate cancer patients, the mechanisms involved in establishing secondary lesions in bone are not well-understood. In this study, the role of the mineralized bone matrix in the process of skeletal metastasis was evaluated. METHODS Attachment, migration, and proliferation responses of human prostate cancer cells to a crude bone protein extract (CBE) were studied. LNCaP and DU145 cells were utilized in 24-hr attachment assays. Boyden chamber chemotactic assays and cell proliferation assays utilized DU145 cells. RESULTS CBE and fibronectin (FN) promoted attachment of DU145 cells, whereas only FN facilitated attachment of LNCaP cells. CBE-mediated adhesion of DU145 cells was reduced by 94% with cycloheximide, by 98% with RGD peptides, and by 94% with an antibody to ΑvΒ3. Although DU145 cells migrated toward FN, CBE did not promote migration of DU145 cells. DU145 cells grown in the presence of CBE-containing media demonstrated a significant reduction in cell number by day 4. The antiproliferative effect of CBE was not due to cell toxicity. CONCLUSIONS In conclusion, results from this study indicate that mineralized bone proteins promote the attachment of DU145 cells in vitro and suggest that bone proteins may play a key role in vivo during the development of metastatic prostate lesions in bone. Prostate 36:14–22, 1998. © 1998 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/34753/1/3_ftp.pd