Faculty Bibliography

Epidemiological research on prostate cancer risk in men throughout the world has identified significant correlations between dietary habits and prostate cancer occurrence. These studies served as a catalyst for exploration into the potential of dietary substances to act as chemopreventive agents against this disease, and include green tea catechins, lycopene, soy isoflavones, pomegranate phenolics, selenium, vitamins E and D, curcumin and resveratrol. Before these agents (in the dietary or purified forms) can be recommended as useful chemopreventive strategies for patients, their activity must be confirmed in rigorously designed clinical trials. This review discusses the preclinical and clinical data available for these dietary agents and describes relevant clinical trials currently being conducted.

The tropical shrub, Rauwolfia vomitoria, is a medicinal plant used traditionally to treat a variety of ailments. A bioactive beta-carboline alkaloid, alstonine, present in this extract was previously shown to have anti-cancer activity against cancer cell lines. This study considers the potential anti-prostate cancer activity of this extract in vitro and in vivo. Rauwolfia vomitoria extract standardized for beta-carboline alkaloids was tested for ability to influence the growth and survival of the human LNCaP prostate cancer cell line. A WST-1 assay was used to measure cell growth, and cell cycle analyses were conducted with flow cytometry. Western blot detection of PARP cleavage and accumulation of cells containing sub-genomic DNA indicated induction of apoptosis. Pathway specific microarray analyses were utilized to identify the effect of Rauwolfia extract on the expression of 225 genes. Mice xenografted with LNCaP cells were treated with the extract or placebo control, and tumor growth was measured for 5 weeks. The effects of the extract on xenografted tumor cell proliferation and apoptosis were measured by in situ BrdU incorporation and TUNEL staining. Rauwolfia extract decreased in vitro cell growth in a dose-dependent manner (p<0.001) and induced the accumulation of G1 phase cells. PARP cleavage demonstrated that apoptosis was induced only at the highest concentration tested (500 microg/ml) which was confirmed by detection of cells containing sub-genomic DNA. The expression of genes associated with DNA damage signaling pathway was up-regulated by Rauwolfia treatment, including that of GADD153 and MDG. The expression of a few cell cycle genes (p21, cyclin D1 and E2F1) was also modulated. These alterations were confirmed by RT-PCR. Tumor volumes were decreased by 60%, 70% and 58% in the groups fed the 75, 37.5 or 7.5 mg/kg Rauwolfia, respectively (Kruskal-Wallis test, p<0.001). The Rauwolfia vomitoria extract significantly suppressed the growth and cell cycle progression of LNCaP cells, in vitro and in vivo.

UNLABELLED:Authors from Iowa City report on the incidence of RCC; they compared the rate of these tumours at autopsy and felt that the decrease found was a result of better antemortem detection, and an increase with time in the frequency of clinically detected renal cancer. A study from New York attempted to determine whether size, or transcapsular extension irrespective of size, was more likely to produce an adverse outcome. They analysed their database of 717 such tumours between 1988 and 2002, and found that absolute tumour size was the more significant of the two findings. OBJECTIVE:To determine which factor was more predictive of adverse outcome in our institutional experience with T2N0M0 and T3N0M0 renal cortical tumours (RCTs) treated surgically, as the current Tumour-Node-Metastasis (TNM) staging system for RCTs differentiates between tumours of >7.0 cm but confined to the renal capsule (T2) and tumours that extend through the renal capsule regardless of size (T3a). MATERIALS AND METHODS/METHODS:We analysed our institutional database of surgical urological oncology for all patients with T2N0M0 and T3aN0M0 RCT treated with partial or radical nephrectomy from 1988 to 2002. All patients with preoperative metastasis, bilateral or multifocal tumours, nonsporadic disease or benign histology were excluded from analysis. A follow-up of > or = 6 months from the time of surgery was required for inclusion. Primary outcomes included local and distant recurrence, and death. RESULTS:In all, 717 patients had a partial or radical nephrectomy for RCT during the study period. After exclusion criteria were applied, 21 patients with T2N0M0 and 97 with T3aN0M0 tumours were eligible; the median (mean, range) age was 63 (16.6-88.3) years and follow-up 30.5 (40.8, 6-162) months. The estimated 5-year disease-free survival was 68% and 85% for T2N0M0 and T3aN0M0 RCT, respectively (P = 0.002). The 5-year disease-specific survival was 81% and 94% for the T2N0M0 and T3aN0M0 groups, respectively (P = 0.085). CONCLUSION/CONCLUSIONS:Patients with T3aN0M0 tumours appear to have better disease-free and disease-specific survival than those with T2N0M0 disease, which suggests that tumour invasion through the renal capsule is not as significant as the absolute tumour size.

Cyclooxygenase (COX) inhibitors have suppressive effects on several types of cancer cells including prostate cancer. In this study, we considered the potential COX-inhibitory activity of a unique anti-inflammatory herbal preparation (Zyflamend; New Chapter, Inc., Brattleboro, VT) and analyzed its effects on the human prostate cancer cell line LNCaP. COX inhibitory activity of Zyflamend was determined by a spectrophotometric-based assay using purified ovine COX-1 and COX-2 enzymes. Effects of Zyflamend on LNCaP cell growth and apoptosis in vitro were assessed by cell counting, Western blot detection of poly ADP-ribose polymerase (PARP) cleavage, and measurement of caspase-3 activity in treated and control cell extracts. Western blotting techniques were conducted to determine the effects of this herbal preparation on the expression of the cell signaling proteins, p21, androgen receptor (AR), phospho-protein kinase C (pPKC)(alpha/beta), and phospho (p)Stat3. The phospohorylation status of several signal transduction phosphoproteins was profiled using a high-throughput phosphoprotein screening assay in treated cells and compared to controls. Zyflamend dramatically decreased COX-1 and COX-2 enzymatic activity. Elevated p21 expression coincided with attenuated cell growth following treatment of LNCaP cells with Zyflamend. PARP cleavage fragments were evident, and caspase-3 activity was upregulated over the control indicating the ability of Zyflamend to induce apoptosis of these cells. Androgen receptor expression levels declined by 40%, and decreases were observed in the active forms of Stat3 and PKC(alpha/beta) in Zyflamend-treated LNCaP cells. Zyflamend inhibited both COX-1 and COX-2 enzymatic activities, suppressed cell growth, and induced apoptosis in LNCaP cells. However, our data suggests that the effects are likely due to COX-independent mechanisms potentially involving enhanced expression of p21 and reduced expression of AR, pStat3, and pPKC(alpha/beta).

BACKGROUND:The authors report their experience with cryosurgical ablation of the prostate in men with high-risk features for prostate carcinoma who were unwilling to undergo radical surgery or radiation therapy. METHODS:Between January 1998 and April 2002, 65 men underwent primary cryosurgery for prostate carcinoma with high-risk features. All patients had biopsy-proven prostate carcinoma without evidence for metastatic disease on magnetic resonance images, computed tomography scans, or radionuclide images of bones. High-risk parameters were defined as either a prostate-specific antigen (PSA) level >/= 10 ng/mL, or a Gleason sum score >/= 8, or both. Patients who had undergone prior surgery, radiation therapy, or cryoablation for prostate carcinoma were excluded from the study. Patients were monitored with physical examination and PSA screening every 3 months and with radiologic imaging when indicated. RESULTS:The median patient age was 72 years (range, 41-86 years), and t he median follow-up was 35 months (range, 4-77 months). There were 2 patients (3.1%) with rectal pain and incontinence. Durable PSA biochemical disease-free survival was noted in 83.3% of patients according to the American Society for Therapeutic Radiology and Oncology (ASTRO) criteria. A 6-year Kaplan-Meier analysis revealed an 81.7% ASTRO survival probability as well as PSA nadir < 4.0 ng/mL and PSA nadir < 1.0 ng/mL projections of 50% and 35%, respectively. One of 8 postcryosurgery biopsies (12.5%) were positive. No patient had progressed at last follow-up, and the overall survival rate was 100%. CONCLUSIONS:Cryoablation was a feasible treatment option in patients with organ-confined prostate carcinoma who had high-risk features. Longer follow-up will be necessary to determine the effectiveness of this approach.

To discuss challenges concerning treatment for chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) and review complementary and alternative medical (CAM) therapies being evaluated for this condition, we performed a comprehensive search of articles published from 1990-2005 using the PubMed, Medline databases. Data from the articles were abstracted and pooled by subject. Keywords cross-searched with CP/CPPS included: complementary, alternative, integrative, therapies, interventions, nutrition, antioxidants, herbs, supplements, biofeedback and acupuncture. Listed articles with no abstracts were not included. Various CAM therapies for CP/CPPS exist including biofeedback, acupuncture, hyperthermia and electrostimulation. Additionally, a variety of in vitro and in vivo studies testing herbal and nutritional supplements were found. Saw palmetto, cernilton and quercetin were the most frequently tested supplements for CP/CPPS. Although many CAM therapies demonstrate positive preliminary observations as prospective treatments for CP/CPPS, further exploratory studies including more randomized, controlled trials are necessary for significant validation as treatment options for this complex disorder.

PURPOSE/OBJECTIVE:Isoflavones have anticancer activities, but naturally occurring isoflavones are predominantly glycosylated and poorly absorbed. Genistein combined polysaccharide (GCP; Amino Up Chemical Co., Sapporo, Japan), is a fermentation product of soy extract and basidiomycetes mycillae that is enriched in biologically active aglycone isoflavones. This study analyzes GCP in vitro and in vivo for potential utility as a prostate cancer chemopreventative agent. EXPERIMENTAL DESIGN/METHODS:Androgen-sensitive LNCaP and androgen-independent PC-3 cells were grown with various concentrations of GCP. In vitro cell growth was analyzed by the WST-1 assay, and apoptosis was assessed by fluorescence-activated cell sorting and detection of poly(ADP-ribose) polymerase cleavage using Western blot techniques. Effects of GCP on expression of cell cycle-regulatory proteins p53 (LNCaP only), p21, and p27 and the protein kinase Akt were considered using Western blot techniques. An in vivo LNCaP xenograft model was used to study the effects of a 2% GCP-supplemented diet on tumor growth in comparison with a control diet. RESULTS:GCP significantly suppressed LNCaP and PC-3 cell growth over 72 h (89% and 78% in LNCaP and PC-3, respectively, at 10 microg/ml; P < 0.0001). This reduction was associated with apoptosis in LNCaP cells, but not in PC-3 cells. GCP induced p27 and p53 (LNCaP only) protein expression within 6 h and suppressed phosphorylated Akt in both cell lines. The 2% GCP-supplemented diet significantly slowed LNCaP tumor growth, increasing apoptosis (P < 0.001), and decreasing proliferation (P < 0.001) over 4 weeks. CONCLUSIONS:GCP has potent growth-inhibitory effects against prostate cancer cell lines in vitro and in vivo. These data suggest GCP has potential as an effective chemopreventive agent against prostate cancer cell growth.

BACKGROUND:Metastatic renal cell carcinoma (RCC) is an aggressive entity that frequently invades the venous system. We evaluated the morbidity and survival of patients with tumor thrombus who undergo cytoreductive nephrectomy. MATERIALS AND METHODS/METHODS:We identified 56 patients from our institution's database who had a primary renal tumor in place and documented metastases at the time of surgery. We reviewed demographic and pathologic characteristics from these patients as well as complications and overall survival. RESULTS:Median age was 58 (37-77). There were 33 patients (59%) who had tumor thrombus with 21 (64%) involving the renal vein, 10 (30%) involving the infradiaphragmatic inferior vena cava (IVC), and 2 (6%) involving the supradiaphragmatic IVC. Median tumor size for thrombus patients was 12 cm (5-29). There were 8 (14.2%) who had complications, including 1 death. Thrombus patients were significantly more likely to have a complication (P = 0.008). Median survival for all patients was 10.7 months (0.3-61). There was no significant difference in overall survival between patients with and without thrombus (P = 0.76). CONCLUSIONS:Patients who undergo cytoreductive nephrectomy with a tumor thrombus have a higher rate of complications as compared to patients undergoing cytoreductive nephrectomy without tumor thrombus. The long-term survival, however, was not statistically different and thus aggressive surgery for select metastatic RCC patients is warranted.

OBJECTIVES/OBJECTIVE:To determine the natural history of patients younger than 40 years (young patient [YP] group) who are diagnosed with a sporadic renal cortical tumor (RCT) and to compare the natural history of these patients with the more typical older patient (OP) with RCT. METHODS:We reviewed our database and identified 34 patients (younger than 40 years old, median age 35) who underwent surgery for a sporadic RCT. The YP group outcomes were compared with 100 patients between 41 and 85 years (median 65). We fit a Cox proportional hazards model to examine the relationship between age at presentation and recurrence risk. RESULTS:The median tumor size in the YP group was 3.8 cm (range 0.6 to 19) and in the OP group was 5.0 cm (range 0.9 to 22; P = 0.225). Tumors were discovered incidentally in 51% and 56% of the YP and OP groups, respectively (P = 0.65). The frequency of partial nephrectomy did not differ between the two groups (35% YP and 30% OP, P = 0.55). The frequency of malignant histologic subtypes did not differ between the groups (P = 0.439). In the YP group, only larger tumor size (hazard ratio 1.23, 95% confidence interval 1.02 to 1.50, P = 0.034) was associated with a statistically significant increased risk of recurrence. Those in the YP group were not more or less likely to develop recurrence than those in the OP group (hazard ratio 0.79, 95% confidence interval 0.22 to 2.85, P = 0.72). The 5-year disease-free survival rate was 73% and 80% in the YP and OP groups, respectively (P = 0.23). The 5-year disease-specific survival rate was 85% and 84% in the YP and OP groups, respectively (P = 0.88). CONCLUSIONS:The findings of our study indicate that the natural history of RCTs is similar in both younger and older patients. Young patients were neither more nor less likely to develop recurrence compared with their older counterparts.

PURPOSE/OBJECTIVE:Recent advances in cryosurgery of the prostate have led to the ability to treat tumors successfully with decreased morbidity. The patients' perspectives of this relatively new technique, however, have not yet been addressed. The purpose of this study was to compare health related quality of life (QoL) as well as prostate-associated symptoms in patients after primary and salvage cryoablation for clinically localized prostate cancer using a self-administered questionnaire. METHODS:A total of 131 consecutive patients who underwent cryoablation of the prostate between 1997 and 2001 were included in this confidential mailing study. The patients were either (a) patients with localized prostate cancer with contraindications for radical surgery, including patients refusing other forms of therapy, or (b) had locally recurrent prostate cancer after failure of radiation therapy. All patients received 3 months of neoadjuvant androgen deprivation therapy prior to cryosurgery and were surgically treated by the same surgeon using an argon-based system. We used the EORTC QLQ-C30, a commonly used, multidimensional instrument together with a supplementing, prostate-cancer-specific module. RESULTS:Eighty-one of the 131 patients (response rate 62%) returned the questionnaires. The two groups were comparable regarding age (mean age 72.8 vs 70.1 for the primary and the salvage group, respectively; p=0.22). The overall QoL scores were high in both groups. Primary cryotherapy patients fared significantly better regarding physical (p=0.005) and social (p=0.024) functioning compared with salvage cryotherapy patients. The most prominent prostate-related symptom in both patient groups was sexual dysfunction, followed by urinary symptoms, which were significantly more severe in the salvage group (p=0.001). Incontinence rates were 5.9 and 10% in the primary and the salvage group, respectively. Severe erectile dysfunction was reported in 86 and 90% of the primary and the salvage group, respectively. CONCLUSIONS:The present study demonstrates that, in selected patients, cryotherapy is a treatment option which has a functional outcome comparable to traditionally used prostate cancer treatments. More information regarding QoL is necessary for appropriate patient counseling and individual decision-making in the presence of various treatment alternatives.