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The optimal therapy for patients with non-metastatic biochemically relapsed prostate cancer (BRPC-M0) after local therapy is elusive. Thus, the evaluation of new non-toxic compounds in BRPC-M0 patients is warranted. PectaSol ® -Modified citrus pectin (P-MCP) is a food supplement categorized as GRAS (Generally Recognized As Safe) by the FDA. It is a competitive inhibitor of the galectin-3 protein, which is involved in cancer pathogenesis. In an early report of the present phase 2 study, P-MCP treatment for 6 months led to prostate-specific antigen doubling time (PSADT) improvement in 75% of patients with BRPC-M0. Herein, we report the second long-term treatment phase of an additional 12 months of P-MCP therapy (4.8 g × 3/day orally) in patients without disease progression after the initial 6 months of therapy. Of the 46 patients that entered the second treatment phase, 7 patients withdrew consent and decided to continue therapy out of pocket, and 39 initiated the second treatment phase. After a total of 18 months of P-MCP treatment, 85% ( n = 33) had a durable long-term response, with 62% ( n = 24) showing decreased/stable PSA, 90% ( n = 35) PSADT improvement, and all with negative scans. No patient had grade 3/4 toxicity. In conclusion, P-MCP may have long-term durable efficacy and is safe in BRPC-M0.

Optimal therapy of biochemically relapsed prostate cancer (BRPC) after local treatment is elusive. An established modified citrus pectin (PectaSol ® , P-MCP), a dietary polysaccharide, is an established antagonist of galectin-3, a carbohydrate-binding protein involved in cancer pathogenesis. Based on PSA dynamics, we report on the safety and the primary outcome analysis of a prospective phase II study of P-MCP in non-metastatic BRPC based. Sixty patients were enrolled, and one patient withdrew after a month. Patients ( n = 59) were given P-MCP, 4.8 grams X 3/day, for six months. The primary endpoint was the rate without PSA progression and improved PSA doubling time (PSADT). Secondary endpoints were the rate without radiologic progression and toxicity. Patients that did not progress by PSA and radiologically at six months continued for an additional twelve months. After six months, 78% ( n = 46) responded to therapy, with a decreased/stable PSA in 58% ( n = 34), or improvement of PSADT in 75% ( n = 44), and with negative scans, and entered the second twelve months treatment phase. Median PSADT improved significantly ( p = 0.003). Disease progression during the first 6 months was noted in only 22% ( n = 13), with PSA progression in 17% ( n = 10), and PSA and radiologic progression in 5% (n = 3). No patients developed grade 3 or 4 toxicity.

Objectives: To compare the ability of 68 Ga -PSMA PET/CT (PSMA PET/CT) and multiparametric MRI (mpMRI) to exclude lymph node invasion (LNI) in patients who undergo radical prostatectomy (RP)., Materials and Methods: A multicenter cohort of patients who underwent PSMA PET/CT and pelvic mpMRI prior to RP with pelvic lymph node dissection (PLND) was analyzed. Increased Ga68-PSMA uptake on PET/CT and enlarged (> 10 mm) or abnormal lymph nodes on mpMRI were considered positive findings. The final surgical pathology served as the standard of reference. The negative predictive value (NPV) was calculated for each modality separately, as well as the combined value., Results: Included were 89 patients with D'Amico intermediate (45%) or high-risk (55%) prostate cancer. The median number of extracted LN was 9 (IQR 6-14). LNI was found in 12 (13.5%) patients. The NPV of mpMRI, PSMA PET/CT, and the two tests combined were 87%, 89%, and 90%, in the entire cohort, 95%, 97%, and 97% in patients with intermediate-risk disease, and 80%, 82%, and 83% in patients with high-risk disease, respectively. The median diameter of LN missed by both imaging and the median intranodal tumor diameter was 5.5 (IQR 3-10) mm and 1 (IQR 1-3) mm, respectively., Conclusions: PSMA PET/CT and mpMRI demonstrated similar performance in excluding pelvic LNI with NPV of approximately 90%. The combination of both tests does not improve NPV significantly. Therefore, even in the era of advanced imaging, PLND is still recommended for accurate staging, especially in the high-risk population.

Introduction: Osteoporosis is more common in elderly men than previously suspected. Prostate cancer patients may have an increased rate of osteopenia and osteoporosis independent of therapy. Osteopenia and fracture risk are accelerated in men receiving androgen deprivation therapy. Nevertheless, little is done by primary care physicians and urologists to diagnose and treat osteoporosis in men., Aims: (1) Assess prostate cancer patients' compliance and adherence to bisphosphonate therapy; (2) Increase awareness for osteoporosis in men diagnosed with prostate cancer among urologists and primary care physicians and to evaluate collaboration between the two disciplines., Methods: We included patients with confirmed diagnosis of prostate cancer who fulfilled one or more of the following criteria: (1) age 70 and above; (2) age 60 and above with androgen deprivation therapy or (3) prior diagnosis of osteopenia and osteoporosis. Qualified patients were referred to DXA bone density test. Patients with osteopenia or osteoporosis, who were naïve to bisphosphonates, received recommendations for oral bisphosphonates. Follow-up lasted 6 months and included 2 office visits to ensure patients' compliance and adherence to recommended therapy., Results: A total of 28 community-based urologists recruited 180 patients. Of the 180 prostate cancer patients, 87 (48%) had osteoporosis and 93 (52%) osteopenia, all were naïve to bisphosphonates. Of the 180 patients, 153 (85%) patients started treatment with bisphosphonates after inclusion; 147/180 (82%) and 136/180 (76%) patients stayed on bisphosphonates for 3 and 6 months respectively. Primary care physicians adopted recommendations for bisphosphonate in 123/180 (68%)., Conclusions: This study showed high compliance and adherence of prostate cancer patients for bisphosphonate recommendation.

Background: Small cell carcinoma of the prostate (SCCP) is a rare subset of prostate cancer (0.5-2% of all prostatic carcinomas), predominantly composed of neuroendocrine (NE) cells, with a very poor prognosis. Irradiation is one of the mainstay options for SCCP local treatment, yet, little is known about the clinical response of these aggressive tumors to radiotherapy., Methods: Using SCID mice, the response to fractionated ionizing radiation (IR) of two unique human NE xenografts of SCCP (WISH-PC2 and WM-4A) was investigated., Results: Fractionated irradiation of WISH-PC2 xenografts using total doses of >24 Gy induced a delay in tumor growth, while total doses of >36 Gy led to local tumor eradication. However, most of the irradiated mice suffered from disseminated metastases. Similarly, in the WM-4A xenograft, a total dose of 20 Gy led to tumor growth delay and some of the mice also developed metastases. Non-irradiated local xenografts failed to disseminate, even following surgical excision of the main tumor mass; however, tumor cells administered intravenously did form metastases. Metastases of both xenografts were located in the adrenal/kidney and inter-scapular regions, areas rich in brown adipose tissue. A correlation was found between the appearance of irradiation-induced metastases and activation of the gelatinase activity of matrix metalloproteinase-9., Conclusions: Clinically, this study raises the possibility that radiation to SCCP may promote metastatic disease. For patients in whom prostate biopsy shows a predominance of small cell cancer, it may be necessary to deliver systemic therapy together with the radiotherapy in order to prevent the development of metastases.

Unlabelled: The aim of this study was to compare the detection of bone metastases by 99mTc-methylene diphosphonate (99mTc-MDP) planar bone scintigraphy (BS), SPECT, 18F-Fluoride PET, and 18F-Fluoride PET/CT in patients with high-risk prostate cancer., Methods: In a prospective study, BS and 18F-Fluoride PET/CT were performed on the same day in 44 patients with high-risk prostate cancer. In 20 of the latter patients planar BS was followed by single field-of-view (FOV) SPECT and in 24 patients by multi-FOV SPECT of the axial skeleton. Lesions were interpreted separately on each of the 4 modalities as normal, benign, equivocal, or malignant., Results: In patient-based analysis, 23 patients had skeletal metastatic spread (52%) and 21 did not. Categorizing equivocal and malignant interpretation as suggestive for malignancy, the sensitivity, specificity, positive predictive value, and negative predictive value of planar BS were 70%, 57%, 64%, and 55%, respectively, of multi-FOV SPECT were 92%, 82%, 86%, and 90%, of (18)F-Fluoride PET were 100%, 62%, 74%, and 100%, and of 18F-Fluoride PET/CT were 100% for all parameters. Using the McNemar test, 18F-Fluoride PET/CT was statistically more sensitive and more specific than planar or SPECT BS (P < 0.05) and more specific than 18F-Fluoride PET (P < 0.001). SPECT was statistically more sensitive and more specific than planar BS (P < 0.05) but was less sensitive than 18F-Fluoride PET (P < 0.05). In lesion-based analysis, 156 lesions with increased uptake of 18F-Fluoride were assessed. Based on the corresponding appearance on CT, lesions were categorized by PET/CT as benign (n = 99), osteoblastic metastasis (n = 46), or equivocal when CT was normal (n = 11). Of the 156 18F-Fluoride lesions, 81 lesions (52%), including 34 metastases, were overlooked with normal appearance on planar BS. SPECT identified 62% of the lesions overlooked by planar BS. 18F-Fluoride PET/CT was more sensitive and more specific than BS (P < 0.001) and more specific than PET alone (P < 0.001)., Conclusion: 18F-Fluoride PET/CT is a highly sensitive and specific modality for detection of bone metastases in patients with high-risk prostate cancer. It is more specific than 18F-Fluoride PET alone and more sensitive and specific than planar and SPECT BS. Detection of bone metastases is improved by SPECT compared with planar BS and by 18F-Fluoride PET compared with SPECT. This added value of 18F-Fluoride PET/CT may beneficially impact the clinical management of patients with high-risk prostate cancer.

Introduction: Neuroendocrine differentiation of prostatic adenocarcinoma is a recognized phenomenon, which is believed to parallel tumor progression to hormone refractory state. Circulating CgA levels were shown to reflect neuroendocrine differentiation and were found to correlate with the stage and the state of hormone refractoriness. Hence, CgA may become a marker for diagnosis, monitoring and management of prostate cancer patients., Patients and Methods: CgA level was measured in plasma samples which were obtained from 40 patients with prostate cancer, using the ELISA kit (DAKO, Glostrup-Denmark). The normal range of CgA was 2-18, SD = 4. The normal threshold was hence set to 26 u/L calculated as upper normal level + 2SD. Additionally, serum levels of PSA, CEA, CA-125, CA-15.3 and CA-19.9 were measured at that time. Clinical data was collected from medical records., Results: Overall, CgA was elevated in 18 patients (45%) including 25% of the patients with organ confined disease, 52.9% with locally advanced disease, 71.4% of the patients with metastases, 75% of the patients with hormone refractory prostate cancer and 23.1% of patients with hormone sensitive disease (p = 0.009). Mean CgA and PSA levels among patients with elevated CgA was 100.2 u/L (27-717) and 301 ng/ml (4.5-1450) respectively. In comparison to 18.8 u/L (14-26) and 14.7 ng/ml (2.6-59.7) respectively, in patients with CgA within the normal range (p < 0.05). PSA at the time of CgA sampling did not differ among the two groups., Conclusions: In this study high plasma CgA levels correlated with known poor prognostic factors including advanced and metastatic disease at the time of presentation, high pretreatment PSA levels and hormone refractoriness. CgA levels which reflect neuroendocrine differentiation of prostatic carcinoma may have a diagnostic, therapeutic and prognostic role in the management of prostate cancer patients.

Approximately 80-90% of prostate cancers are androgen dependent at initial diagnosis. The androgen receptor (AR) is present in most advanced prostate cancer specimens and is believed to have a critical role in its development. Today, treatment of prostate cancer is done by inhibition of AR using antiandrogens such as flutamide (pro-drug of hydroxyflutamide), nilutamide, and bicalutamide. However, there is currently no noninvasive imaging modalities to detect, guide, and monitor specific treatment of AR-positive prostate cancer. (R)-3-Bromo-N-(4-fluoro-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methyl-propanamide [18F]-1 and N-(4-fluoro-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide [18F]-2, derivatives of hydroxyflutamide, were synthesized as a fluorine-containing imaging agent candidates. A three-step fluorine-18 radiosynthesis route was developed, and the compounds were successfully labeled with a 10+/-3% decay corrected radiochemical yield, 95% radiochemical purity, and a specific activity of 1500+/-200 Ci/mmol end of bombardment (n = 10). These labeled biprobes not only may enable for the future quantitative molecular imaging of AR-positive prostate cancer using positron emission tomography but may also allow for image-guided treatment of prostate cancer.

Objectives: The extent of the required preoperative workup of patients who are candidates for radical prostatectomy is still controversial. Traditionally, cystoscopy has been reserved only for those patients who present with hematuria. However, several investigators have reported significant incidental cystoscopic findings among these patients and advocated the routine use of cystoscopy before radical prostatectomy. In view of the conflicting recommendations, we elected to assess the role of routine cystoscopy in a series of patients with prostate cancer at our institute., Methods: We retrospectively reviewed the cystoscopic findings of 225 consecutive patients with organ-confined prostate carcinoma scheduled for radical prostatectomy. Rigid cystoscopy was performed before surgery either in an outpatient setting or on the operating table just before the operation., Results: Significant cystoscopic findings were noted in 3 (1.3%) of 225 patients. These included a bladder stone in 1 patient, superficial bladder tumor in 1 patient, and a post-sphincteric urethral polyp containing prostatic adenocarcinoma in a third patient. This polyp was resected transurethrally and the patient was treated thereafter with irradiation because of local extension. None of the 3 patients had microscopic hematuria on urinalysis to suggest the findings. Cystoscopy was uneventful in all patients, apart from occasional mild hematuria., Conclusions: These results show that the treatment of patients who were candidates for radical prostatectomy was affected by the findings of preoperative cystoscopy in less than 1% of the cases. We believe that in view of the low yield of cystoscopic findings in these patients, in an era in which cost effectiveness is a major issue, the routine use of cystoscopy before radical prostatectomy is not justified.

Objectives: To verify whether bladder dysfunction detected by urodynamic studies prior to radical prostatectomy can predict postoperative continence status., Material and Methods: Twenty patients diagnosed with prostate cancer had multichannel subtracted filling and voiding videocystometry before undergoing radical retropubic prostatectomy. Postoperatively, all patients had periodic clinical assessment of continence status., Results: On preoperative filling cystometry, detrusor instability with a maximal detrusor pressure greater than 15 cm H2O was demonstrated in 12/20 patients (60%). Postoperatively, 11/20 patients (55%) were continent, 4 (20%) had mild stress incontinence and 5 (25%) complained of episodic urge incontinence. However, only 5 of the 12 patients with preoperatively diagnosed detrusor instability manifested clinical urge incontinence after surgery (positive predictive value = 41.6%)., Conclusion: The incidence of preoperative detrusor instability in our series was high, but little correlation was found between this finding and postoperative incontinence.

Transurethral thermal treatment has been used to relieve obstructive voiding symptoms in 10 patients with prostate cancer. All patients failed previous endocrine treatment for the relief of obstructing urinary symptoms. Temperature ranging from 46 degrees C to 47 degrees C was applied transurethrally using Thermex II thermal system. Treatment was given in a single session for a duration of 180 minutes on an outpatient basis without sedation. Mean duration of follow-up was 8.5 months (range 4-13 months). Maximal urine flow rate, post-voiding residual volumes and changes in subjective symptoms were used to assess treatment response. Removal of an indwelling catheter was possible in all 3 patients with chronic retention. Urinary infection (2 patients) and temporary retention (3 patients) were the only complications recorded. The preliminary results suggest that transurethral hyperthermia is a well-tolerated, safe and effective procedure for obstructive voiding symptoms in patients with hormone refractory prostate cancer. Longer follow-up and a larger group of patients is required to assess this alternative modality.

The conversion of testosterone (T) to dihydrotestosterone (DHT) has been demonstrated to be catalysed by at least two isoforms of human steroid 5 alpha-reductase, designated types I and II. Type II 5 alpha-reductase expression predominates in human accessory sex tissues, localized to the fibromuscular stromal compartment. The type I isoform predominates in skin, prostatic epithelia and, to a lesser extent, in prostatic fibromuscular stroma. The significance of the type I isoform to prostatic cellular growth and function remains undefined. In cultured DU145 cells, we evaluated the metabolism of [14C]-T and demonstrated the time-dependent formation of [14C]-DHT. Oxidative metabolism (conversion of [14C]-T to [14C]-androstenedione) and the formation of conjugated androgen metabolites occurred at a relatively low rate in the DU145 cells. Using human type I 5 alpha-reductase cDNA, Northern blot analysis of DU145 cell mRNA revealed high levels of type I isoform expression. Analogous probing of the DU145 cells with a human 5 alpha-reductase II cDNA failed to reveal expression of the type II isoform. The expression of functional type I activity has been confirmed pharmacologically using isoform-selective 5 alpha-reductase inhibitors. Reductive metabolism of [3H]-T in the DU145 cells was inhibited in a concentration-dependent manner by LY306089, a potent non-steroidal type I-selective inhibitor (IC50 = 10.0 nM). SKF105657, a steroidal type II-specific inhibitor was distinctly less active at inhibiting [3H]-DHT formation. LY306089 was a non-competitive inhibitor of type I 5 alpha-reductase in DU145 cellular homogenates with an apparent Ki value of 4.0 nM. These studies have identified and pharmacologically defined type I 5 alpha-reductase activity in an androgen-insensitive prostatic cancer cell line and provide the basis for additional investigations into the significance of type I 5 alpha-reductase to human prostatic pathophysiology.

We evaluate the metabolic inhibitory, antiproliferative, and antisecretory effects of LY300502, a benzoquinolinone human-specific type I-selective steroid 5alpha-reductase inhibitor in LNCaP human prostatic adenocarcinoma cell cultures. Reductive metabolism of [3H-T] in the LNCaP cells was inhibited in a concentration-dependent manner by LY300502 (IC50 approximately 5.77 nM). The proliferative responses of LNCaP cells to LY300502 were examined in the presence of 0.1 NM testosterone (T), a concentration that stimulates maximal LNCaP cell numbers 40% above control levels. LY300502 significantly anatagonized T-induced stimulation of LNCaP cellular proliferation at concentrations greater that 10 nM (P<0.05), and at 1,000 nMcompletely blocked the mitogenic effects of T on LNCaP cells. In the absence of androgen, LY300502 had no effect on LNCaP cellular proliferation. In the presence of 100 nM T, an androgen concentration that maximally stimulates in vitro PSA production, LY300502 significantly antagonized T-induced PSA secretion at a concentration equal to or greater than 30 nM (P<0.05). These studies provide the basis for additional investigations into the pathophysiologic significance of type I 5alpha-reductase to prostatic cancer and the potential utility of selective inhibitors as therapeutic agents.

Patients undergoing pelvic lymphadenectomy and radical retropubic prostatectomy are traditionally considered to be at high risk for postoperative venous thromboembolic complications. A prospective deep venous thrombosis screening regimen was initiated at our medical center in 1990 following 2 cases of fatal pulmonary embolism that occurred after hospital discharge. During a 3-year period 245 consecutive patients undergoing radical retropubic prostatectomy for prostate cancer were screened postoperatively for lower extremity deep venous thrombosis using ultrasound duplex scanning with color Doppler flow imaging. The results were correlated only with the development of clinical deep venous thrombosis. No additional diagnostic modalities were used to confirm a normal venous system in asymptomatic patients. Venous thromboembolic complications were encountered in 9 of the 245 patients (3.6%). In 2 patients deep venous thrombosis was associated with nonfatal pulmonary embolism. Only 2 of the 9 cases of deep venous thrombosis were detected by color Doppler flow imaging screening. The striking decrease in the incidence of deep venous thrombosis following radical prostatectomy in the last decade and the low yield of screening at a single point in time may warrant reconsideration of the need for deep venous thrombosis screening among patients undergoing pelvic lymphadenectomy and radical retropubic prostatectomy for prostate cancer.

Between 1986-1991 we treated 50 men with adenocarcinoma of the prostate by radical prostatectomy. Ages ranged from 44-74 and clinical stages were A-C. Follow-up lasted 1-63 months (mean 15.1) and was designed to rule out recurrence and/or spread of the disease and to evaluate quality of life. The rate of complications was low, the postoperative course short and uneventful, and there was preservation of urinary continence in 96% and of potency in 10.2%. As compared with radiotherapy, surgery gave superior results and is recommended.