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Purpose: The aim of this study was to assess the clinical feasibility of magnetic resonance imaging (MRI) T1 mapping using T1FLASH for assessment of prostate lesions., Methods: Participants with clinical suspicion for prostate cancer (PCa) were prospectively enrolled between October 2021 and April 2022 with multiparametric prostate MRI (mpMRI) acquired on a 3 T scanner. In addition, T1 mapping was accomplished using a single-shot T1FLASH technique with inversion recovery, radial undersampling, and iterative reconstruction. Regions of interest (ROIs) were manually placed on radiologically identified prostate lesions and representative reference regions of the transitional zone (TZ), benign prostate hyperplasia nodules, and peripheral zone (PZ). Mean T1 relaxation times and apparent diffusion coefficient (ADC) values (b = 50/b = 1400 s/mm 2 ) were measured for each ROI. Participants were included in the study if they underwent ultrasound/MRI fusion-guided prostate biopsy for radiologically or clinically suspected PCa. Histological evaluation of biopsy cores served as reference standard, with grading of PCa according to the International Society of Urological Pathology (ISUP). ISUP grades 2 and above were considered clinically significant PCa for the scope of this study. Histological results of prostate biopsy cores were anatomically mapped to corresponding mpMRI ROIs using biopsy plans. T1 relaxation times and ADC values were compared across prostate regions and ISUP groups. Across different strata, T1 relaxation time, ADC values, and diagnostic accuracy (area under the curve [AUC]) were compared using statistical methods accounting for clustered data., Results: Of 67 eligible participants, a total of 40 participants undergoing ultrasound/MRI fusion-guided prostate biopsy were included. Multislice T1 mapping was successfully performed in all participants at a median acquisition time of 2:10 minutes without evident image artifacts. A total of 71 prostate lesions was radiologically identified (TZ 49; PZ 22). Among those, 22 were histologically diagnosed with PCa (ISUP groups 1/2/3/4 in n = 3/15/3/1 cases, respectively). In the TZ, T1 relaxation time was statistically significantly lower for PCa compared with reference regions ( P = 0.029) and benign prostate hyperplasia nodules ( P < 0.001). Similarly, in the PZ, PCa demonstrated shorter T1 relaxation times versus reference regions ( P < 0.001). PCa also showed a trend toward shorter T1 relaxation times (median, 1.40 seconds) compared with radiologically suspicious lesions with benign histology (median, 1.47 seconds), although statistical significance was not reached ( P = 0.066). For discrimination of PCa from reference regions and benign prostate lesions, T1 relaxation times and ADC values demonstrated AUC = 0.80 and AUC = 0.83, respectively ( P = 0.519). Discriminating PCa from radiologically suspicious lesions with benign histology, T1 relaxation times and ADC values showed AUC = 0.69 and AUC = 0.62, respectively ( P = 0.446)., Conclusions: T1FLASH-based T1 mapping yields robust results for quantification of prostate T1 relaxation time at a short examination time of 2:10 minutes without evident image artifacts. Associated T1 relaxation times could aid in discrimination of significant and nonsignificant PCa. Further studies are warranted to confirm these results in a larger patient cohort, to assess the additional benefit of T1FLASH maps in conjunction with mpMRI sequences in the setting of deep learning, and to evaluate the robustness of T1FLASH maps compared with potentially artifact-prone diffusion-weighted imaging sequences., Competing Interests: Conflicts of interest and sources of funding: Francesco Giganti is a recipient of the 2020 Young Investigator Award (20YOUN15) funded by the Prostate Cancer Foundation/CRIS Cancer Foundation. Francesco Giganti reports consulting fees from Lucida Medical LTD outside of the submitted work. The authors have no further conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The aim of our study was to evaluate the impact of prostate biopsy technique (transrectal ultrasound (US)-prostate biopsy (PBx) versus multiparametric magnetic resonance imaging (mpMRI) targeted prostate biopsy (MRI-PBx) on intraoperative nerve-sparing and the rate of secondary neurovascular-bundle resection (SNR) in patients undergoing robot-assisted laparoscopic radical prostatectomy (RARP). A real-time investigation with a frozen-section examination (NeuroSAFE) microscopically excluded or confirmed prostate cancer invasion of the nerve structures resulting in preservation of the neurovascular bundle or SNR. Additionally, we analyzed risk factors related to SNR, such as longer operation time and postoperative complications., Methods: The total study cohort was stratified according to non-nerve-sparing versus nerve-sparing RARP. Patients with nerve-sparing approach were then stratified according to biopsy technique (PBx vs. MRI-PBx). Further, we compared PBx versus MRI-PBx according to SNR rate., Results: We included a total of 470 consecutive patients, who underwent RARP for PCa at our institution between January 2016 and December 2019. Patients with a preoperative MRI-PBx had a 2.12-fold higher chance of successful nerve-sparing (without SNR) compared to patients with PBx (p < 0.01). Patients with preoperative MRI-PBx required 73% less intraoperative SNR compared to patients with PBx (p < 0.0001). Prior MRI-PBx is thus a predictor for successful nerve-sparing RARP approach., Conclusion: Preoperative MRI-PBx led to better oncological outcomes and less SNR. Young patients with good erectile function could benefit from a preoperative MRI-PBx before nerve-sparing RARP., (© 2021 The Authors. The Prostate published by Wiley Periodicals LLC.)

To reduce noise pollution and consequently stress during robot-assisted laparoscopic radical prostatectomy (RALP) the aim of our study was to evaluate the silent operation theatre optimisation system (SOTOS) in its effectiveness. In the operating room (OR) the noise level is between 80 and 85 decibel (dB). Noise corresponds to a major stress factor for surgical teams and especially surgeons. The use of the da Vinci surgical system entails an additional aspect of noise in the OR. The SOTOS surgical team used wired or wireless headphone/microphone combinations to communicate. We measured sound pressure levels in two different locations in the OR and the heart rate of every surgical team member as an indicator of the stress level. We further captured subjective acceptance of SOTOS as well as perioperative data such as surgical time. We prospectively randomised 32 RALP patients into two study arms. Sixteen surgeries were performed using SOTOS and 16 without (control). Overall, the mean sound pressure level in the SOTOS group was 3.6 dB lower compared to the control (p < 0.001). The highest sound pressure level measured was 96 dB in the control group. Mean heart rates were 81.3 beats/min for surgeons and 90.8 beats/min for circulating nurses. SOTOS had no statistically significant effect on mean heart rates of the operating team. Subjective acceptance of SOTO was high. Our prospective evaluation of SOTOS in RALP could show a significant noise reduction in the OR and a high acceptance by the surgical stuff., (© 2020. Springer-Verlag London Ltd., part of Springer Nature.)

Purpose: 68Ga-PSMA PET/CT imaging is a promising modality for the staging of recurrent prostate cancer (PCa). Current evidence suggests limited diagnostic value of the 68Ga-PSMA PET/CT in PSA-levels ≤0.3ng/mL. Experimental data have demonstrated na increase in PSMA-expression in PCa metastases by androgen deprivation in vitro. The aim of the current study was to investigate a possible enhancing effect of PSMA with low-dose androgen deprivation in patients with BCR and low PSA-levels., Materials and Methods: Five patients with PCa and BCR, following radical prostatectomy, underwent 68Ga-PSMA PET/CT. A consecutive 68Ga-PSMA PET/CT was performed 6 to 11 days after injection of 80mg of Degarelix (Firmagon®). We recorded PSA and testosterone serum-levels and changes of PSMA-uptake in 68Ga-PSMA PET/CT images., Results: Median PSA prior 68Ga-PSMA PET/CT was 0.27ng/mL. All patients had a decrease in testosterone serum levels from median 2.95μg/l to 0.16μg/l following Degarelix injection. We observed an increase in the standardized uptake value (SUV) in PSMA-positive lymphogenous and osseous lesions in two patients following androgen deprivation. In another two patients, no PSMA positive signals were detected in either the fi rst or the second scan., Conclusion: Our preliminary results of this feasibility assessment indicate a possible enhancing effect of PSMA-imaging induced by low-dose ADT. Despite several limitations and the small number of patients, this could be a new approach to improve staging by 68Ga-PSMA PET/CT in PCa patients with BCR after primary therapy. Further prospective studies with larger number of patients are needed to validate our findings., Competing Interests: None declared., (Copyright® by the International Brazilian Journal of Urology.)

Deregulation of the insulin-like growth factor (IGF) axis and dysbalance of components of the IGF system as potential therapeutic targets have been described in different tumor types. IGF2 is a major embryonic growth factor and an important activator of IGF signaling. It is regulated by imprinting in a development- and tissue-dependent manner and has been implicated in a broad range of malignancies including prostate cancer (PCa). Loss of imprinting (LOI) usually results in bi-allelic gene expression and increased levels of IGF2. However, the regulatory mechanisms and the pathophysiological impact of altered IGF2 expression in PCa remain elusive. Here, we show that in contrast to many other tumors, IGF2 mRNA and protein levels were decreased in 80% of PCa in comparison with non-neoplastic adjacent prostate and were independent of LOI status. Instead, IGF2 expression in both tumors and adjacent prostate depended on preferential usage of the IGF2 promoters P3 and P4. Decreased IGF2 expression in tumors was strongly related to hypermethylation of these two promoters. Methylation of the A region in promoter P4 correlated specifically with IGF2 expression in the 20% of PCa where IGF2 was higher in tumors than in adjacent prostate. We conclude that IGF2 is downregulated in most PCa and may be particularly relevant during early stages of tumor development or during chemotherapy and androgen deprivation. PCa differs from other tumors in that IGF2 expression is mainly regulated through methylation of promoter-specific and not by imprinting. Targeting of promoter-specific regions may have relevance for the adjuvant treatment of PCa., (© 2017 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.)

Background: Patient-reported health-related quality of life (HRQOL) differs between treatment options for prostate carcinoma. Long-term HRQOL data in brachytherapy series are scarce. Therefore, we analyzed prostate-specific and general HRQOL in patients treated with brachytherapy for prostate carcinoma after long-term follow-up., Methods: Two hundred ninety-six patients with prostate carcinoma were treated with brachytherapy (01/1998-11/2003). General and prostate-specific HRQOL were measured using EORTC-QLQ-C30 and EORTC-QLQ-PR25, respectively. Patients were asked to complete the questionnaires after a median follow-up of 141 (119-181) months. QLQ-C30 results were compared to the German reference population. QLQ-PR25 results were compared to an earlier follow-up after a median of 51 months (no published QLQ-PR25 reference population for comparison). Additionally, a literature review on HRQOL data in brachytherapy series was performed., Results: One hundred six (35.8%) patients were lost to follow-up, 70 (23.6%) had died. 120 (40.5%) patients were contacted. 80 questionnaires were returned (27% of the original cohort; 91% of alive patients were ≥70 years). Sexual activity declined over time (mean scores: 40.5 vs. 45.5; p = 0.006), hormonal treatment-related symptoms, problems associated with incontinence aids, and burden of obstructive urinary symptoms did not differ significantly compared to the 51-month follow-up. General HRQOL was numerically better in our cohort as compared to the German reference population (> 16% relative difference for both age strata; < 70 and ≥70 years)., Conclusions: Our results indicate that symptom-burden after long-term follow-up and associated prostate-specific HRQOL remains relatively stable from 51 to 141 months. General HRQOL in surviving patients was numerically better compared to the reference population.

Objectives: To evaluate in a prospective, controlled, nonrandomized study the surgical stress and acute-phase systemic response in robotic-assisted laparoscopic prostatectomy (RALP) compared to open radical retro-pubic prostatectomy (ORRP) by measuring humoral mediators., Methods: Forty consecutive patients undergoing either RALP or ORRP were prospectively included to assess the extent of systemic response. Blood samples were collected before surgery (T1), at the time of prostatectomy (T2), at the time of wound closure (T3), and 12 h (T4), 24 h (T5), and 48 h (T6) after surgery, and assayed for interleukins (IL-6 and IL-10), C-reactive protein (CRP), and hemoglobin. A 2-sided p < 0.05 was considered to indicate significance., Results: Baseline levels of IL-6, IL-10, and CRP were comparable in both arms of the study. IL-6 and IL-10 increased in both groups during surgery and reached maximum levels at 12 and 24 h after surgery. The RALP and RRP groups differed significantly at T2 (p = 0.009), T3 (p = 0.046), T5 (p = 0.05) and T6 (p = 0.0007) for IL-6, and at T3 (p = 0.05) and T4 (p = 0.05) for IL-10. CRP levels differed significantly at 48 h postoperative (p = 0.0053). The maximum levels of all 3 mediators in the RALP group were significantly lower than those in the open surgery group. Patients in the RALP group experienced less pain from day 2 to 4 according to the Visual Analog Scale (p < 0.05)., Conclusions: The study suggests that IL-6 and IL-10 are useful objective markers for surgical stress and that tissue trauma and activation of post-aggression metabolism seem to be less in RALP compared to ORRP., (© 2017 S. Karger AG, Basel.)

Background: Our study is the first evaluation of nodal metastatic prostate cancer (PCa) to mesorectal lymph nodes (MLN) detected by (68) Ga-PSMA-PET/CT., Methods: We retrospectively analyzed 76 consecutive PCa patients who underwent (68) Ga-PSMA-PET/CT: 61 PCa patients with biochemical recurrence (BCR) after curative treatment and 15 high-risk PCa before primary therapy. We assessed PET-positive MLN, which are indicative for PCa., Results: We detected PET-positive lesions for PCa in (68) Ga-PSMA-PET/CT in 66 of 76 (87%) patients. Nodal disease was imaged in 47 of 66 (71%) patients. Indicative mesorectal nodal lesions for PCa were detected in 12 of 76 (15.8%) patients. The median number of PET-positive MLN was one per patient. Seven of twelve patients had recurrent PCa after radical prostatectomy with a median PSA value of 1.84 ng/ml (range 0.31-13). Five of twelve patients had untreated first diagnosed high-risk PCa with median PSA value of 90 ng/ml (range 4.6-93) at PET/CT, respectively. For all PET positive MLN a morphological correlate was found in CT (shortest diameter median 4 mm [range 4-21]; longest diameter median 7.5 mm [range 5-25]). After PET/CT, four patients with recurrent PCa received hormonal therapy, one patient was treated with directed radiation therapy of MLN, one patient received chemotherapy, and one patient was treated with pelvic lymph node dissection. Three high-risk PCa patients received hormonal therapy, and two patients were treated with adjuvant hormonal therapy after radical prostatectomy., Conclusions: Detection and exact location of nodal metastasis for PCa is crucial for the choice of treatment and the patient's prognosis. (68) Ga-PSMA-PET/CT seems to improve the detection of nodal metastasis in PCa, especially concerning mesorectal lymph nodes., (© 2016 Wiley Periodicals, Inc.)

Purpose: Binding of (68)Ga-PSMA-HBED-CC ((68)Ga-PSMA) at prostate cancer (PC) cells increases over time. A biphasic protocol may help separating benign from tumor lesions. The aim of this study was the retrospective evaluation of a diagnostic incremental value of a dual-time point (biphasic) (68)Ga-PSMA-PET/CT in patients with prostate cancer., Methods: Retrospective analysis of 35 consecutive patients (49-78 years, median 71) with newly diagnosed PC (12/35) or recurrence of PC (23/35). PET/CT (Gemini TF16, Philips) was acquired 1 h and 3 h p. i. of 140-392 MBq (300 MBq median) (68)Ga-PSMA, followed by a diagnostic contrast CT. PET findings were correlated with histology or unequivocal CT findings. Semiquantitative PET data (SUVmax, SUV mean) were acquired and target-to-background-ratios (T/B-ratio) were calculated for benign and malign lesions for both time points. Size of lymph nodes (LN) on diagnostic CT was recorded. Statistical analysis was performed for assessment of significant changes of semiquantitative PET-parameters over time and for correlation of size and uptake of lymph nodes., Results: One hundred and four lesions were evaluated. Sixty lesions were referenced by histology or unequivocal CT findings, including eight (13.3 %) histopathologically benign lymph nodes, 12 (20 %) histopathologically lymph node metastases, 12 (20 %) primary tumors, three (5 %) local recurrences, and 25 (41.7 %) bone metastases. Forty-four lesions were axillary LN with normal CT-appearance. Benign lesions had significantly lower SUVmax and T/B-ratios compared with malignant findings. Malign lesions showed a significant increase of both parameters over time compared to benign findings. There was no correlation between LN size and SUVmax. The sensitivity, specificity, the positive predictive value and negative predictive value of PET/CT regarding pelvic LN was 94 %, 99 %, 89 %, and 99.5 %, respectively., Conclusions: In contrast to benign tissues, the uptake of proven tumor lesions increases on (68)Ga-PSMA-PET/CT over time. A biphasic PET-study may lead to a better detection of tumor lesions in unequivocal findings.

Objective: To evaluate urethral catheter (UC) versus suprapubic tube (SPT) without stenting the anastomosis at robot-assisted radical prostatectomy (RALP) regarding surgical outcome and catheter-associated discomfort. One year after surgery, continence and patient satisfaction were evaluated., Materials and Methods: Sixty-two patients undergoing RALP were prospectively randomized to urinary drainage with UC or with SPT. Functional results were assessed with standardized questionnaires (IPSS, IPSS Bother Score, IIEF and Visual Analogue Scale) preoperatively, after catheter removal and 1 year after surgery. Moreover, bother by the catheter as well as pain due to the catheter was assessed., Results: At personal hygiene, SPT was significantly less bothersome on the day of surgery as well as POD 1-6. Pain caused by the catheter did not differ significantly between the two groups except for POD 5 and 6, when the SPT performed significantly better. Differences regarding voiding parameters after catheter removal did not reach statistical significance. One year after surgery, no significant difference between the two groups was found regarding urinary function and IPSS. Though not statistically significant either, the need for the incision of bladder neck contracture (BNC) in two patients in the UC group is of note, as in the SPT group, no BNC occurred., Conclusion: Draining the bladder with SPT only is a feasible option in patients undergoing RALP. Patients with SPT are significantly less bothered by the catheter at personal and genital hygiene compared to UC. The risk of BNC seems to be reduced in the SPT group.

Background: The first evaluation of pelvic extended lymph node dissection (pLND) in oligometastatic prostate cancer (PCa) detected by (68)Ga-PSMA PET/CT., Methods: Retrospective analysis of 35 PCa patients underwent (68)Ga-PSMA PET/CT affected by biochemical recurrence (BCR) after curative treatment (n = 23) or before primary therapy of high-risk PCa (n = 12). We performed pLND associated with pathologic imaging in 17 men with nodal oligometastatic PCa., Results: Indicative lesions for PCa in PET/CT were detected in 91.4% (32 of 35) of patients. Nodal, bone, visceral (pulmonary), and within the prostate suspected disease were detected in 72% (23 of 32), 16% (5 of 32), 6% (2 of 32), and 47% (15 of 32) of patients, respectively. Median serum PSA in patients with pathological radiotracer uptake in recurrent and high-risk PCa patients was 2.9 ng/ml (range 0.18-30) and 19.5 ng/ml (range 6-90), respectively. The median number of removed lymph nodes with pLND in recurrent and high-risk PCa was 10 (range 4-17) and 12 (range 8-29) per patient and the median number of positive lymph nodes was 1 (range 1-2) and 3 (2-3) per patient, respectively. In total, two false positive and one false-negative lymph node were found. Diagnostic accuracies per nodal lesion in total of 213 removed nodes: sensitivity, 94%; specificity, 99%; positive predictive value (PPV), 89%, and negative predictive value (NPV), 99.5%. After pLND, 53% (9 of 17) of patients received androgen deprivation therapy and/or radiation therapy and hormonal therapy, while 47% (8 of 17) of patients remained free of any post-surgery therapy. Follow-up PSA remained less than 0.2 ng/ml in 82% (14 of 17) of patients. After pLND, immediate BCR (PSA never measured less than 0.2 ng/ml) in 18% (3 of 17) of patients was recorded., Conclusions: This represents the first study of pLND in the setting of nodal oligometastatic PCa detected by (68)Ga-PSMA PET/CT. The use of (68)Ga-PSMA PET/CT could be to improve the accuracy for the detection of nodal micrometastases. These promising findings need validation in larger studies., (© 2015 Wiley Periodicals, Inc.)

Background: The primary therapeutic target for non-organ-confined prostate cancer is the androgen receptor (AR). Main strategies to ablate AR function are androgen depletion and direct receptor blockade by AR antagonists. However, incurable castration resistant prostate cancer (CRPC) develops resistance mechanisms to cope with trace amounts of androgen including AR overexpression and mutation in the AR ligand binding domain., Methods: The CRPC cell model VCaP derivative of a prostate cancer bone metastasis was used in vitro and in nude mice in vivo to examine the effects of immediate testosterone boost on CRPC cells. In addition, a testosterone tolerant cell model was established by incremental acclimatization of VCaP cells to 1 nM testosterone. The effects of androgen withdrawal and testosterone boosts on gene expression were assessed by quantitative real-time polymerase chain reaction, ELISA, and Western blots. Tumor cell proliferation was evaluated with a BrdU test., Results: Testosterone boosts on CRPC VCaP cells eliminate tumor cells to a higher extent than androgen withdrawal in androgen tolerant cells. The pronounced decrease of tumor cell proliferation was accompanied by a marked downregulation of AR expression regarding full-length AR and splice variant AR V7., Conclusions: Acquiring castration resistance of prostate cancer cells by AR overexpression and amplification obviously sensitizes such cells to testosterone concentrations as low as physiological values. This introduces novel therapeutic means to treat CRPC with non-toxic measures and may find clinical implementation in intermittent androgen deprivation regimens., (© 2013 Wiley Periodicals, Inc.)

Background: Cabazitaxel (Cbz) is an approved second-line treatment in metastatic castration-resistant prostate cancer (mCRPC) following docetaxel therapy with a significant survival benefit compared with mitoxantrone. However, grade 3/4 toxicities were reported in 82% of patients., Objective: To report on the safety results of mCRPC patients treated within a compassionate-use programme in Germany., Design, Setting, and Participants: A total of 111 patients with a mean age of 67.9 yr (range: 49-81 yr) and progressive mCRPC were included. Patients had received a mean number of 12.7 ± 10.8 cycles (range: 6-69 cycles) of docetaxel with a mean cumulative dose of 970.9 mg/m(2); mean time from last docetaxel application to progression was 6.95 mo (range: 2-54 mo). Of the patients, 31.5% progressed by prostate-specific antigen (PSA) increase only; the remainder had a combination of PSA increase and clinical progression., Intervention: Cbz at a dosage of 25mg/m(2) intravenously every 3 wk combined with 5mg of oral prednisone twice a day., Outcome Measurements and Statistical Analysis: Treatment-associated toxicity was the primary study end point; progression-free and overall survival were secondary end points. A descriptive statistical analysis was performed., Results and Limitations: Patients received a mean number of 6.5 ± 2.2 cycles of Cbz and a mean cumulative dose of 160.3 ± 51.5mg/m(2). Grade 3 and 4 treatment-emergent adverse events were recorded in 34 patients (30.6%) and 18 patients (16.2%), respectively. Grade 3/4 anaemia, neutropenia, and thrombocytopenia were reported in 4.5%, 7.2%, and 0.9% of the patients, respectively. Neutropenic fever was reported in 1.8% of the patients. Grade 3/4 gastrointestinal toxicity was identified in 4.5% of the patients. Three patients died because of Cbz-related toxicity. Granulocyte colony-stimulating growth factors were used in 17.1% of patients. The limitations are due to the nonrandomised nature of the trial., Conclusions: Treatment with Cbz is tolerable and is associated with a low incidence of serious adverse events in a real-world patient population with CRPC. The outcome of serious adverse events can be minimised with proactive treatment management and conscientious monitoring., (Copyright © 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Docetaxel had been the only treatment of castration-resistant prostate cancer (CRPC) that demonstrated a survival benefit for the patients. After its approval, no considerable progress has been made for several years until cabazitaxel and abiraterone acetate demonstrated a significant survival benefit in phase III clinical trials. Apart from that several other new drugs appeared including inhibitors of the androgen receptor (MDV3100), endothelin receptor antagonists (atrasentan, zibotentan), bone-targeted drugs (denosumab, Alpharadin) and immunotherapies (sipuleucel-T) capable of improving the prognosis of patients with CRPC. Here, we review the most recent advances in the treatment of CRPC and highlight the most promising new agents currently being investigated in clinical trials.

Background: Neuroendocrine differentiated tumor cells (NETC) can be found in a large portion of prostate carcinoma (PCa) specimens. This is the first study to systematically quantify and analyze the influence of the NETC distribution and of their secretory products, serotonin, bombesin, and gastrin, on angiogenesis and in the clinical follow-up of PCa patients., Methods: 175 PCa specimens were included in this study. NETC were displayed using the marker CgA. Specimens showing a high expression of CgA were analyzed for serotonin, bombesin, and gastrin. Blood vessels were stained with the epitope CD34. Data was analyzed for inter-correlation and its correlation to clinical-pathological parameters and the results of a mid-term follow-up., Results: The number of NETC was correlated with the pT-status and the Gleason score. Specimens with high NETC expression had an increased microvessel density (MVD). No correlation between the neurosecretory products and the clinical-pathological parameters was found. High NETC expression, high bombesin expression and increased MVD were associated with early treatment failure in the follow-up., Conclusion: NETC have an influence on angiogenesis and are correlated with the clinical-pathological parameters. A high expression of NETC is associated with an early failure of treatment. Our study underlines the importance of NETC in prostate cancer., (Copyright © 2011 Wiley Periodicals, Inc.)

Background: Neuroendocrine (NE) cells of the prostate are known to be androgen-independent and NE peptides like gastrin-releasing peptide (GRP) or neuron-specific enolase (NSE) can stimulate growth in a paracrine manner, and this is thought to be one of the escape mechanisms in castration-resistant prostate cancer (CRPCa). In a longitudinal study, we investigated the development of the NE serum factors GRP, NSE, and chromogranin A and their correlation with prostate-specific androgen (PSA) during hormonal treatment., Materials and Methods: Thirty two patients, with histology-proven, localized or metastatic prostatic carcinoma (PCa), who were undergoing therapy with LHRH analogue or a combination of LHRH analog and peripheral androgen blockade, took part in the study. In addition, eight healthy volunteers were each tested twice for serum GRP to elicit a "physiological" standard value. Blood samples were taken periodically from each patient within an 18-month time frame., Results: We defined the standard value for GRP in the healthy participants as 0.852 ng/ml (mean  +  2 SD) and observed that the GRP values for patients with PCa were significantly higher (P = 0.034). There was a positive correlation between PSA and GRP in patients with biochemical failure. CgA correlated with PSA development in the CRPCa patients. NSE values rose steadily over the study period, but with no correlation to PSA., Conclusion: Our data confirm that NE factors are elevated during hormonal treatment of prostate cancer. GRP is higher in PCa patients undergoing androgen deprivation therapy and is possibly involved in the initiation of hormonal escape in PCa., (Copyright © 2010 Wiley-Liss, Inc.)

Purpose: Enhanced surgical techniques and standardised selection criteria have led to a higher rate of nerve-sparing (NS) radical prostatectomy (RP) procedures. The aim of this study was to evaluate the clinical value of intraoperative frozen sections (IFS) during nerve-sparing radical prostatectomy (NSRP)., Materials and Methods: Thousand and eighty-three patients with localised prostatic carcinoma were treated using retropubic RP (from 2004 to 2006). Two hundred and eighty-seven of the 1083 documented cases received NS. One hundred and thirty procedures were carried out with IFS from the area of the neurovascular bundles and 157 without IFS. The decision to use IFS was made intraoperatively and based on clinical suspicion of possible positive resection margins in the area of the bundles., Results: In the NS group with IFS, the results revealed positive margins in nine (6.9%) out of 130 cases, resulting in subsequent resection of the ipsilateral neurovascular bundle. The final histological report on this group revealed four additional patients (3.1%) with positive margins, but only one (0.7%) in the area of the previous neurovascular bundle. The final histopathologic reports on the 157 NS cases without IFS showed that the positive margin was in the area of the previous neurovascular bundle in only one (0.6%) of the nine cases with positive margins (5.7%)., Conclusion: According to our data, there is no need for routine IFS during NSRP. The negative predictive value for infiltration of the NVB is high, and IFS can be dispensed with. Intraoperative biopsies should be taken in those cases where the surgeon is in doubt about the resection margins in the area of bundles.

The plakophilins, members of the armadillo-repeat family, consist of three different proteins (PKP1-3) that are specifically recruited to desmosomal plaques in a highly cell type-specific manner. Using immunofluorescence, immunoelectron microscopy, and immunoblot, we found that all three plakophilins occurred in luminal and basal cells of the pseudostratified prostate epithelium. The analysis of 135 cases of prostatic adenocarcinomas grouped into tumors with low (Gleason score < or = 6), intermediate (Gleason score 7), and high Gleason score (8 < or = Gleason score < or = 10) showed that the expression of PKP1 was reduced or lost in adenocarcinomas with high Gleason scores. The expression of PKP2 was unchanged in all prostatic adenocarcinomas analyzed. In contrast, PKP3 expression was increased in carcinomas with high Gleason scores in comparison with carcinomas with low Gleason scores. In DU 145 cell lines with either overexpression or knockdown of PKP3, both imbalances resulted in fewer desmosomal cell contacts. In addition, overexpression of PKP3 in DU 145 cells led to an augmentation in proliferation rate. Our data imply that both loss of PKP1 and up-regulation of PKP3 expression are biologically important events in prostate cancer and are associated with a more aggressive phenotype.

Neovascular targeting is an established approach for the therapy of prostate cancer (PCa). Cationic liposomes have been shown to be absorbed by immature vascular endothelial cells due to negative electric charge of their outer cell membrane. We aimed to evaluate the antitumoural efficacy of paclitaxel encapsulated in cationic liposomes for the treatment of PCa. Tumours were generated by subcutaneous injection of 10(6) MatLu tumour cells into the right hind leg of 21 male Copenhagen rats. After tumour growth, the animals were treated by an i.v. infusion with either 5% glucose (Gl), paclitaxel (Pax), cationic liposomes (CL) or paclitaxel encapsulated in cationic liposomes (EndoTAG-1) on days 12, 14, 16 and 19. Treatment was initiated on day 12 after tumour inoculation at mean tumour volumes of 0.31+/-0.13 mm(3). On the last day of treatment, animals treated with EndoTAG-1 had the significantly lowest tumour volumes with 2.49+/-0.84 cm(3) vs. Pax (5.59+/-0.45 cm(3)) vs. CL (3.87+/-1.25 cm(3)) vs. GL (5.17+/-1.70 cm(3)). The quantification of MVD showed the lowest count for EndoTAG-1-treated tumours (11.78+/-2.68 vessels/mm(2)) followed by Gl (15.64+/-6.68 vessels/mm(3)), Pax (18.22+/-9.50 vessels/mm(3)) and CL (40.9+/-32.8 vessels/mm(3)). The data confirm that neovascular targeting with EndoTAG-1 is a promising new method for the treatment of PCa by reducing the primary tumour mass and demonstrating benefits in the suppression of angiogenesis in comparison with the conventional treatment.

Objective: To describe the localization and to assess the clinical implications of areas of undetected prostate cancer in radical prostatectomy (RP) specimens, focusing on patients with unilaterally negative preoperative biopsy cores., Patients and Methods: The study included 149 of 559 consecutive patients (26.7%) who had RP for prostate cancer. Unilateral prostate cancer was diagnosed from prostate biopsies, taken by several physicians, but > or = pT2c disease was present in the RP specimen. The prostate was dissected by standardized transversal cuts and tumour areas were mapped by one genitourinary pathologist. To estimate the tumour size and location, areas of prostate cancer were transferred to a digital grid database representing the prostate by 794 units., Results: The most frequent location of undetected prostate cancer was in the dorsalateral region and in the apex of the prostate. The mean tumour volume of the false-negative lobe was significantly lower than contralaterally (18.9 vs 47.5 units, P < 0.001). In 36 of 149 patients (24.2%), the tumour volume on the negative biopsy side was equal or higher than on the positive biopsy side; in the final RP specimen, 60 patients (40.3%) had capsular involvement on the negative biopsy side., Conclusion: Significantly many patients with newly diagnosed prostate cancer remain clinically understaged. The apical and dorsolateral region of the prostate are not adequately represented in current biopsy strategies. Undetected tumour areas are often clinically significant by size and capsular involvement, indicating a direct clinical implication when planning nerve-sparing RP or focal therapy. Our results show a continuing need for optimized and standardized biopsy protocols.

Background: We evaluated the long-term health-related quality of life (HRQoL) after modern prostate brachytherapy (PB)., Patients and Methods: The European Organization for Research and Treatment of Cancer (EORTC) prostate cancer quality-of-life questionnaire, QLQ-PR25, and the modified International Continence Society (ICS) male questionnaire were sent to 296 men treated with PB at the University Medical Center Mannheim. To evaluate the influence of age, we subclassified two groups: group 1 <65 years, group 2 > or =65 years. 258 of the 296 patients were alive at the time of assessment. Of 238 questionnaires (92% response rate), 231 were suitable for analysis. Median follow-up was 51 months., Results: Of group 1 77.8% and of group 2 73.4% of the men were in good, very good or excellent health. There was a low rate of moderate (10.4%) or strong (1.0%) symptoms regarding urinary functioning. Stress incontinence was uncommon. Only 28.2% reported moderate or strong (up to 17.6%) symptoms regarding sexual functioning. In group 1 48.6% and in group 2 25.0% of patients reported no or minor erectile dysfunction (p < 0.007). There was no severe overall rectal dysfunction (<2%)., Conclusion: Our data substantiate the favorable long-term HRQoL outcomes associated with modern PB techniques. Significant age differences were observed in sexual symptoms and less pronounced age differences in urinary symptoms. We found a low rate of urinary symptoms and no evidence of severe rectal dysfunction.

Objective: To compare serum vascular endothelial growth factor C (VEGF-C) levels in patients with benign prostatic hyperplasia (BPH) and prostate cancer (PCa) and analyze VEGF-C levels in relation to clinicopathologic parameters., Study Design: Fifty-eight patients with PCa and 61 patients with BPH were included in this study. Serum VEGF-C levels were assessed by enzyme-linked immunosorbent assay., Results: The serum VEGF-C level for patients with PCa was 3,432.06 +/- 1,851.07 as opposed to 3,166.68 +/- 1,921.2 for patients with BPH. There was no statistically significant difference between the 2 groups (p = 0.4448). There was no correlation of VEGF-C to tumor stage, grading or the preoperative prostate-specific antigen values., Conclusion: We cannot recommend VEGF-C serum level as a marker for tumor growth in PCa.

Background: Brachytherapy (BT) is an established treatment option for low risk prostate cancer. The aim of this study was to determine the long-term complications and side effects of the procedure in an up to 13 year long single center follow-up analysis., Material: A total of 505 patients were treated by BT for prostate cancer between May 1991 and August 2005. Cohort I (n=412; May 1991 to November 2003) was evaluated by written questionnaire (modified ICS male) and patient chart evaluation in terms of side effects and secondary interventions. In cohort II (n=148; January 2002 to August 2005) perioperative complications were investigated., Results: The mean follow-up was 5.5 years. Perioperative complications were present in 5.4% of patients. Transurethral resection of the prostate was a common secondary intervention, performed in 7% of cases. The rate of incontinence was 6.3% in the long-term follow-up, the rate of potency was 43.5% in those patients who were potent before BT and no hormonal manipulation was performed at any time., Conclusion: BT is a minimally invasive procedure for the treatment of localised "low risk" prostate cancer. Perioperative complications are rare, secondary intervention may be necessary and the patient has to be informed of possible impotence, incontinence and lack of ejaculation.

Objective: To compare prostate carcinoma, with and with no lymph node metastasis, to benign prostatic hyperplasia (BPH) tissue for lymphatic vessel density (LVD) and the expression of the lymph-endothelial specific growth factor, vascular endothelial growth factor C (VEGF-C), to determine their role in lymphogenic metastasis., Patients, Materials and Methods: Lymphatic vessels were stained using lymphatic vessel endothelial hyaluronan receptor 1 and assessed in standard areas. The expression of VEGF-C was assessed by the number of positive epithelial cells. The data were compared with the clinical staging., Results: The lowest LVD was found in tumorous areas as opposed to periphery and nontumorous tissue (P = 0.007; P < 0.001). The highest LVD was in BPH tissue (P < 0.001). There was no correlation with clinical staging. There was more VEGF-C staining in pN1 than in pN0 and in BPH specimens (P = 0.002)., Conclusion: LVD is not a prognostic variable for the process of lymphogenic metastasis in prostate cancer. VEGF-C is up-regulated in prostate cancer and its correlation with lymph node status suggests a role for the development of lymph node metastasis, e.g. via an increased permeability of lymphatic vessels.

Purpose: IGF-I serum levels have been demonstrated as being associated with prostate cancer (PCa) and can serve as a predictive factor for the risk of PCa development. However, the role of IGF-II in PCa and its importance as a predictive marker is still unclear. Our aim was to determine PSA and IGF-II serum levels in patients with PCa and benign prostatic hyperplasia (BPH) and to analyse the value of IGF-II as an additional predictive factor in the diagnostics of PCa., Methods: 112 patients who underwent surgery for BPH or PCa (no hormonal treatment, no further malignancies) were included in this study ((I) 38 PCa, PSA < or = 15 ng/ml; (II) 34 PCa, PSA > 15 ng/ml; (III) 40 BPH). Preoperative serum levels of total PSA and total IGF-II were determined by ELFA and ELISA, respectively., Results: PSA levels were (I) 5.7+/-1.9 ng/ml; (II) 25.0+/-11.5 ng/ml and (III) 4.0+/-2.8 ng/ml. (II) was statistically associated with a high grading (2b/3; p = 0.0182), a high Gleason sum score (7-10; p = 0.0049) and a non-organ confined tumor (T3/4; p = 0.0009) compared to (I), all Chi2 test. IGF-II levels were significantly higher in PCa (I+II) compared to BPH (833.8+/-238.9 ng/ml vs. 633.3+/-141.4 ng/ml, p < 0.0001, t-test). Both PSA and IGF-II were associated with tumor staging (p = 0.0097, p = 0.0308; t-test). No significant correlation was observed between PSA and IGF-II levels. Logistic regression analysis revealed that the combination of PSA and IGF-II improves the prediction of tumor staging in PCa (p = 0.0175 and p = 0.0459, Wald test). Additionally, the combination of PSA and IGF-II can significantly increase discrimination between BPH and PCa; each p < 0.0001, Wald test., Conclusions: This study provides evidence that IGF-II serum levels may serve as an additional parameter for (a) improved determination of tumor staging and (b) better discrimination between BPH and PCa.

There is an evidence that components of the insulin-like growth factor (IGF)-signaling pathway are involved in the development and progression of prostate cancer. The aim of the present study was to provide a comprehensive analysis of the expression levels of proteins of the IGF axis in prostate cancer. We studied expression of the ligands IGF-I and IGF-II, the inhibitory IGF binding protein-3, the type I IGF receptor (IGF-IR), and the downstream mediator insulin receptor substrate-1 by immunohistochemistry in 56 tissue specimens (28 low-grade and 28 high-grade prostate adenocarcinomas). Protein expression in tumor areas, prostatic intraepithelial neoplasias (PINs), and adjacent benign prostatic tissue were evaluated regarding staining intensity and fraction of positive cells. An immunoreactivity score was established from staining intensity and fraction of positive cells, and correlated with the prognostic clinicopathologic parameters prostate-specific antigen serum levels, Gleason score, and TNM stage. The expression levels of all proteins investigated, except IGF binding protein-3, were up-regulated in PIN and in cancer. IGF-I and IGF-II expression showed a higher expression in high-grade compared with low-grade tumor areas. IGF-I and IGF-II and insulin receptor substrate-1 immunoreactivity was higher in tumors from patients with preoperative prostate-specific antigen serum levels 10 ng/mL or greater, and IGF-II expression was correlated with Gleason score. The data indicate significant alterations in the IGF system as prostate cancer develops. Differential expression of growth-stimulating components of the IGF system may be associated with the malignant phenotype and more aggressive tumor behavior. Expression of IGFs, especially IGF-II, may be predictors of the outcome of prostate cancer.

Background: NE tumor cells are present in virtually all prostatic adenocarcinomas. As they express no androgen receptor they are hormone independent. During anti-androgenic therapy their number increases. Their prognostic value is controversial., Material and Methods: In 233 patients with prostatic carcinoma the NE differentiation was determined in a hot spot (7.9 mm(2)) with maximum CgA positive cell density. A high NE differentiation (HNE) was defined by a least 30 NE tumor cells, while less means a low NE differentiation (LNE). In addition the occurrence of NE tumor cells was defined as solitary or clustered (> or =5 NE tumor cells in close proximity)., Results: In advanced and high grade tumors more and clustered NE tumor cells could be found than in low grade and organ confined tumors. Moreover HNE tumors and occurrence of NE clusters resulted in a significant shorter progression-free interval., Conclusions: Besides the quantity of NE differentiation the quality of the growth pattern of NE tumor cells is of relevance in prostatic carcinoma.

Purpose: S100 proteins comprise a family of calcium-modulated proteins that have recently been associated with epithelial tumors. We examined the expression of two members of this family, S100A8 and S100A9, together with the S100 receptor RAGE (receptor for advanced glycation end products) in human prostate adenocarcinomas and in prostatic intraepithelial neoplasia., Experimental Design: Tissue specimens of 75 patients with organ-confined prostate cancer of different grades were analyzed by immunohistochemistry for expression of S100A8, S100A9, and RAGE. In addition, in situ hybridization of S100A8 and S100A9 was done for 20 cases. An ELISA was applied to determine serum concentrations of S100A9 in cancer patients compared with healthy controls or to patients with benign prostatic hyperplasia (BPH)., Results: S100A8, S100A9, and RAGE were up-regulated in prostatic intraepithelial neoplasia and preferentially in high-grade adenocarcinomas, whereas benign tissue was negative or showed weak expression of the proteins. There was a high degree of overlap of S100A8 and S100A9 expression patterns and of S100A8 or S100A9 and RAGE, respectively. Frequently, a gradient within the tumor tissue with an increased expression toward the invaded stroma of the prostate was observed. S100A9 serum levels were significantly elevated in cancer patients compared with BPH patients or healthy individuals., Conclusion: Our data suggest that enhanced expression of S100A8, S100A9, and RAGE is an early event in prostate tumorigenesis and may contribute to development and progression or extension of prostate carcinomas. Furthermore, S100A9 in serum may serve as useful marker to discriminate between prostate cancer and BPH.

Neuroendocrine (NE) tumor cells in prostatic carcinoma (PCa) may influence tumor proliferation by a paracrine stimulus. The role of NE tumor cells is discussed controversially. This study investigates the influence of NE tumor differentiation on proliferation in PCa. Neuroendocrine differentiation, Ki-67, and Polo-like kinase 1 were studied immunohistochemically in 73 consecutive prostatectomies. Polo-like kinase 1 (PLK1) expression was also studied by Western and Northern blot analysis. Tumors were classified as high NE (HNE) and low NE differentiated (LNE), and depending on the growth pattern, with solitary and clusters of NE tumor cells. Low NE differentiated tumors were defined as less than 30 and HNE as 30 or more NE tumor cells per hot spot. Patients were followed by serum prostate-specific antigen (PSA) analysis. Neuroendocrine differentiation was present at least focally in 70% of tumors; 57% were HNE and 43% LNE. Solitary NE tumor cells were more often found in low-grade PCa, whereas clusters of NE tumor cells were more frequent in high-grade PCa. PLK1 messenger RNA and protein as well as Ki-67 were overexpressed in tumor tissue compared with tumor-free tissue. A stronger proliferation as determined by Ki-67 and PLK1 expression was present in HNE tumors compared with LNE tumors and in tumors with clusters in contrast to tumors with solitary NE tumor cells. Analysis for PSA relapse-free survival showed an earlier progression in HNE than in LNE tumors and in PCa with clusters of NE tumor cells. A significant and clustered NE differentiation in PCa may lead to an increased proliferation and earlier tumor progression, whereas few and solitary NE tumor cells have no prognostic impact.

The management of prostate cancer is one of the core tasks for urologists today. This review focuses on therapeutic options for the curative and palliative treatment of prostate cancer. Within the area of urological competence, radical prostatectomy remains the standard procedure for the curative treatment of localised prostate cancer. Recently, interest in minimally-invasive procedures such as brachytherapy, focused ultrasound and cryotherapy has increased considerably. Established palliative treatment strategies include hormonal treatment schemes as the gold standard. Chemotherapeutic regimes are used for the hormone refractory disease. In addition to both the standard and new urological therapeutic options, promising experimental systemic strategies for the generalised disease are presented in this review.

Objectives: Prostate cancer (PCa) is a heterogeneous tumour entity with known interindividual differences in biological behaviour regarding tumour aggressiveness and metastatic potentiaL To date, the prediction of the metastatic status of patients with PCa has not been possible. To identify the molecular causes behind these differences, the gene expression profiles of two cell lines (LNCaP and LNCaP C4-2) with different metastatic potentials were examined using DNA microarray technology., Materials and Methods: LNCaP and LNCaP C4-2 cells were cultured under standard conditions. RNA was isolated using Trizol extraction. After processing the total RNA according to the manufacturer's instructions, we performed Affymetrix GeneChip analysis with HG-U133A chips. Data analysis was performed using NetAffx, dChip, GenMAPP and OMIM software., Results: After statistical evaluation of the raw data, we obtained a set of 158 differently expressed probe sets in the LNCaP and LNCaP C4-2 cells. The search for genes associated with proliferation, cell metabolism, growth factors, metastatic potential and tumour progression in this list revealed a number of 42 differently expressed probe sets. The comparison of this list of probe sets with the literature resulted in a list of 14 differently expressed genes which could well contribute to the metastatic potential and progression of PCa. Of these 14 genes only 6 (Cip1, IGF-1, NK4, CXCL 12, ILGF2R, RHOE) have already been associated with PCa, whereas the other 8 genes (FSTL-1, SOCS-2, Midkine, Thrombospondin 1, Secretory leukocyte protease inhibitor, Desmoglein 2, MLT 1, PTPRF) had not been previously related to PCa., Conclusion: DNA microarray technology offers the possibility of screening a large number of genes with regard to alterations in the expression level or mutations. In this study, we identified 14 genes that are most probably associated with the higher metastatic potential of LNCaP C4-2 cells as compared to LNCaP cells. Eight of these 14 genes are potential new molecular markers for assessing the metastatic potential of PCa, or may serve as therapeutical targets.

Evaluation of the accuracy of descriptive and physiological parameters calculated from signal intensity-time curves using T1-weighted dynamic contrast enhanced MRI (DCE MRI) to differentiate prostate cancers from the peripheral gland. Twenty-seven patients with prostate cancers were examined with DCE MRI prior radical prostatectomy. Regions of interest were defined in tumors and non-affected areas in the peripheral zone. Dynamic data were parameterized in amplitude and exchange rate constant (kep) using a two-compartment model. Additionally, relative slope during 26, 39, 52 and 65 s, areas under the curve (AUC) and time to start of signal intensity increase (tlag) were determined. Vessel density (VD) of excised prostates was quantified in tumor areas using a CD34 stain. The parameter slope52 showed 20% higher values (P<0.001) in tumors than in the peripheral gland and compared with the other parameters the largest area under the ROC curve (0.81). The minimum total error rate was attained at a cut-point of 0.021, yielding a sample value of sensitivity and specificity of 70% and 88%, respectively, and a bias-corrected sum of sensitivity and specificity of 1.54. In addition, amplitude (P<0.001), kep (P=0.03) and AUC (P<0.001) were significantly higher in tumors. tlag did not discriminate carcinomas from glandular tissue. VD was higher in tumors than in the non-affected peripheral prostate (P=0.05). However, none of the dynamic parameters in carcinomas showed a significant correlation with VD or Gleason score. Although pharmacokinetic modeling in DCE MRI showed potential to discriminate prostate cancers from peripheral prostate tissue, descriptive parameters of the early signal enhancement after contrast media injection reached higher sensitivity and specificity., (Copyright 2004 Springer-Verlag)

The use of doxorubicin as a chemotherapeutic agent is hindered by its toxic side effects on the normal cells of the body. The objective of this study was to determine if micelle-delivered doxorubicin could increase the effectiveness of doxorubicin against prostate carcinoma cells. Rat prostate carcinoma cells (MatLu) were cultured under standard conditions. Phosphate-buffered saline (PBS), doxorubicin and/or micelle solution (Pluronic 10500 solution) was added to the cell suspensions and incubated for 3 h. After incubation, cells were washed twice. Analysis consisted of: 1) immediate cell count and 2) proliferation assay at 24 and 144 h. After 24 h, samples with micelle-incorporated doxorubicin had 75% (10% pluronic with 10 microg/ml doxorubicin) and 80% (1% pluronic with 10 microg/ml doxorubicin) cell proliferation results compared with the control group. After 144-h incubation, these same two groups demonstrated cell proliferation results of only 30 and 43% of the control group. The in vitro cytotoxicity of doxorubicin against prostate carcinoma cells was dramatically increased by incorporating the molecule with polymeric micelles., (Copyright 2004 Springer-Verlag)

Purpose: Due to the lack of specific markers the analysis of lymphatic vessel density (LVD) has been almost impossible in the past. We report the novel specific marker for lymphatic endothelium, lymphatic vessel endothelial hyaluronan receptor (LYVE-1), in prostatic, benign prostatic hyperplasia (BPH) and prostate cancer (PCa) tissue. Normal blood vessels were additionally quantified in BPH and PCa., Materials and Methods: LYVE-1 lymphatics (LVD) and CD34 blood vessels were assessed in 20 paraffin sections of BPH and 50 of PCa tissue by immunohistochemistry in a standardized experimental setting. The regions of PCa, periphery of the tumor and nontumorous regions of the PCa specimens, and BPH tissue were evaluated. Double staining was done (LYVE-1/CD34). Acquired data were interrelated and compared to the pathological parameters of the specimens., Results: Double staining revealed numerous CD34 blood vessels but only a few LYVE-1 lymphatic vessels in BPH and PCa sections. Mean LVD +/- SD was distinctly lower (0.55 +/- 0.93) in PCa tissue than in tumor periphery (2.45 +/- 1.93) and nontumorous (3.16 +/- 2.23) tissue (p <0.0001). Maximum LVD was observed in BPH (7.17 +/- 3.61), which differed markedly from nontumorous areas of PCa specimens (p <0.001). In contrast to LVD, significantly more blood vessels were found in PCa (116.00 +/- 39.25) than in BPH (60.30 +/- 19.34) tissue (p <0.001)., Conclusions: LYVE-1 is a specific lymphatic endothelial marker in benign and malignant prostate tissues. It is a useful new marker for the investigation of lymphatics. To our knowledge we report the immunohistochemical visualization and quantification of lymphatic vessels in prostatic tissue for the first time. In contrast to the stimulated angiogenesis of blood vessels in PCa, the destruction of lymphatic vessels occurs rather than lymphangiogenesis.

Background: Clinical use of gene therapy is limited by the poor efficacy and accuracy of intracellular DNA delivery. Known concepts of DNA transfection have not yet become clinical routine in the treatment of human disorders. We therefore focused on new transfection methods using different forms of acoustic energy as potentially safe and topographically applicable methods for gene delivery in the field of urology., Materials and Methods: Three different cell lines (prostatic and urothelial cancer, benign kidney) were transfected by different forms of acoustic energy. The effect of several parameters of electromagnetic shock wave treatment (number and frequency of impulses, energy flow density and plasmid concentration) as well as focused ultrasound on the transfection rate was assessed in a standardized experimental setup. The transfection rate was measured through reporter genes (pEGFP) by FACScan. Transfection by lipofectamine and electroporation served as positive controls., Results: All cell lines were transfectable by acoustic energy. Maximum transfection rate was achieved using focused ultrasound (49.5o%; 200 W, 500 ms, 200 microg/ml DNA). 31.3% of kidney cells were transfected by electromagnetic shock waves (1500 impulses, 200 microg/ml DNA, 0.5 mJ/mm2 energy density, 2 Hz). Plasmid strand breaks were identified as a limiting factor of the transfection rate., Conclusion: Transfection by acoustic energy, especially focused ultrasound, can be achieved at a high level in different cell lines. The possible topical application to urological organs and the low level of side-effects make acoustic energy a promising new gene therapy treatment option in urology.

Background: The microvessel density (MVD) is often used as a quantitative parameter for angiogenesis. The aim of this study was to evaluate the three most commonly used endothelial markers of microvessels, CD31, CD34 and vWF, in benign and malignant prostatic tissue., Materials and Methods: Fifteen benign hyperplastic prostate and 54 prostate cancer specimens were immunohistochemically stained for CD31/CD34/vWF. The MVD obtained by each marker was quantified by a vessel count in standardized grids within the area of maximum angiogenesis. The data on MVD was interrelated and compared to tumor staging, grading and clinical follow-up., Results: A significant correlation of the CD31/CD34/vWF-MVD data was observed in BPH tissue, but not in PCa. In PCa, the most sensitive marker for newly derived blood vessels was CD34. While CD34-MVD demonstrated a significant association with tumorgrading and PSA follow-up, CD31- or vWF-MVD did not., Conclusion: CD34 is a suitable marker for the immunohistochemical visualization of microvessels in benign and malignant prostate tissue.

The aim of the study was to quantify the expression of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF) in prostate cancer and adjacent non-tumorous tissue in a standardized experimental set-up and to evaluate the paracrine effects of three endothelial stimuli on neovascularisation. Immunohistochemical staining of prostate cancer (PCa) specimens for VEGF, bFGF, EGF and the endothelial marker CD31 was performed (n=56). Sections were analyzed for growth factor-positive cancer/epithelial cells as well as staining intensity in (I) malignant and (II) non-tumorous tissue. Within PCa the topographic relationship (TR) of maximum microvessel density (MWD) and maximum expression of each growth factor was assessed. The number of VEGF- and EGF-positive cells in PCa was significantly enhanced compared with non-tumorous tissue (p<0.0001), whereas there was no difference in staining intensity. In contrast, the staining intensity of bFGF sections revealed a stronger expression in non-tumorous tissue compared with PCa (p<0.0001). In benign glands, VEGF, EGF and bFGF expression is chiefly restricted to basal cells. VEGF and EGF displayed a close TR in 65 and 57% of cases, respectively, whereas bFGF revealed a close TR in only 43% of PCa specimens. The results outline the relationship of the investigated growth factors and angiogenesis in PCa, which is strongest for VEGF and EGF. The relevance of VEGF and EGF is underlined by the increased number of positive cancer cells. Although previously reported to be a pro-angiogenic growth hormone, bFGF appears to play an assimilably minor role in the angiogenesis of PCa.

AKT/PKB is a central signaling molecule related to stimulation of cell proliferation and inhibition of apoptosis. Perturbations of AKT expression and function play an important role in tumor development and progression. We wanted to determine (a) whether AKT is overexpressed in human prostatic tumors, (b) whether AKT expression is correlated with tumor grade, and (c) whether AKT expression correlates with clinicopathological parameters. AKT expression was investigated by immunohistochemistry in sections from 56 paraffin-embedded prostate specimens displaying benign prostatic tissue (BPT), prostatic intraepithelial neoplasia (PIN), and primary tumors graded 2-5 according to Gleason. The staining intensity for AKT was significantly more pronounced in tumors compared to BPT, with PIN ranging between BPT and carcinomas. Similarly, the fraction of AKT-positive cells was higher in tumors than in BPT. A score of AKT expression (calculated as product from intensity and fraction of positive cells) ranging from 0-6 was also significantly higher in tumors than in BPT. Furthermore, the intensity of AKT expression in tumors showed a positive correlation with high preoperative serum levels of prostate specific antigen (PSA >/= 10 ng/ml, p = 0.0325). These data show that AKT is upregulated in prostate cancer and that expression is correlated with tumor progression., (Copyright 2003 Wiley-Liss, Inc.)

Aim: The suitability of dynamic parameters of the two-compartment model for detecting prostate carcinomas and its correlation with tumor microvascular density were evaluated., Methods: The study included 43 patients with biopsy-proven prostate carcinoma: 28 were examined by 1.0-T MRI (Turbo-FLASH) and 15 by 1.5-T MRI (FLASH) with infusion of 0.1 mmol/kg Gd-DTPA. Signal time curves were parametrized with an open two-compartment model in amplitude and exchange rate constants (k(ep)). The microvascular density of resected prostate carcinomas was determined., Results: The microvascular density in the tumors was significantly higher than in the adjacent healthy prostate tissue and correlated in both sequences with k(ep). Prostate carcinomas of the peripheral zone were demarcated by amplitude and k(ep). In the Turbo-FLASH sequence there was a significant difference between the tumor tissue and healthy peripheral zone in terms of k(ep) and in the FLASH sequence in terms of amplitude., Conclusion: Prostate carcinomas can be visualized with dynamic T1-weighted MR sequences using a two-compartment model. Moreover, the parameter k(ep) reveals the microvascular density in the tumor and can thus provide valuable clinical information for characterizing the tumors.

The surgical and medical management of carcinoma of the prostate is a central issue in urology. Radical prostatectomy is the standard procedure in the curative therapy of locally confined carcinoma of the prostate. Recently, alternative minimally invasive options such as brachytherapy and the still experimental focused ultrasound and cryotherapy have gained in interest. Further palliative schemes such as hormonal ablation and chemotherapy have become established in the management of locally advanced and generalized carcinoma or elderly patients. It was our objective to give an account of these established and new urological therapy options in the management of carcinoma of the prostate.

Poly(ADP-ribosyl)ation plays important roles in cellular DNA repair mechanisms as well as in cellular proliferation and genomic stability. Four carcinoma cell lines, LNCaP, PC-3, C4-2 and MatLu, and one prostate epithelial cell line, PNT1A, were tested using the H10 antibody to poly(ADP-ribose) by Western blotting and FACS analysis for basal and activated (10 mM H2O2) PARP activity. In both analyses, higher levels of basal polymer were present in the LNCaP cell line than in the prostate epithelial cell line or the MatLu cell an line. LNCaP cells demonstrated greater than 90% positive analyzed cells in FACS analysis both before and after treatment with H2O2. PNT1A epithelial cells demonstrated evidence of polymer presence only after treatment with H2O2. Microsatellite instability due to increased oxidative damage in tumor cells has been proposed as a means for accumulation of genetic changes. As oxidative stress can stimulate poly(ADP-ribose) reactions, an increased presence of the polymer may indicate a high level of oxidative damage occurring in the tumor cells, contributing to higher levels of genetic instability towards progression.

New approaches to treat prostate cancer (PCA) are utilizing gene therapy and aim to correct the disease at the genetic level. Getting a gene efficiently into the target cell is the subject of much interest. We used a holmium laser for transfecting rat PCA cells with the reporter gene pEGFP. By FACS analysis and fluorescence microscopy, we could demonstrate that cellular delivery of plasmid DNA was possible with high efficiencies up to 41.3%. Therefore, transfection of PCA cells by holmium laser might offer a promising new gene transfer strategy to PCA with minimal invasiveness.

Background: Gene therapy is expected to play a major role in medical treatment in the future. Several different methods for DNA transfection exist. We evaluated the efficacy and effects of transfection by acoustic energy in a standardized prostate cancer model., Methods: Subcutaneous implantation of Dunning tumors was followed by injection of pEGFP-DNA plasmid. Tumors were treated by acoustic energy with different parameter settings and the transfection rate was assessed by FACScan., Results: Standardized experimental conditions resulted in minor intragroup deviations. Intratumoral injection resulted in a transfection rate of 0.3% (control group). The statistically significant increase of 4.6% in cell transfection rate was gained by applying acoustic energy., Conclusions: DNA transfection of solid tumors can be mediated by the application of acoustic energy. Achieved transfection rates are encouraging and imply therapeutical levels. Prodrug activation or suicide gene therapy are possible fields of investigation in the treatment of prostate cancer.