Search

Prostate cancer (PC) is common among men and has become a significant societal issue. Localized PC has a good prognosis with appropriate treatment. Prostatectomy, particularly robot-assisted radical prostatectomy (RARP), has become a common treatment since the da Vinci prostatectomy was approved by the FDA in 2001. The current study aimed to assess the learning curve for RARP, focusing on anastomosis time, using the cumulative sum (CUSUM) method. Data were collected from Nagoya City University Hospital between May 2011 and December 2018 and included 469 surgeries performed by experienced surgeons. Our findings indicated that, on average, 11 patients were required to complete the initial phase and 24 patients were required to complete the consolidation phase of anastomosis. Additionally, for complete resection of pT2c cases, 16 cases were required for the initial phase and 27 cases were required for the consolidation phase. The CUSUM method proved useful for visualizing trends in surgical proficiency, although the study noted potential confounding biases and limitations in evaluating surgical proficiency based solely on surgical time or positive surgical margins., (© 2024. The Author(s), under exclusive licence to Springer-Verlag London Ltd., part of Springer Nature.)

Objective: To analyze nerve sparing performance at an early stage of robot-assisted radical prostatectomy, and the correlation between the surgeons' experience and the risk of a positive surgical margin in patients treated with robot-assisted radical prostatectomy., Methods: Patients' records from January 2009 to March 2013 were retrospectively reviewed, and 3469 patients with localized prostate cancer were identified at 45 institutions. Individual surgeon's experience with nerve sparing was recorded as the number of nerve sparing cases among total robot-assisted radical prostatectomies beginning with the first case during which nerve sparing was carried out. Patients were selected by propensity score matching for nerve sparing, and predictive factors of positive surgical margins were analyzed in patients with and without positive surgical margins., Results: A total of 152 surgeons were studied, and the median number of robot-assisted radical prostatectomy cases for all surgeons was 21 (range 1-511). In all, 54 surgeons (35.5%) undertook nerve sparing during their first robot-assisted radical prostatectomy case. For 2388 patients selected with (1194) and without (1194) nerve sparing, predictive factors for positive surgical margin were high initial prostate-specific antigen level (P < 0.0001), high biopsy Gleason score (P = 0.0379), presence of neoadjuvant hormone therapy (P = 0.0002) and surgeon's experience with >100 cases (P = 0.0058). Thus, nerve sparing was not associated with positive surgical margins., Conclusion: The surgeon's experience influences the occurrence of positive surgical margins, although a considerable number of surgeons carried out nerve sparing during their early robot-assisted radical prostatectomy cases. Surgeons should consider their own experience and prostate cancer characteristics before carrying out a nerve sparing robot-assisted radical prostatectomy., (© 2017 The Japanese Urological Association.)

Introduction: We aimed to perform a multi-institutional study using a national database led by the Japanese Society of Endourology to investigate the effect of surgeon or hospital volume on the safety of robot-assisted radical prostatectomy (RARP)., Materials and Methods: Clinical data of 3,214 patients who underwent RARP for the treatment of clinically localized prostate cancer between April 2012 and March 2013 in Japan were evaluated. Surgical outcomes and all intra- and perioperative complications were collected., Results: The intraoperative complication rate was 0.56%. In a total number of 241 patients, 261 perioperative complications were observed. The following percentages of patients presented the Clavien-graded complications: 7.2%, grades 1-2; 0.84%, grade 3; and 0.093%, grade 4a. No cases of multiple organ dysfunction or death (grades 4b and 5) were found. Multivariable logistic regression analysis showed that the hospital volume (OR 3.6; p = 0.010) for intraoperative complications and surgeon volume (OR 0.19; p < 0.0001) and extended lymph node discectomy (OR 3.9; p < 0.0001) for perioperative complications were significant independent risk factors., Conclusions: Hospital volume for intraoperative complications and surgeon volume and extended lymph node dissection for perioperative complications were significantly associated with increased risk of each complication in RARP., (© 2017 S. Karger AG, Basel.)

Herein, we investigated therapeutic potential of a novel histone lysine demethylase 1 (LSD1) inhibitor, NCL1, in prostate cancer. Hormone-sensitive prostate cancer cells, (LNCaP) and castration resistant cancer cells (PC3 and PCai1) were treated with NCL1, and LSD1 expression and cell viability were assessed. Prostate cancer cells showed strong LSD1 expression, and cell viability was decreased by NCL1. ChIP analysis showed that NCL1 induced H3K9me2 accumulation at the promoters of androgen-responsive genes. NCL1 also induced G1 cell cycle arrest and apoptosis. In addition, autophagosomes and autolysosomes were induced by NCL1 treatment in LNCaP. Furthermore, LC3-II expression was significantly increased by NCL1 and chloroquine. In mice injected subcutaneously with PCai1 and intraperitoneally with NCL1, tumor volume was reduced with no adverse effects in NCL1-treated mice. Finally, LSD1 expression in human cancer specimens was significantly higher than that in normal prostate glands. In conclusion, NCL1 effectively suppressed prostate cancer growth without adverse events. We suggest that NCL1 is a potential therapeutic agent for hormone-resistant prostate cancer.

Objectives: To compare the surgical outcomes of laparoscopic radical prostatectomy and robot-assisted radical prostatectomy, including the frequency and location of positive surgical margins., Methods: The study cohort comprised 708 consecutive male patients with clinically localized prostate cancer who underwent laparoscopic radical prostatectomy (n = 551) or robot-assisted radical prostatectomy (n = 157) between January 1999 and September 2012. Operative time, estimated blood loss, complications, and positive surgical margins frequency were compared between laparoscopic radical prostatectomy and robot-assisted radical prostatectomy., Results: There were no significant differences in age or body mass index between the laparoscopic radical prostatectomy and robot-assisted radical prostatectomy patients. Prostate-specific antigen levels, Gleason sum and clinical stage of the robot-assisted radical prostatectomy patients were significantly higher than those of the laparoscopic radical prostatectomy patients. Robot-assisted radical prostatectomy patients suffered significantly less bleeding (P < 0.05). The overall frequency of positive surgical margins was 30.6% (n = 167; 225 sites) in the laparoscopic radical prostatectomy group and 27.5% (n = 42; 58 sites) in the robot-assisted radical prostatectomy group. In the laparoscopic radical prostatectomy group, positive surgical margins were detected in the apex (52.0%), anterior (5.3%), posterior (5.3%) and lateral regions (22.7%) of the prostate, as well as in the bladder neck (14.7%). In the robot-assisted radical prostatectomy patients, they were observed in the apex, anterior, posterior, and lateral regions of the prostate in 43.0%, 6.9%, 25.9% and 15.5% of patients, respectively, as well as in the bladder neck in 8.6% of patients., Conclusions: Positive surgical margin distributions after robot-assisted radical prostatectomy and laparoscopic radical prostatectomy are significantly different. The only disadvantage of robot-assisted radical prostatectomy is the lack of tactile feedback. Thus, the robotic surgeon needs to take this into account to minimize the risk of positive surgical margins., (© 2014 The Japanese Urological Association.)

Objective: To present our experience of a novel technique, bladder neck sling suspension technique, in patients undergoing robot-assisted radical prostatectomy (RARP) and evaluate its efficacy for improving early continence outcomes after RARP in comparison with that of the standard technique., Methods: Fifty-seven consecutive patients underwent RARP between August 2011 and April 2012. We performed RARP with and without bladder neck sling suspension technique for 27 (sling group) and 30 (nonsling group) patients, respectively, and compared the urinary outcome between the groups. Both subjective and objective assessments of urinary incontinence were performed before and after RARP., Results: The International Prostate Symptom Score (P <.05) and International Consultation on Incontinence Questionnaire-Short Form (P <.05) in the sling group were significantly lower, and Expanded Prostate Cancer Index Composite urinary incontinence score (P <.05) in the sling group was higher than those in nonsling group, 4 weeks after RARP. In addition, mean pad weight gain on 1-hour pad test in the sling group was significantly smaller than that in the nonsling group, 4 weeks after RARP (P <.05). Both patient perception and objective data of urinary incontinence 4 weeks after RARP were better in the sling group than in the nonsling group. Valsalva maneuver during cystography demonstrated that the mean posterior urethrovesical angle in the sling group was smaller than that in the nonsling group (P <.001)., Conclusion: Bladder neck sling suspension technique is a simple and feasible procedure in RARP and can improve the early return of continence after RARP, although additional larger studies are required to confirm this finding., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: To determine the effect of prostate weight on the preoperative and postoperative outcomes of robotic-assisted laparoscopic radical prostatectomy with a posterior approach to the seminal vesicle., Methods: This retrospective study examined prospectively collected data on 219 robotic-assisted laparoscopic radical prostatectomies performed from May 2011 to February 2013. Patients were divided into four groups based on pathologic prostate weight: <30 g, 30-49 g, 50-79 g, and ≥80 g. Continence and sexual function were assessed using validated questionnaires., Results: Of the 219 patients, 19, 143, 51, and 6 had prostates weighing <30 g, 30-49 g, 50-79 g, and ≥80 g, respectively. Significant differences were found between the preoperative Gleason scores, total operative times, and robotic times of the groups. Both estimated blood loss and anastomosis time tended to be greater in the higher prostate weight groups, but the differences were not significant. No significant differences were observed in transfusion rate, length of catheterization, complication incidence, or positive surgical margins. The return of urinary function, as determined by questionnaire scores, was not affected by prostate weight., Conclusions: Robotic-assisted laparoscopic radical prostatectomy can be performed safely and with similar perioperative outcomes, regardless of prostate weight. Indeed, oncological outcome, urinary continence, and complications were similar across the prostate weight groups, suggesting that robotic-assisted laparoscopic radical prostatectomy with a posterior approach to the seminal vesicle may be performed effectively on men with large prostates, despite greater surgical times.

Background: Bladder neck transection is one of the most difficult procedures for robot-assisted laparoscopic radical prostatectomy (RALP), particularly in patients who have undergone previous transurethral resection of the prostate (TUR-P), and in those with large median lobes or prostate cancer protruding into the bladder neck. To ensure negative surgical margins and safely preserve the ureteral orifices during bladder neck transection, we propose the use of the transurethral resectoscope for making the incision in the bladder neck before initiating RALP. Thus, we developed a technique for bladder neck transection to facilitate this operation in such patients., Case Presentation: Two Japanese men, aged 61 and 63 years, who were diagnosed with prostate cancer, received a transurethral marking incision of the bladder neck before starting RALP; prostate cancer developed in one patient after TUR-P and the other patient had cancer protruding into the bladder neck. A transurethral resectoscope was used to closely observe the ureteral orifices and bladder necks; the bladder necks were marked to indicate the depth from the mucosa to the muscular layer. During the RALP, the bladder necks were dissected to indicate the depth of the marking incision. The surgical margins were negative and perioperative complications did not occur. The Foley catheters were removed on postoperative day 6, according to the usual protocol. No urinary leakage from the anastomosis sites was observed., Conclusion: This technique, involving the use of an ordinary transurethral resectoscope, may be an easy procedure to ensure negative surgical margins, safely preserve the ureteral orifices, avoid increasing the bladder neck diameter, and achieve a good quality vesicourethral anastomosis that prevents the risk of suture-related tissue tears.

Background: Bone metastasis is a serious problem for individuals with prostate cancer, and the effects of the anticancer drug docetaxel (DTX) are insufficient. We therefore examined the therapeutic potential of magnetic cationic liposomes (MCL) in a novel rat model that allows the evaluation of tumor immunity. The effects of MCL thermotherapy were compared with those of DTX as a conventional therapy for the treatment of bone metastatic prostate cancer., Methods: Prostate tumor tissues were transplanted into the femurs of model rats divided into four groups: control, MCL, DTX, and MCL + DTX. Tumors were injected with MCL, and alternating magnetic field (AMF) irradiation was performed three times a week. Tumor proliferation and bone destruction were evaluated by proliferating cell nuclear antigen positivity, computed tomography, and CD68-positive cell number, while tumor immunity was evaluated by heat shock protein (HSP) 70 expression and CD8-positive lymphocyte number., Results: We successfully established a novel femur metastasis model of prostate cancer, and demonstrated that tumor proliferation and bone destruction in the MCL and MCL + DTX groups were significantly suppressed compared with control and DTX groups. MCL thermotherapy concurrently induced necrosis and apoptosis. The expression of HSP70 in the MCL and MCL + DTX groups was also significantly increased, and tumor immunity was enhanced through the induction of CD8-positive lymphocytes., Conclusion: MCL thermotherapy was clearly more effective than DTX in treating bone metastatic prostate cancer. A combination of MCL thermotherapy and DTX therefore deserves consideration as a novel treatment for this disease., (Copyright © 2013 Wiley Periodicals, Inc.)

Background: Few reports can be found in the literature with respect to the impact of neoadjuvant hormonal therapy (NHT) on operative parameters on laparoscopic radical prostatectomy (LRP) in a large study. The aim of this study was to evaluate the safety and efficacy of NHT prior to LRP for locally confined prostate cancer., Methods: From January 2004 to September 2009, 342 patients undergoing LRP were analyzed, specifically comparing 72 patients who received NHT to 270 who did not. All patients were in clinical stage T2 and nerve sparing LRP were not included., Results: The mean patient age, preoperative prostate specific antigen (PSA), clinical stage, and biopsy Gleason grade were similar for the NHT and the non-NHT LRP groups. The median blood loss and the median operative time were also similar. There were no differences in the intraoperative complication rate of rectum injury, blood transfusion, and open surgery conversion. The positive surgical margin rate was significantly improved in NHT patients. Moreover, PSA recurrence within two years was significantly less in long-term NHT than in non-NHT patients., Conclusions: LRP was shown as a safe and efficacious procedure in patients who have received NHT. Perioperative morbidity of NHT patients undergoing LRP appears equivalent to non-NHT patients, with lower positive surgical margin, and PSA recurrence rate.

Background: Elucidating the mechanisms of metastasis in prostate cancer, particularly to the bone, is a major issue for treatment of this malignancy. We previously reported that an androgen-independent variant had higher expression of glutathione S-transferase pi (Gst-pi) compared with a parent androgen-dependent transplantable rat prostate carcinoma which was established from the transgenic rat for adenocarcinoma of the prostate (TRAP)., Methods: A new cell line, PCai1, was established from the androgen-independent tumor and investigated its metastatic potential in nude mice. The tumorigenesis of PCai1 cells in vivo was studied by subcutaneous transplantations into nude mice. The growth in the microenvironment of the prostate was studied by orthotopic transplantation of PCai1 cells into nude mice. The metastatic potential of PCai1 cells was studied by tail vein injections. Effects of Gst-pi knocked down were analysis in PCai1 cells., Results: PCai1 frequently formed metastatic lesions in the lung and lymph nodes after orthotopic implantation in the prostate. Intravenous injections of PCai1, metastasis to lung and bone were obvious. PCai1 had strong expression for Gst-pi, therefore we tried knocked down Gst-pi. Gst-pi-siRNA in vitro significantly suppressed cell proliferation rate. In addition, high levels of intracellular reactive oxygen species (ROS) were recognized in the Gst-pi knockout., Conclusions: Gst-pi expression of the prostate cancers are dependent on metastatic site, and that Gst-pi has an important role in adapting prostate cancer for growth and metastasis involving an alteration of ROS signals., (Copyright © 2011 Wiley Periodicals, Inc.)

Because recovery of erectile function and avoidance of positive surgical margins are important but competing outcomes with prostate cancer therapy, the decision to preserve or resect a neurovascular bundle (NVB) during laparoscopic radical prostatectomy (LRP) should be firmly based on information concerning the presence and location of extracapsular extension. In the current retrospective study, the propriety of actual decisions was assessed using preoperative magnetic resonance imaging (MRI), combining T2-weighted imaging (T2WI) with diffusion-weighted imaging (DWI), the apparent diffusion coefficient (ADC), numbers of positive biopsy cores, tumor volume and the Gleason score. MRI before prostate biopsy was performed in 35 patients who underwent LRP for clinically localized prostate cancer. A single radiologist retrospectively assessed whether the tumor localization, capsular penetration, seminal vesicle invasion, NVB involvement, and MRI findings correlated with the postoperative histological results. With the postoperative specimens, 83 lesions demonstrated a Gleason score of 6 or more. Using T2WI with and without DWI and ADC, 39 and 27 of 54 lesions were correctly identified, respectively, the difference being significant. For cancers in the transitional zone, using a threshold Gleason score of 3 or greater, sensitivity was also significantly higher for T2+DWI+ADC than for T2WI alone. Of 35 patients, using all available clinical information (biopsy results including Gleason score, tumor location, percentage of positive biopsy cores, and the percentage of tumor-involved core tissue), we found that the preoperative and postoperative staging were concordant in 25 cases. There is no universal consensus for nerve-sparing LRP; therefore, we performed an additional analysis using simplified clinically defined selection criteria (PSA level >15ng/mL, cT2, less than two positive biopsy scores in the unilateral lobe and less than 30% tumor volume, and a Gleason score of 6). Using this criteria, we selected 12 of 35 patients, and the detection rate of NVB involvement by MRI combined T2WI + DWI + ADC maps was 100% in their 30 lesions, and therefore we consider it safe to perform nerve-sparing LRP using our criteria. Our findings suggest that NVB can be safely preserved in patients with low-grade tumors using simplified clinically defined selection criteria to determine margin involvement.

Purpose: There is ongoing discussion as to the necessity for certain surgical procedures being limited to high through-put institutions. To cast light on this question regarding use of open as compared to laparoscopic radical prostatectomy (LRP) the present study was conducted focusing on biochemical (PSA) recurrence-free survival of Japanese patients with clinically localized prostate carcinomas., Materials and Methods: From April 2004 to December 2010 we identified 579 patients undergoing LRP (n=245) and retropubic radical prostatectomy (RRP) (n=334) who did not undergo immediate adjuvant therapy (radiation and/or hormonal) and whose PSA levels were lower than 25 ng/ml. Preoperative prostate specific antigen (PSA) level, clinical stage, biopsy Gleason score and pathological features were assessed and Kaplan-Meier estimates of biochemical recurrence (BCR)-free survival were compared. A Cox regression model analysis was performed to determine predictors of biochemical recurrence., Results: Median follow up was 35 months(2- 115). On univariate analysis the LRP group had a slightly lower pathological T stage (p<0.001), higher biopsy Gleason score (p<0.001), but much more organ confined disease (p=0.001) than the RRP group. BCR-free survival did not significantly differ between LRP and RRP groups with preoperative PSA <6, clinical stage T1c,T2a, pathological stage T3 or more, biopsy Gleason score of 8 or more, pathological Gleason score of 6 or less and 8 or more, extra-capsular extension and negative surgical margin. The 3-year BCR-free survival rates were 91.0%(RRP) and 82.2%(LRP) (p<0.001)., Conclusion: We conclude that in general LRP may be associated with a less positive outcome than BCR for resection of low risk prostate cancers. Therefore indications for LRP should be very carefully monitored.

We describe a case of embryonal rhabdomyosarcoma of the prostate in a 20-year-old man with a history of acute lymphatic leukemia at 6 years of age. He presented with gross hematuria and high fever. The level of prostate-specific antigen (PSA) was 27.9 ng/ml. Computed tomography revealed a suspected infectious cyst in the prostate. After antibiotic treatment was begun, the PSA level normalized. However, the patient later suffered bladder tamponade. A biopsy of the prostate revealed embryonal rhabdomyosarcoma. Chemotherapy with vincristine, actinomycin D, cyclophosphamide, and ifosfamide was begun according to the treatment protocol of the Japan Rhabdomyosarcoma Study Group. The tumor shrank, and partial remission was obtained after 1 course of chemotherapy. During treatment for acute lymphatic leukemia at the age of 6 years, the patient had been exposed to a cumulative radiation dose of 10 Gy across his entire body. It has been reported that 88% of postradiation sarcomas are KIT-positive, and we suspect that our patient suffered a postradiation sarcoma, because his tumor was KIT-positive. This is the first report of postradiation sarcoma manifesting as an embryonal rhabdomyosarcoma of the prostate.

There is no effective standard therapy for the treatment of hormone-refractory prostate cancer (HRPC), and treatments vary among different medical institutions with efforts to improve results. The present retrospective investigation was performed to assess the outcomes of second line, third line, and fourth line therapies. A total of 142 patients with HRPC were treated at Nagoya City University Hospital and its affiliate hospitals during the 10 years between October 1996 and August 2006. Patient background and treatments given after hormone refractory phase were determined, with especial attention to 50% or greater decrease rates of serum PSA levels and other variables with three common regimens based on: estramustine phosphate (EMP); diethylstilbestrol diphosphate (DES); and dexamethasone (DEX). With second line therapy for HRPC, the response rate was highest with EMP, whereas best outcomes were apparent with DES as a third line or fourth line therapy. However, overall survival for all cases and particularly with those having a poorly differentiated lesion, was best with EMP in any time period. Although there is no generally established optimal treatment for HRPC, our analysis supports the efficacy of EMP based on second line therapy response rates and optimal prognosis with longer term use.

Background: Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is expressed in certain human cancers. Ligand-induced PPAR-gamma activation can result in growth inhibition and differentiation in these cancer cells; however, the precise mechanism for the anti-proliferative effect of PPAR-gamma ligands is not clear., Methods: In this study, we examined the expression of PPAR-gamma in human prostate cancer and the effect of two PPAR-gamma ligands, 15 deoxy-Delta(12,14)-prostaglandin J2 (15d-PGJ2) and troglitazone, on prostate cancer cell growth., Results: PPAR-gamma is frequently over-expressed in androgen independent prostate cancer cell lines and human prostate cancer tissues (22 of 47; 47%). Both 15d-PGJ2 and troglitazone inhibited proliferation and DNA synthesis of prostate cancer cell lines in a dose-dependent manner, and slightly increased the proportion of cells with S-phase DNA content. Prostate specific antigen (PSA) promoter reporter assays showed that troglitazone and 15d-PGJ2 down-regulated androgen stimulated reporter gene activity in prostate cancer cell lines LNCaP. Interestingly, LNCaP with troglitazone dramatically suppressed PSA protein expression without suppressing AR expression., Conclusions: Taken together, these results suggest that PPAR-gamma ligands may be a useful therapeutic agent for the treatment of prostate cancer.

Androgen plays an important role in the growth of prostate cancer, but the molecular mechanism that underlies the development of resistance to anti-androgen therapy remains unknown. In this paper, we review the role of cell cycle regulators and steroid receptor co-activators for prostate cancer growth and survival. Cyclin E has been shown to increase the transactivation activity of the human androgen receptor and the proliferation of prostate cancer cells. On the other hand, p27 using an adenovirus vector was shown to reduce the size of tumors of human prostate cancer xenografts. Steroid receptor coactivator-3 (SRC-3) is often over-expressed in prostate cancers. Our results indicate that overexpression of SRC-3 can modulate the AKT (protein kinase B) signaling pathway and stimulate cell growth in prostate cancer. In contrast, down-regulation of SRC-3 expression by small interfering RNA suppresses cell growth.

We performed a radical retropubic prostatectomy on a 59-year-old male patient who was diagnosed with prostatic carcinoma. Pathological findings revealed a ductal adenocarcinoma in the left lobe of the prostate, and a conventional well-differentiated adenocarcinoma in the right lobe. Immunohistochemistry revealed that CA19-9 was positive in the ductal adenocarcinoma, and prostate-specific antigen was positive in the conventional well-differentiated adenocarcinoma. Since there was an increase in the level of serum CA19-9, which had decreased postoperatively, along with the appearance of local recurrence and bone metastasis, we treated the patient with cisplatin and gemcitabine. As a result, the level of serum CA19-9 was normalized and a reduction of the metastatic focus was observed.

A total of 161 patients underwent radical retropubic prostatectomy at our 11 institutions in the three-year period from January 2001 to December 2003. The numbers per institution ranged from 1-36, with 5 institutions conducting 20 or more (131 cases), and 6 performing less than 15 (30 cases). Here we examined the differences in operation parameters and patient outcome between these two groups. Time for surgery, associated loss of blood, lymphadenectomy, preservation of neurovascular bundles, time for removal of indwelling catheters, post-operation complications, and subsequent urinary incontinence, were assessed. There were no differences between the two groups of hospitals, except with regard to surgery time and incontinence, where the period to 'pad-free' was an average of more than 40 days longer in institutions undertaking only a small number of operations. From our experience with radical retropubic prostatectomy, series of hospitals, there is no reduction in safety with such intervention performed by institutions undertaking only a small number of operations.

One of the most critical issues in prostate cancer clinic is emerging hormone-refractory prostate cancers (HRPCs) and their management. Prostate cancer is usually androgen dependent and responds well to androgen ablation therapy. However, at a certain stage, they eventually acquire androgen-independent and more aggressive phenotype and show poor response to any anticancer therapies. To characterize the molecular features of clinical HRPCs, we analyzed gene expression profiles of 25 clinical HRPCs and 10 hormone-sensitive prostate cancers (HSPCs) by genome-wide cDNA microarrays combining with laser microbeam microdissection. An unsupervised hierarchical clustering analysis clearly distinguished expression patterns of HRPC cells from those of HSPC cells. In addition, primary and metastatic HRPCs from three patients were closely clustered regardless of metastatic organs. A supervised analysis and permutation test identified 36 up-regulated genes and 70 down-regulated genes in HRPCs compared with HSPCs (average fold difference > 1.5; P < 0.0001). We observed overexpression of AR, ANLN, and SNRPE and down-regulation of NR4A1, CYP27A1, and HLA-A antigen in HRPC progression. AR overexpression is likely to play a central role of hormone-refractory phenotype, and other genes we identified were considered to be related to more aggressive phenotype of clinical HRPCs, and in fact, knockdown of these overexpressing genes by small interfering RNA resulted in drastic attenuation of prostate cancer cell viability. Our microarray analysis of HRPC cells should provide useful information to understand the molecular mechanism of HRPC progression and to identify molecular targets for development of HRPC treatment.

Background: Magnetite cationic liposomes (MCLs) can be used to induce hyperthermia because they generate heat in an alternating magnetic field (AMF). This study aimed at developing more practical method for MCL hyperthermia examining the effect of MCL-induced hyperthermia on human prostate cancer in vivo., Materials and Methods: A newly developed AMF generator incorporating a solenoid with a ferrite core (FC) was used. Human prostate cancer cells (PC-3 and LNCap) were injected subcutaneously into nude mice. MCLs were injected into tumor nodule and the mice were exposed into AMF three times at 24-hr intervals (repeated hyperthermia; RH) until complete tumor regression was observed., Results: Irradiation with an AMF generated by newly developed device can adequately increase the temperature of tumor tissue. Frequent RH resulted in complete tumor regression in all nude mice., Conclusion: RH using MCLs may be a promising new therapy for hormone-refractory human prostate cancer in the future.

Transcription factor nuclear factor kappaB (NF-kappaB) controls gene expression of a number of genes, including cytokines such as interleukin-6 (IL-6), granulocyte-macrophage (GM)-CSF, and interleukin-8 (IL-8). IL-6 is known to play important roles in the growth of prostate cancer cells, activation of androgen receptor, and prostate-specific protein expression. NF-kappaB is activated by extracellular signals such as proinflammatory cytokines, chemotherapeutic reagents, and radiation. Here we demonstrate that cisplatin (CDDP) and etoposide (VP-16) induce nuclear translocation of NF-kappaB in prostate cancer cell lines, followed by secretion of IL-6. We also demonstrated that the growth of hormone-independent prostate cancer cell lines can be inhibited by the anti-NF-kappaB reagent N-acetyl-L-cysteine (NAC). These observations indicate that NF-kappaB can be a target of new adjuvant therapy against hormone refractory prostate cancer.

From the supernatant of rabbit bone marrow, we isolated an organ-specific factor, which was related with the metastasis of prostate cancer to the bone and examined its adhesion to prostate cancer cells (PC-3). Molecular weight and amino acid sequence analyses of the active component obtained by high performance liquid chromatography revealed that a component identical to the alpha chain of hemoglobin accounted for 80% of the biological activity. Hemoglobin showed over 50% adhesion to PC-3 cells but only 10% adhesion to human colon cancer cell lines, representative of organ non-specific metastasis, and leukemia cells line, representative of a non-solid tumor. Some substance in the bone marrow may promote the first step of adhesion of cancer cells to bone marrow in the metastasis of prostate cancer to the bone, possibly an amino acid sequence or some tertiary structure similar to hemoglobin.

Objectives: Osteopontin (OPN), a secreted adhesive glycoprotein, has been shown to be produced in excessive amounts in a variety of experimental models of malignancy. Increased levels of OPN exist in blood from the lungs, breasts, and gastrointestinal tracts of cancer patients with metastases. However, there have been no reports on the expression of OPN in human urological malignancies. The present study investigates the presence of OPN in adenocarcinoma of the human prostate and in benign prostatic hyperplasia (BPH)., Patients and Methods: Using prostate tissue from 34 patients with primary prostate cancer, 13 patients with prostate cancer after having undergone hormonal therapy, and 12 patients with BPH, formalin-fixed paraffin sections were prepared. Specimens were obtained by needle biopsy or radical prostatectomy. Immunohistochemical staining (ABC method) was then performed. Staining was divided into either negative or positive categories., Results: Positive staining of OPN was observed on cancer cells and macrophages in 52.9% of the primary prostate cancers and 14.5% of the prostate cancers after hormonal therapy. In BPH specimens, 66.7% of the cases displayed positive staining of OPN. The staining level of OPN showed no correlation with serum prostate-specific antigen, but did correlate with stage, differentiation, and Gleason's score., Conclusions: The result postulates that the expression of OPN is an indicator of cell differentiation; however, it cannot be used as a marker of malignancy in prostate cancer.

One of the delicate problems in a cancer treatment is the acquisition of a tolerance for a medicine. Antiandrogen treatment is valid in treatment of prostate cancer, but the disease develops into hormone-refractory prostate cancer after a uniformity period. The molecular mechanisms of recurrence and endocrine therapy failure in prostate cancer have remained unclear. In this paper we discuss the hormone-refractory prostate cancer that has been reported by many investigators.

Purpose: Cell adhesion molecules (CAMs) have been considered to play key roles in cancer metastasis through binding of cancer cells to the endothelial cells or matrix. We have found that constitutive expression of E-selectin, ICAM-1 (intercellular adhesion molecule-1) and VCAM-1 (vascular cell adhesion molecule-1) on the cell surface of prostate cancer cell lines, PC-3 LNCaP, and DU145. In an attempt to explain the highly metastatic potential of these cells, we investigated expression of CAMs. Since these expressed CAMs are known to be regulated by a transcription factor NF kappa B. We have examined if NF kappa B is activated in these prostateccell lines., Material and Method: Expression of E-selectin, ICAM-1. Sialyl-Lewis X, LFA-1 (lymphocyte function-associated antigen-1), integrin alpha 4, and integrin beta 1 were examined by indirect immunofluorescent staining and Western blotting using specific monoclonal antibodies. We then examined whether pro-inflammatory cytokines known to stimulate NF kappa B, IL-1 and TNF, could drive the nuclear translocation of NF kappa B Ten ng/ml of recombinant human IL-1 beta or TNF alpha was added to the cell culture and the CAMs level, as well as nuclear translocation of NF kappa B, was examined., Results: The staining levels of ICAM-1, VCAM-1, and integrin beta 1 were highly elevated in PC-3 and DU145. In surprising, NF kappa B was retained in the cytoplasm (as an inactive form) and not detectable in the nucleus (active form) as demonstrated by immunofluorescence. Although time-dependent expression of these molecules were explored, the level of ICAM-1 and VCAM-1 on the cell surface were unchanged. However, nuclear translocation of NF kappa B could be induced., Conclusion: These observations indicate that while the signaling pathway to NF kappa B is intact, it is not directed to induction of its target CAM genes. It is possible that other transcription factors might be involved in these cells and that they might to be constitutively stimulated during the carcinogenesis of prostate cancer.

Background: Estrogens are suspected to play a role in the pathogenesis of benign prostatic hyperplasia (BPH) and prostate cancer. In this study, the expression of aromatase messenger ribonucleic acid (mRNA) was determined, and these levels were quantitated, in human prostatic tissues to evaluate the role of estrogens in the pathogenesis of BPH and prostate cancer., Methods: Prostatic tissues were obtained either by retropubic prostatectomy, radical prostatectomy, or radical cystectomy from patients with BPH, prostate cancer, and bladder cancer. The expression of aromatase mRNA in the prostatic tissues was studied by Southern blot analysis of the reverse transcription and polymerase chain reaction technique (RT-PCR) products. Aromatase mRNA levels were measured in human prostatic tissues by the RT-PCR using a fluorescent primer., Results: Aromatase mRNA was identified in all specimens by Southern blot analysis of the RT-PCR products. The concentrations of aromatase mRNA (mean +/- SD) which were measured by fluorometric quantitation in 16 of 19 patients with BPH and in 3 of 4 patients with prostate cancer, were 1.81 +/- 3.02, and 0.84 +/- 0.27, x 10(-3) attomoles/micrograms of total RNA, respectively., Conclusions: These results demonstrate local formation of estrogen in the prostates of patients with BPH and prostate cancer. Controlled studies will be necessary to determine whether this may be a factor in the development of BPH and prostate cancer.