Whole-gland salvage treatment for recurrent prostate cancer after initial definitive radiotherapy: A case series of 125I brachytherapy and robot-assisted radical prostatectomy.

PURPOSE: To analyze outcomes following whole-gland salvage treatments applied to patients with pathology-proven, locally recurrent prostate cancer following primary definitive radiotherapy. MATERIAL AND METHODS: Eighteen consecutive patients who received whole-gland salvage treatments at our institution were retrospectively reviewed. All patients underwent transperineal template-guided mapping biopsy (TTMB) using the standard iodine-125 (125I) brachytherapy (BT) setup. Twelve patients received 125I BT, and six patients underwent robot-assisted laparoscopic prostatectomy (RARP). Prostate-specific antigen (PSA) failure was determined using the Phoenix definition (nadir + 2 ng/ml) following BT and a PSA level of > 0.2 ng/ml following RARP. Toxicities were graded according to CTCAE version 4.0. RESULTS: The median follow-up times were 71 and 11 months for the BT and RARP groups, respectively. In the BT group, the median dose to 90% of the prostate was 131 Gy. The median time to biochemical failure was 47 months, and the biochemical relapse-free survival (BRFS) rates were 56% (95% confidence interval [CI]: 33-94%) and 46% (95% CI: 25-88%) at 3 years and 5 years, respectively. Four patients (33%) developed grade 2 genitourinary (GU) toxicity, and two (17%) developed grade 3 GU toxicity. No patients developed grade ≥ 2 gastrointestinal (GI) toxicity. In the RARP group, three out of six patients (50%) had PSA failure, and four patients (67%) developed grade 2 GU toxicity. No patients developed grade 3 GU toxicity or grade ≥ 2 GI toxicity. On pre-salvage magnetic resonance imaging (MRI), no patients were suspected of having T3 or higher stage lesions. However, three patients (50%) had pT3a and two patients (33%) had pT3b (i.e., seminal vesicle invasion) stage lesions. CONCLUSIONS: Whole-gland salvage BT is an effective treatment with an acceptable toxicity profile. The pathology findings from RARP imply that there is a room for improvement in diagnoses made by MRI in the pre-salvage setting.

Selection of patients who would not require long-term prostate-specific antigen monitoring after low-dose-rate brachytherapy.

PURPOSE: To identify patients at extremely low risk of biochemical recurrence (BCR) of prostate cancer after low-dose-rate brachytherapy (LDR-BT) to determine when prostate-specific antigen (PSA) monitoring can be stopped. METHODS AND MATERIALS: We retrospectively reviewed clinicopathologic data of patients with prostate cancer who underwent LDR-BT between 2003 and 2011. Of 1569 patients reviewed, 689 (43.9%) received combination external beam radiotherapy, and 970 (61.8%) had neoadjuvant hormonal therapy. We stratified patients according to risk factors identified by multivariate analysis and assessed the factors for an association with BCR (defined as ≥2 ng/mL higher than the nadir). RESULTS: The median followup was 96 months. Of 1531 patients who were BCR-free at 3 years after treatment, 76 subsequently developed BCR; of 1500 who were BCR-free at 5 years, 45 eventually had BCR. On multivariate analysis, independent risk factors for BCR were the National Comprehensive Cancer Network risk group at diagnosis and PSA levels at 3 or 5 years after radiotherapy. In the low-risk group, no patient with a PSA level ≤0.2 ng/mL at 3 years after radiotherapy subsequently developed BCR. In the intermediate-risk group, no patients with a PSA level ≤0.2 ng/mL at 5 years subsequently developed BCR. CONCLUSIONS: The National Comprehensive Cancer Network risk group at diagnosis and PSA values at 3 and 5 years after LDR-BT are independently associated with a risk of later BCR. Using these two factors may help to select patients for whom PSA monitoring could be stopped because they have an extremely low risk of later BCR.

The Initial Case Report: Salvage Robotic Assisted Radical Prostatectomy After Heavy Ion Radiotherapy.

Salvage radical prostatectomy is one of treatments after radiation therapy to patients with prostate cancer. To date, no case of the salvage robotic assisted radical prostatectomy (RARP) following heavy ion radiotherapy (HIRT) has been published. We report on a 70-year-old man with a history of HIRT for prostate cancer in 2011. For 3 years after. HIRT, his serum PSA levels were permissible range. However, his PSA levels were increased. We had diagnosis localized prostate cancer after HIRT. We had carried out salvage RARP. Until 10 months after salvage RARP, his PSA level was not detectable.

Schmorl Nodes Mimicking Osteolytic Bone Metastases.

Bone is the third most common site of metastasis from upper tract urothelial carcinoma after radical nephroureterectomy. Although bone biopsy is the gold standard for the diagnosis of bone metastases, they can usually be diagnosed on the basis of imaging tests. We describe a case of upper tract urothelial carcinoma after radical nephroureterectomy presenting with a Schmorl node in the third lumbar vertebra, mimicking lytic bone metastasis. Differentiation of bone metastases from Schmorl nodes is essential for the appropriate management of patients with malignancy.

Preoperative prognostic factors for biochemical recurrence after robot-assisted radical prostatectomy in Japan.

PURPOSE: We investigated oncological outcomes in Japanese patients who underwent robot-assisted radical prostatectomy (RARP). MATERIALS AND METHODS: This study included 389 patients who underwent RARP at a single institution with a follow-up period of at least 1 year. Preoperative findings were compared with biochemical recurrence (BCR). Predictors of BCR-free survival (BCRFS) were evaluated by univariate and multivariate Cox proportional hazard model analyses, and a risk stratification model based on the relative risks of BCR was established. RESULTS: Fifty incidences of BCR were noted during a median follow-up period of 28.7 months (range, 12.1-80.0 months). The BCRFS rate for the entire cohort at the median follow-up time was 85.9 %; the 1-, 3-, and 5-year estimates were 91.0, 85.1, and 81.1 %, respectively. From univariate analyses, prostate-specific antigen (PSA), PSA density, biopsy Gleason score, and percent positive core were significantly associated with BCR. Multivariate analysis showed that PSA [hazard ratio (HR), 2.75; p = 0.001], percent positive core (HR, 2.22; p = 0.001), and biopsy Gleason score (HR, 2.61; p = 0.007) were independent predictors of BCR. CONCLUSION: This study at a single Japanese center demonstrates that RARP provides a satisfactory BCRFS rate. This report provides a framework with which to estimate oncological outcomes in patients who underwent RARP for localized prostate cancer. Our results support the increased use of RARP for the treatment of localized prostate cancer in Japan.

Learning curve and perioperative outcomes of robot-assisted radical prostatectomy in 200 initial Japanese cases by a single surgeon.

PURPOSE: The aim of the present study was to investigate the learning curve and perioperative outcomes in 200 consecutive patients with prostate cancer who underwent robot-assisted radical prostatectomy (RARP). PATIENTS AND METHODS: Between August 2006 and August 2011, 200 patients with prostate cancer underwent RARP and were enrolled in this study. We prospectively collected the demographic data and analyzed the pathologic and functional outcomes. The operative outcomes analyzed were total operative time, estimated blood loss (EBL), positive surgical margin (PSM), incontinence, and perioperative complications. We also evaluated the relationship between the surgeon's experience and operative variables. RESULTS: The sloping learning curve for this surgeon showed that total operative time was strongly correlated with the accumulation of experience for the initial 25 cases (|rs|=0.71, P<0.001). The average EBL was not strongly correlated with additional experience (|rs|<0.7). The PSM rate for the first 50 cases was significantly higher than that of the next 150 cases (34.8% vs 19.4%, P=0.035). The complication rate among the first 50 patients was significantly higher than that among the remaining 150 patients (32% vs 12.7%, P=0.002). The incontinence rate at 12 months was significantly higher for the first 100 cases compared with that for the next 100 cases (9.0% vs 1.0%, P=0.009). For the surgeon to optimize total operative time, PSM rate, complication rate, and incontinence rate, slope learning curves of 25, 50, 50, and 100 cases were needed. CONCLUSIONS: The functional and pathologic results of this minimally invasive procedure seemed to be promising. Distinct learning curves were observed with respect to operative time, PSM, complication rate, and incontinence rate. Exposure to 100 surgeries would be necessary for a surgeon to adequately master the required skills.

Robotic versus open radical cystectomy: prospective comparison of perioperative and pathologic outcomes in Japan.

OBJECTIVE: In Japan, no study has compared the perioperative outcomes observed between robot-assisted radical cystectomy (RARC) and open radical cystectomy (ORC). This study aimed at a prospective comparison of the perioperative outcomes between RARC and ORC performed by a single surgeon. METHODS: Between 2008 and 2011, 26 bladder cancer patients underwent radical cystectomy by one surgeon, 11 robotically and 15 by open procedure. We prospectively collected perioperative and pathological data for these 26 patients, and retrospectively compared these two different surgical procedures. RESULTS: The RARC cohort had a significant decrease in both estimated blood loss (656.9 vs. 1788.7 ml, P=0.0015) and allogeneic transfusion requirement (0 vs. 40%, P=0.0237). The total operative time was almost the same (P=0.2306) but increased duration of bladder removal and lymphadenectomy was observed in the RARC cohort (P=0.0049). Surgery-related complication rates within 30 days were not significantly different (P=0.4185). Positive surgical margin was observed in three patients in the ORC cohort and in one patient in the RARC cohort (P=0.4664). The RARC cohort had a larger number of removed lymph nodes than the ORC cohort, and the difference was statistically significant (20.7 vs. 13.8, P=0.0421). CONCLUSIONS: We confirmed that RARC is safe and yields acceptable outcomes in comparison with ORC for the treatment of bladder cancer if it is performed by a surgeon who has experience of over 60 cases of robot-assisted radical prostatectomy. It is hoped that RARC will gain acceptance in Japan as a minimally invasive surgery for muscle-invasive bladder cancer.

Risk stratification of survival by lymphovascular invasion, pathological stage, and surgical margin in patients with bladder cancer treated with radical cystectomy.

BACKGROUND: The aim of this study was to investigate prognostic factors and develop a prognostic factor-based risk stratification model for disease-specific survival (DSS) in a radical cystectomy (RC) series. METHODS: The patient cohort comprised 194 consecutive patients with bladder cancer treated with RC. Univariate and multivariate Cox proportional hazard model analyses were performed to identify significant prognostic factors for DSS. A risk stratification model was developed based on the relative risks (RRs) of DSS. RESULTS: Median follow-up period was 26.8 months. The 1-, 3-, and 5-year DSS were 88.0, 74.0, and 64.9%, respectively. In the univariate analysis, pathological T (pT) (≥ pT2), lymphovascular invasion (LVI), non-urothelial carcinoma component, surgical margin (SM), and lymph node metastases (pN) were significantly associated with poor prognosis. In the multivariate analysis, pT (≥ pT2), LVI, and SM were independent factors for predicting poor prognosis. Based on these results, patients were stratified into three risk groups: low (RR = 1.00-3.626), intermediate (5.860-9.826), and high (21.24). The 1-, 3-, and 5-year survival rates were 96.9, 85.1, and 85.1% in the low-risk group, 83.0, 63.4, and 43.8% in the intermediate group, and 51.0, 19.4, and 19.4% in the high-risk group, respectively. The differences among these groups were significant. CONCLUSIONS: In our RC series, pT (≥ pT2), LVI, and SM were independent prognostic factors. This information may be useful to identify patients with poor prognosis, who might be good candidates for innovative treatment.

Radical retropubic prostatectomy with running vesicourethral anastomosis and early catheter removal: our experience.

OBJECTIVES: To assess the outcomes of patients undergoing radical retropubic prostatectomy (RRP) with a running vesicourethral anastomosis and catheter removal on postoperative day 3 or 5. METHODS: From February 2006 through December 2007, 55 patients underwent RRP at our institution. All procedures were performed by a single surgeon using a running suture for the vesicourethral anastomosis. A cystogram was carried out before catheter removal in all patients. The initial 23 of 55 patients (Group 1; n = 23) had the cystogram on postoperative day 5, the other 32 patients (Group 2; n = 32) had the cystogram on postoperative day 3. Removal of the catheter was only carried out if there was no anastomotic extravasation. RESULTS: The success rate of catheter removal in group 1 and 2 was 100% and 96.9%, respectively. Overall continence rates were 83.3%, 87% and 90.7% at 24, 48 and 72 h after removal of the catheter, respectively. There was no significant difference in terms of continence rate between groups 1 and 2. None of the patients had acute urinary retention and/or anastomotic stricture after catheter removal. CONCLUSIONS: These findings suggest that an advanced running vesicourethral anastomosis during RRP is technically feasible, allowing safe early catheter removal in most patients.

Establishment and characterization of a new squamous cell carcinoma cell line, TMUU-08, derived from human bladder cancer.

Human squamous cell carcinoma (SCC) of the bladder is a rare malignancy that represents less than 5% of bladder tumors. In contrast to non-bilharzial SCC, bilharzial SCC is a distinct pathological disease that is rarely encountered in Japan. The majority of patients with non-bilharzial SCC present with a poorly differentiated, muscle-invasive tumor with no previous episode of urothelial carcinoma (UC). Even in the absence of distant metastases, the prognosis of patients with non-bilharzial SCC of the bladder remains dismal because patients die of localized recurrence. This is in contrast to UC in which distant metastasis accounts for the great majority of recurrence. The 5-year survival rate of the patients treated for non-bilharzial SCC of the bladder was only about 10%. To date, large numbers of reports have examined the establishment of a human bladder cancer cell line with UC. However, few reports exist regarding the establishment of the human bladder cancer cell line with SCC. In the present study, we established a new cell line (TMUU-08) from the metastatic lymph node of a patient with SCC of the bladder. The TMUU-08 cell line of human bladder SCC was characterized. These results indicate that TMUU-08 cells might be useful in basic studies not only in the treatment but also etiology of human bladder SCC.

Establishment of orthotopic mouse superficial bladder tumor model for studies on intravesical treatments.

Various animal models of bladder tumor have been developed for the preclinical evaluation of therapeutic modalities for the treatment of bladder cancers. The ideal model for the investigation of therapeutic effects of proposed novel intravesical treatments requires the mass of the implanted tumor to be confined to the urothelium of the bladder at least for the initial phase. However, previously reported bladder tumor models are not suitable for the evaluation of intravesical therapies for the treatment of superficial bladder cancer, since the muscle invasive tumors have developed from the beginnings of the experiments. These models are too aggressive to study local treatment effects. In the current study, we demonstrated that careful instillation of MBT-2 mouse bladder cancer cells into the bladder of a syngenic C3H/HeJ mouse could establish a superficial bladder tumor with an incidence of 100%. The procedure and technique for handling animals are simple for standard animal investigators. Maintenance of the in vitro conditions of MBT-2 cells without contamination of Mycoplasma and careful selection of the substrain of C3H mouse seem to be essential for stable tumor establishment. This bladder tumor model appeared to be easy to reproduce among several investigators in different institutions. The orthotopic bladder tumor model, which was confined to urothelium, lets us evaluate various intravesical treatment strategies.

Effects of a KiSS-1 peptide, a metastasis suppressor gene, on the invasive ability of renal cell carcinoma cells through a modulation of a matrix metalloproteinase 2 expression.

Although effects of a metastasis suppressor gene, KiSS-1, have been postulated to be mediated by its receptor, hOT7T175, the mechanism of such effects remains unknown. This study was designed to evaluate the mechanism of how KiSS-1 works and to assess effects of a synthesized truncated KiSS-1 protein on the invasive ability of renal cell carcinoma (RCC) cells. Four RCC cell lines, Caki-1, KU19-20, RSP and RSM, were investigated to determine mRNA expressions of KiSS-1, its receptor, hOT7T175, matrix metalloproteinases (MMPs) and MMP inhibitors. While all cell lines demonstrated hOT7T175 mRNA expressions, only Caki-1 had KiSS-1 transcripts. A synthesized truncated KiSS-1 peptide, metastin (45-54), produced a marked suppression of the invasive ability in KU19-20 cells, which were deficient for KiSS-1 transcripts, but not in Caki-1 cells. Metastin (45-54) also increased the ability of KU19-20 cells to attach to collagen 4. Both MMP-2 mRNA levels and protein production were significantly decreased only in KU19-20 cells by metastin (45-54). In conclusion, metastin (45-54) may have potential therapeutic use by suppressing the motility and invasive ability of RCC cells which possess hOT7T175 with either a negative expression or very low expression level of KiSS-1 through, at least in part, the down-regulation of MMP-2.

[First 24 Japanese cases of robotic-assisted laparoscopic radical prostatectomy using the daVinci Surgical System].

In Japan, as of September 2007, prostatectomy is conducted with open surgical procedures in more than 90% of the cases. Following the first reported robotic prostatectomy by Binder, et al. in 2000, a robotic-assisted laparoscopic radical prostatectomy (RALP) using the daVinci Surgical System (Intuitive Surgical, Inc., Sunnyvale, California, USA) has been extensively used as a standard procedure with gratifying results in the United States. In the Asian region, in contrast, RALP is still in an introductory phase. Recently, we introduced RALP in Japan. A total of 24 patients received robotic surgery within a year since August 2006. RALP was completed in all patients without conversion to open surgery, except for the first patient in whom a restriction to a 2-hour operation had been imposed by the Ethical Committee. The mean operative time using the daVinci device and the mean estimated blood loss were 232.0 (range; 136-405) minutes and 313.0 (range; 10-1,000) ml, respectively. The training program we recently developed proved remarkably effective in reducing the learning curve of robotic surgery in Japan, where there is no person with expertise in this operating procedure. In particular, the intraoperative guidance given by the expert was useful after relevant problematic points were delineated by operators who received comprehensive video-based image training and actually performed robot surgery in several cases. With direct intraoperative guidance by the mentor during cases 13 and 14, both the operation time and estimated blood loss was markedly reduced.

Prediction of bone metastases by combination of tartrate-resistant acid phosphatase, alkaline phosphatase and prostate specific antigen in patients with prostate cancer.

OBJECTIVE: The clinical value of serum tartrate-resistant acid phosphatase (TRACP), prostate specific antigen (PSA), alkaline phosphatase (ALP), and prostatic acid phosphatase (PACP) for the prediction of bone metastases in prostate cancer were investigated. METHODS: TRACP, PACP, ALP, and PSA serum levels were measured in 215 patients with prostate cancer, including 160 without and 55 with bone metastases. Correlation of serum marker levels with bone metastases was assessed using receiver operating characteristics (ROC) analysis. Sensitivity, specificity, accuracy, positive and negative predictive values were calculated for each serum marker. Multivariate stepwise logistic regression analysis was used to identify independent predictors for the presence of bone metastasis. RESULTS: Mean serum TRACP, PACP, ALP, and PSA levels were significantly elevated in patients with bone metastases compared with those without (P < 0.05). PSA and PACP levels increased significantly with clinical stage of the disease, whereas TRACP and ALP levels only increased significantly in stage D2. Serum TRACP levels correlated significantly with extent of disease on bone scans. ROC analyses showed no significant differences in area under the curve for these markers. Logistic regression analysis demonstrated that PSA, ALP, and TRACP were significant predictors of bone metastasis. Predicted and observed risks of bone metastasis were well correlated when TRACP, ALP, and PSA were combined and bone scan could have been omitted in 70% of patients by assessing these three markers. CONCLUSIONS: Serum TRACP can be considered a useful predictor of bone metastases in prostate cancer. A combination of TRACP, ALP, and PSA can obviate the need for a bone scan in 70% of cases.

Highly efficient gene delivery for bladder cancers by intravesically administered replication-competent retroviral vectors.

PURPOSE: In an attempt to improve viral delivery of potentially therapeutic genes via an intravesical route, we have recently developed murine leukemia virus-based replication-competent retrovirus (RCR) vectors. EXPERIMENTAL DESIGN: We evaluated the transduction efficiency of intravesically administered RCR vectors to bladder tumor using orthotopic animal models to determine their potential as delivery vectors for bladder cancer. RESULTS: The RCR vector containing green fluorescent protein (GFP) marker gene achieved efficient in vitro transmission of the GFP transgene. Murine bladder tumor-2 mouse bladder tumors exposed to intravesically administered RCR vectors exhibited 0%, 9.2 +/- 2.9%, and 30.0 +/- 6.2% of GFP expression at 9, 18, and 27 days after exposure in the orthotopic model, respectively. Orthotopic KU-19-19 human bladder tumors exposed to intravesically administered RCR vectors exhibited 3%, 85 +/- 1.0%, and 100% of GFP expression at 7, 21, and 35 days after exposure, respectively. GFP staining was observed only in the tumor cells in the bladder. No detectable PCR products of GFP gene could be observed in distant organs. Treatment with RCR vectors containing yeast cytosine deaminase (CD) gene plus 5-fluorocytosine (5-FC) dramatically inhibited the growth of preestablished murine bladder tumor-2 tumors. A single course of 5-FC treatment resulted in a 50% animal survival in mice exposed to RCR-CD compared with a 0% survival in all controls over a 70-day follow-up period. CONCLUSIONS: Intravesically administered RCR vectors can efficiently deliver genes to orthotopic bladder tumor without viral spread in distant organs. RCR-CD/5-FC suicide gene therapy promises to be a novel and potentially therapeutic modality for bladder cancer.

[Bladder carcinoma metastases presenting as intraperitoneal dissemination without local recurrence: a case report].

A 76-year-old woman presented with gross hematuria and was referred to our OPD. Cystoscopy showed broad-based papillary tumors on the left bladder wall. TUR-BT was performed and pathological diagnosis was grade 3 transitional cell carcinoma of pT1a. Although no intravesical tumor recurrence had been observed, a solid palpable mass was noted in the lower abdomen nine months after TUR-BT, and computed tomography suggested a large ovarian tumor. Subsequently performed was the operation at Gynecology, which revealed a large tumor involving the whole major omentum. Frozen sections of the tumor were diagnosed as transitional cell carcinoma metastases of the bladder cancer, and the final pathological report was the same. Although receiving 4 courses of M-VAC systemic chemotherapy after the operation, she died 14 months later. Autopsy disclosed intraperitoneal cancer dissemination and metastases without any intravesical nor left perivesical tumor recurrence, and it was suggested that the bladder tumor metastases occurred not by direct invasion but by either lymphatic or vascular mechanism in this case.