全並 賢二

BACKGROUND: Recently, various novel robotic systems have been put into clinical use. The aim of the present study was to assess the perioperative outcomes of robot-assisted radical prostatectomy (RARP) using the Hugo™ RAS system, one of brand-new robot-assisted surgical platforms. METHODS: We performed RARP with the Hugo™ RAS system in 13 cases of localized prostate cancer (PCa) between August 2023 and February 2024 at our hospital. The perioperative outcomes of these 13 patients were assessed. RESULTS: The median operative and console times were 197 (interquartile range [IQR], 187-228) and 134 min (IQR, 125-157), respectively. The median docking time was 7 min (IQR, 6-10), and the median estimated blood loss was 150 mL (IQR, 80-250). The vesical catheter was removed on postoperative day 6 in all cases. A positive surgical margin was observed in one patient (7.7%), and none experienced major perioperative complications, defined as Clavien-Dindo classification ≥3. The median postoperative length of stay was 8 days (IQR, 8-8.5). CONCLUSIONS: This was the first study to focus on RARP using the Hugo™ RAS system in Japan. Although further investigations should be conducted to assess the long-term oncological and functional outcomes, the Hugo™ RAS system could provide safe and favorable perioperative outcomes for patients with localized PCa undergoing RARP.

OBJECTIVES: The optimal indication and survival benefits of prophylactic urethrectomy (PU) during radical cystectomy remain unclear. Therefore, this study aims to evaluate the impact of urethra-preserving surgery (UPS) on oncological outcome including its recurrence patterns, and to establish an optimal urethral management strategy with a novel UPS technique in the robotic era. PATIENTS AND METHODS: We retrospectively analyzed 281 male patients with bladder cancer who received radical cystectomy (RC) (115 with and 166 without PU) at our institutions between 2010 and 2023. Subsequently, perioperative and oncological outcomes were assessed between propensity score-matched cohorts. RESULTS: Urethral recurrence (UR) occurred in 5 patients (5/166, 3.0%), all of whom underwent open-RC. Three among those (1.8%) with concomitant metastasis were died of cancer. There were no statistically significant differences between the PU and UPS groups in urethral-recurrence free survival (urethral-RFS) (P = .14), local-RFS (P = .59) and overall survival (OS) (P = .84) in the entire cohort. However, the UPS group showed significantly worse urethral-RFS (P = .008), local-RFS (P = .005) and OS (P = .03) in patients with high-risk of UR. Analysis of recurrence patterns revealed that UPS in high-risk patients significantly increased local recurrence (25.8% vs. 5.0%, P = .02). Conversely, a novel robotic-UPS technique demonstrated significantly favorable perioperative outcomes, comparable local-RFS (P = .79) and OS (P = .16) without UR (0/134, 0%) when compared to robotic-PU. Robotic-UPS also exhibited significantly better local-RFS (P =.007) and OS (P < .001) than open-UPS. CONCLUSIONS: UR-related death was rare and PU did not show a survival benefit for the entire cohort. However, inappropriate UPS in patients at high-risk of UR may increase local recurrence which might be responsible for poor survival after UPS rather than disease progression derived from UR. The robotic-UPS has the potential to reduce unnecessary PU, urethral and local recurrence without compromising survival.

INTRODUCTION: Postoperative Legionella pneumonia is very rare. CASE PRESENTATION: A 71-year-old male patient with prostate cancer (cT2bN0M0) underwent a robotic-assisted radical prostatectomy. On the 5th postoperative day, the patient developed chills and a fever of 39.2°C. Chest radiography revealed decreased permeability in the right middle lung field, leading to the diagnosis of postoperative pneumonia. Antimicrobial therapy was initiated immediately. Blood tests on postoperative day 10 revealed mild liver function abnormalities, electrolyte abnormalities, and a markedly elevated inflammatory response. Legionella pneumonia was suspected based on blood sample results and systemic symptoms, such as diarrhea and nausea. Furthermore, Legionella antigens were detected in the patient's urine, prompting further administration of levofloxacin. The patient's subsequent clinical course was favorable. CONCLUSION: When bacterial pneumonia fails to respond to antimicrobial therapy and systemic symptoms develop, atypical pneumonia, caused by pathogens such as Legionella pneumophila, should be considered even in cases of postoperative pneumonia.

OBJECTIVE: To evaluate the safety and efficacy of robot-assisted radical cystectomy using an intracorporeal ileal conduit in older compared to younger patients. METHODS: We retrospectively analyzed 122 patients who underwent robot-assisted radical cystectomy with an intracorporeal ileal conduit at Fujita Health University Hospital and Fujita Health University Okazaki Medical Center between 2012 and 2022. Patients were categorized into two groups: older (age ≥ 75 years; n = 53) and younger (age < 75 years; n = 69). Perioperative outcomes, complications, recurrence-free survival, cancer-specific survival, and overall survival were compared between the cohorts. RESULTS: The groups had no significant differences in perioperative outcomes, such as estimated blood loss, operative time, and blood transfusion rate. However, hospital stay was longer in the older patients than in the younger group (19 vs. 16 days; p < 0.001). The 30-day minor and major complication rates were 33.3% and 13.0%, respectively, for the younger group and 50.9% and 9.4% for the older group (p = 0.11). Urinary tract infection and bowel ileus were the most common complications in both groups. No significant differences were observed in recurrence-free survival, cancer-specific survival, and overall survival between the groups (p = 0.58, p = 0.75, and p = 0.78), and subgroup analysis in ≥cT3 revealed the older group tended to have poorer cancer-specific survival and overall survival (p = 0.07 and p = 0.01). Multivariate analysis indicated that older age was not associated with high-grade complications and cancer-specific survival. CONCLUSIONS: Robot-assisted radical cystectomy with an intracorporeal ileal conduit is a safe and effective treatment option for older patients.

For patients with testicular tumors who need the surgical management, open retroperitoneal lymph node dissection (O-RPLND) is considered the gold standard treatment. However, recently, robot-assisted RPLND (R-RPLND) has gained popularity as a minimally invasive therapy alternative to O-RPLND and laparoscopic RPLND. Here, we report the case of a 32-year-old man presenting with a left testicular teratoma with several enlarged left para-aortic lymph nodes. After the orchiectomy, the patient underwent R-RPLND with an operation time of 279 min, console time of 189 min, bleeding volume of 59 mL, and no significant complications, resulting in a successful outcome. To the best of our knowledge, this is the first reported case of R-RPLND in Japan. Based on our experience, R-RPLND may provide safe and effective outcomes; however, further research is required before the widespread implementation of this technique.

BACKGROUND: Recently, robot-assisted surgery has been widely used to treat several urological cancers. Robot-assisted radical nephrectomy (RARN) was approved by the health insurance system in April 2022; however, RARN with inferior vena cava tumor thrombectomy (IVCTT) is still challenging. Also, its safety and feasibility have not yet been established owing to lack of literature, especially in Japan. CASE DESCRIPTION: We performed RARN with IVCTT in four patients between April 2022 and March 2023 at Fujita Health University Hospital. To reduce the risk of tumor embolism and major hemorrhage, an "IVC-first, kidney-last" robotic technique was developed. The safety and feasibility of RARN with IVCTT were evaluated by assessing the perioperative outcomes. Three women and one man were enrolled in this study. The median age was 72 years, and the tumor was on the right side in all cases. According to the Mayo Clinic thrombus classification, two patients were classified as level I, and the others were classified as level II. The two patients at level I did not undergo presurgical treatments, whereas the others at level II underwent presurgical treatments, which were combinations of tyrosine kinase inhibitors and immune-checkpoint inhibitors. The median operation and console times were 341 and 247 min, respectively. The median bleeding volume was 577 mL, and no complications beyond grade III of the Clavien-Dindo classification were observed. The median length of postoperative hospital stay was 10 days. CONCLUSIONS: Although the sample size was relatively small, we demonstrated the safety and feasibility of RARN with IVCTT in the Japanese population.

This study aimed to assess the risks and benefits of selective clamping in robot-assisted partial nephrectomy (RAPN). We retrospectively analyzed 372 patients who had undergone RAPN at our hospital between July 2010 and March 2021. After propensity score matching between the full and selective clamping groups, perioperative outcomes and postoperative preservation ratio of the estimated glomerular filtration rate (eGFR) were compared at 6 and 12 months of follow-up. After propensity score matching, we evaluated 47 patients from each group. While no significant differences were observed in surgical time, warm ischemia time, or incidence rates of all grades of complications between the two cohorts, the estimated blood loss (EBL) was significantly lower in the full clamping group than in the selective clamping group (30 vs. 60, p = 0.046). However, no significant intergroup differences were observed in the postoperative preservation ratio of eGFR at 6 or 12 months of follow-up (full clamping 94.0% vs. selective clamping 92.7%, p = 0.509, and full clamping 92.0% vs. selective clamping 91.6%, p = 0.476, respectively). Selective clamping resulted in higher EBL rates than did full clamping in RAPN. However, selective clamping provided no renal functional advantage over full clamping in our propensity-score-matched cohort.

Alanine-serine-cysteine transporter 2 (ASCT2) has been associated with increased levels of metabolism in various malignant tumors. However, its biological significance in the proliferation of prostate cancer (PCa) cells remains under investigation. We used the cBioPortal database to assess the effect of ASCT2 expression on the oncological outcomes of 108 PCa patients. To evaluate the function of ASCT2 in castration-sensitive PCa (CSPC) and castration-resistant PCa (CRPC), LNCaP cells and the ARV7-positive PCa cell line, 22Rv1, were assessed using cell proliferation assays and Western blot analyses. The ASCT2 expression level was associated with biochemical recurrence-free survival after prostatectomy in patients with a Gleason score ≥ 7. In vitro experiments indicated that the growth of LNCaP cells after combination therapy of ASCT2 siRNA and enzalutamide treatment was significantly reduced, compared to that following treatment with enzalutamide alone or ASCT2 siRNA transfection alone (p < 0.01, 0.01, respectively). After ASCT2 inhibition by siRNA transfection, the growth of 22Rv1 cells was significantly suppressed as compared with negative control siRNA via downregulation of ARV7 both in fetal bovine serum and androgen-deprivation conditions (p < 0.01, 0.01, respectively). We demonstrated that ASCT2 inhibition significantly reduced the proliferation rates of both CSPC and CRPC cells in vitro.

OBJECTIVES: To evaluate the risk factors for postoperative ileus in patients who underwent robot-assisted radical cystectomy with intracorporeal urinary diversion. METHODS: We retrospectively analyzed 78 patients with bladder cancer who underwent robot-assisted radical cystectomy with intracorporeal urinary diversion at Fujita Health University between 2011 and 2021. Baseline characteristics and perioperative outcomes were compared between the cohorts with and without ileus. Logistic regression analysis was used to identify the risk factors for postoperative ileus. RESULTS: Out of the 78 patients included in this study, 20 (25.6%) developed postoperative ileus. The ileus cohort was associated with a significantly lower Geriatric-8 score (P = 0.003) and a higher rate of previous abdominal/pelvic surgery (P = 0.04) compared with those of the nonileus cohort. Significantly longer intestinal tract reconstruction time, hospital stay, time to mobilization, fluid intake, solid intake, flatus, and stool were observed in the ileus cohort. According to the results of the logistic regression analysis, the Geriatric-8 sum (P = 0.009), time to mobilization (P = 0.03), and time to fluid intake (P = 0.004) were independent predictors of postoperative ileus. In the model predicting postoperative ileus, the area under the receiver operating characteristic curve was 0.716, and the cutoff value of the Geriatric-8 sum was 13. CONCLUSIONS: Early mobilization and fluid intake and low Geriatric-8 scores were significant risk factors for postoperative ileus. Preoperative Geriatric-8 evaluation is a useful tool for predicting postoperative ileus. Comprehensive enhanced recovery after surgery, including key components, may help bowel recovery and prevent subsequent ileus.

To assess the perioperative and short-term functional outcomes of robot-assisted partial nephrectomy (RAPN) with intraoperative navigation using an ultra-high-resolution computed tomography (UHR-CT) scanner, we retrospectively analyzed 323 patients who underwent RAPN using an UHR-CT or area-detector CT (ADCT). Perioperative outcomes and the postoperative preservation ratio of estimated glomerular filtration rate (eGFR) were compared. After the propensity score matching, we evaluated 99 patients in each group. Although the median warm ischemia time (WIT) was less than 25 min in both groups, it was significantly shorter in the UHR-CT group than in the ADCT group (15 min vs. 17 min, p = 0.032). Moreover, the estimated blood loss (EBL) was significantly lower in the UHR-CT group than in the ADCT group (33 mL vs. 50 mL, p = 0.028). However, there were no significant intergroup differences in the postoperative preservation ratio of eGFR at 3 or 6 months of follow-up (ADCT 91.8% vs. UHR-CT 93.5%, p = 0.195; and ADCT 91.7% vs. UHR-CT 94.0%, p = 0.160, respectively). Although no differences in short-term renal function were observed in intraoperative navigation for RAPN in this propensity score-matched cohort, this study is the first to demonstrate that UHR-CT resulted in a shorter WIT and lower EBL than ADCT.

Objective: This study aimed to compare the perioperative and long-term functional outcomes between robot-assisted partial nephrectomy (RAPN) and open partial nephrectomy (OPN) in Japanese patients. Methods: We retrospectively analyzed 242 patients who underwent either RAPN or OPN between 2007 and 2017 at our hospital. Propensity score matching was carried out between the two groups at a ratio of 1:1. Perioperative outcomes and postoperative estimated glomerular filtration rates (eGFR) were compared at one and three years of follow-up. Results: After propensity score matching, we evaluated 39 patients from each group. The ischemia duration of the RAPN group was significantly shorter than that of the OPN group (18 vs. 24, p < 0.001). Moreover, the estimated blood loss (EBL) was significantly lower in the RAPN group than in the OPN group (50 vs. 174, p < 0.001). However, there were no significant differences in the postoperative eGFR between the two groups at one or three years of follow-up (OPN 54.8 vs. RAPN 61.2, p = 0.109, and OPN 54.8 vs. RAPN 55.5, p = 0.262, respectively). Conclusion: RAPN resulted in shorter ischemia durations and lower rates of EBL than did OPN; however, no differences in long-term renal function were observed between RAPN and OPN in our propensity-score matched Japanese cohort.

PURPOSE: The incidence of secondary bladder cancer after treatment for localized prostate cancer (PCa) remains unclear. In this study, PCa cases treated with brachytherapy (BT) were evaluated to assess the incidence of a second malignancy of bladder cancer in a Japanese cohort. MATERIALS AND METHODS: Overall, 969 patients treated with BT at our hospital between July 2006 and January 2019 were included in the study cohort. The incidence and predictors of secondary bladder cancer were also assessed. RESULTS: The incidence of secondary bladder cancer was 1.5% (n = 14). Of the seven factors (age, pretreatment PSA, Gleason score, cTNM stage, prostate volume, total activity, and combined external beam), prostate volume and total activity showed significant differences between the cohorts with and without secondary bladder cancer (P = .03 and P = .001, respectively). Upon comparison of the seven parameters for the 969 patients treated with BT, we found that only the total activity factor was affected by the incidence of secondary bladder cancer in the multivariate analysis (P = .007). CONCLUSION: The incidence of secondary bladder cancer was evaluated after BT for PCa. Total activity was associated with the incidence of secondary bladder cancer in Japanese patients who received BT.

BACKGROUND: To compare perioperative and long-term oncological outcomes and recurrence patterns between robot-assisted radical cystectomy with intra-corporeal urinary diversion (iRARC) and open radical cystectomy (ORC). METHODS: We retrospectively analyzed 177 bladder cancer patients who received iRARC or ORC at Fujita Health University between 2008 and 2020. Our primary endpoint was long-term oncological outcomes. As a secondary endpoint, we examined perioperative outcomes, complications, and recurrence patterns. These outcome measures were compared between the propensity score (PS)-matched cohorts. RESULTS: PS-matched analysis resulted in 60 matched pairs from iRARC and ORC groups. The iRARC cohort was associated with significantly longer operative time (p = 0.02), lower estimated blood loss (p < 0.001), lower blood transfusion rate (p < 0.001), shorter length of hospital stay (p < 0.001), fewer overall complications (p = 0.03), and lower rate of postoperative ileus (p = 0.02). There was no statistically significant difference between iRARC and ORC in 5-year RFS (p = 0.46), CSS (p = 0.63), and OS (p = 0.71). RFS and CSS were also comparable, even in locally advanced (≥ cT3) disease. Multivariate analysis identified lymphovascular invasion as a robust predictor of RFS, CSS, and OS. The number of recurrence was similar between the groups, while extra-pelvic lymph nodes were more frequent in iRARC than that in ORC (22.7% vs. 7.7%). CONCLUSIONS: iRARC has favorable perioperative outcomes, fewer complications, and comparable long-term survival outcomes, including locally advanced (≥ cT3) disease, compared to that in ORC. Our results need to be validated in prospective randomized clinical trials.

Indoleamine 2,3-dioxygenase 1 (IDO1) is a key enzyme associated with immunomodulation through its regulation of the tryptophan-kynurenine (Kyn) pathway in advanced cancers, including metastatic renal cell carcinoma (mRCC). However, the failure of IDO1 inhibitors when used in combination with immune checkpoint inhibitors (ICIs), as observed in clinical trials, raises a number of questions. This study aimed to investigate the association of tryptophan 2,3-dioxygenase (TDO) and IDO1 with cancer development and resistance to immunotherapy in patients with RCC. In our analysis of RCC tissue samples, tissue Kyn levels were elevated in advanced-stage RCC and correlated well with TDO expression levels in RCC tumor cells. In patients with mRCC, TDO rather than IDO1 was expressed in RCC tumor cells, showing a strong association with Kyn expression. Furthermore, immunohistochemical staining of TDO was strongly associated with the staining intensity of forkhead box P3, as well as ICI therapy response and survival in patients with mRCC. Our study is the first to show that TDO expression in tumor tissues is associated with progression and survival, confirming its potential as a predictive biomarker of primary resistance to immunotherapy in patients with mRCC. Our findings suggest that strategies aimed at inhibiting TDO, rather than IDO1, in combination with ICI therapy may aid in the control of mRCC progression.

Objectives: To evaluate the outcomes of robot-assisted partial nephrectomy (RAPN) in cystic renal tumors. Materials and Methods: We retrospectively analyzed patients who underwent RAPN for either cystic (n = 46) or solid (n = 271) renal tumors at Fujita Health University between 2010 and 2019. Cystic renal tumors were diagnosed using cross-sectional imaging. Perioperative, oncologic, and functional outcomes were assessed. Results: The median follow-up periods were 38, 41, and 37 months in the total, cystic, and solid groups, respectively. Most patient characteristics were similar among both groups, while the median age of the cystic group was significantly lower than that of the solid group (p = 0.02). Most perioperative variables and complications were comparable between the two groups. There was no significant difference between the groups in perioperative renal function. The estimated glomerular filtration rate preservation rates were 93.1% and 89.2% in the cystic and solid groups, respectively (p = 0.17). The cystic group showed a higher benign histology rate (19.6% vs 7%) and lower Fuhrman grade than the solid group (24.3% vs 15.1% in grade 1, and 73% vs 81.3% in grade 2), although there was no statistically significant difference between the two groups. In the solid group, 10 patients (3.7%) experienced recurrence, and 2 patients (0.7%) died of renal-cell carcinoma, while none of the patients with cystic tumors experienced recurrence. There was no statistically significant difference between the cystic and solid tumors with respect to 5-year recurrence-free survival (p = 0.18), cancer-specific survival (p = 0.55), and overall survival (p = 0.35). Conclusions: RAPN for cystic renal tumors appears to be safe and feasible with perioperative, long-term functional and oncologic outcomes comparable with those in solid tumors. RAPN can be a safe and effective surgical option for cystic renal tumors.

OBJECTIVES: To investigate whether a deep learning model from magnetic resonance imaging information is an accurate method to predict the risk of urinary incontinence after robot-assisted radical prostatectomy. METHODS: This study included 400 patients with prostate cancer who underwent robot-assisted radical prostatectomy. Patients using 0 or 1 pad/day within 3 months after robot-assisted radical prostatectomy were categorized into the "good" group, whereas the other patients were categorized into the "bad" group. Magnetic resonance imaging DICOM data, and preoperative and intraoperative covariates were assessed. To evaluate the deep learning models from the testing dataset, their sensitivity, specificity and area under the receiver operating characteristic curve were analyzed. Gradient-weighted class activation mapping was used to visualize the regions of deep learning interest. RESULTS: The combination of deep learning and naive Bayes algorithm using axial magnetic resonance imaging in addition to clinicopathological parameters had the highest performance, with an area under the receiver operating characteristic curve of 77.5% for predicting early recovery from post-prostatectomy urinary incontinence, whereas machine learning using clinicopathological parameters only achieved low performance, with an area under the receiver operating characteristic curve of 62.2%. The gradient-weighted class activation mapping methods showed that deep learning focused on pelvic skeletal muscles in patients in the good group, and on the perirectal and hip joint regions in patients in the bad group. CONCLUSIONS: Our results suggest that deep learning using magnetic resonance imaging is useful for predicting the severity of urinary incontinence after robot-assisted radical prostatectomy. Deep learning algorithms might help in the choice of treatment strategy, especially for prostate cancer patients who wish to avoid prolonged urinary incontinence after robot-assisted radical prostatectomy.

OBJECTIVES: To assess the impact of two cycles of neoadjuvant chemotherapy (NAC) in patients who underwent nephroureterectomy for high-risk cN0M0 upper tract urothelial carcinoma (UTUC), and to evaluate the efficacy of NAC in patients with localised disease (≤cT2). PATIENTS AND METHODS: We retrospectively analysed patients with high-risk cN0M0 UTUC who received NAC followed by surgery, compared with a matched cohort who underwent initial surgery at Fujita Health University during 2005-2019. Baseline and tumour characteristics, overall survival (OS), cancer-specific survival (CSS), and recurrence-free survival (RFS) were compared between the cohorts. Cox proportional hazards models were used to identify predictors of survival. RESULTS: There were 117 and 67 patients in the study group and the control group, respectively. Significantly higher pathological downstaging (pDS) and lower lymphovascular invasion (LVI) were observed in the study group than in the control group (48% vs 22%, P = 0.008 and 29% vs 46%, P = 0.045, respectively). The NAC group had significantly better 5-year OS (79% vs 53%, P = 0.003), 5-year CSS (84% vs 66%, P = 0.008), and 5-year RFS (80% vs 61%, P = 0.001) than the control group. The OS benefit of NAC was observed even in patients with localised (≤cT2) disease (P = 0.019). Patients with LVI showed significantly worse CSS both in pathologically locally advanced (≥pT3) and in localised (≤pT2) tumours (P = 0.048 and P = 0.018, respectively). Multivariate analysis identified LVI, NAC, and pDS as independent predictors of OS. Male sex and post-NAC LVI were identified as predictors of worse survival in patients who underwent NAC. CONCLUSIONS: Two cycles of NAC improved the survival of patients with high-risk UTUC, even in patients with localised disease. Although two cycles of NAC appear to be effective in cN0M0 high-risk UTUC including localised disease, additional larger sample size multicentre prospective studies comparing short-course NAC regimens followed by surgery and surgery alone are required.

INTRODUCTION: Robot-assisted partial nephrectomy (RAPN) is emerging as an effective treatment oncologically and functionally for clinically localized renal tumors. However, RAPN in high-complexity tumors with a Preoperative Aspects and Dimensions Used for an Anatomical score ≥10 remains challenging. In this study, the feasibility of RAPN for high-complexity tumors was assessed. METHODS: The study cohort consisted of 177 cases with clinically localized renal cell carcinoma who had undergone RAPN at our hospital from July 2010 to February 2018. They were assessed for perioperative parameters and trifecta achievement (ie, negative surgical margins, warm ischemia time <25 minutes, and no complications). RESULTS: Among the 177 cases who had undergone RAPN, 60 had high-complexity tumors, and 117 had non-high-complexity (ie, intermediate- or low-complexity) tumors. There were no significant differences in the operative and console times between the cohorts, but estimated intraoperative blood loss was much lower in the non-high-complexity group. Although the average warm ischemia time was less than 25 minutes in both groups, it was significantly shorter in the non-high-complexity group. Trifecta achievement rates significantly differed between the high- and non-high-complexity groups (68.3% vs 86.3%). Comparisons of four operative parameters (ie, BMI, tumor size, endophytic properties, and hilar tumor) using univariate analysis in the 60 high-complexity tumor cases showed that BMI and tumor size were independent factors (P = 0.05 and 0.018, respectively). In multivariate analysis, tumor size was the only factor directly associated with trifecta achievement (P = 0.029). CONCLUSION: The trifecta achievement rate was significantly lower in the high-complexity group. Only tumor size affected trifecta achievement during RAPN in cases with high-complexity tumors (Preoperative Aspects and Dimensions Used for an Anatomical score ≥10).

© 2020 Background: Disease progression in castrate-resistant prostate cancer (PCa) is most commonly driven by the reactivation of androgen receptor (AR) signaling and involves AR splice variants including ARV7. Materials and methods: We used the ARV7-positive PCa cell line, 22Rv1, to study the relationship of the PCa marker α-methylacyl-CoA racemase (AMACR), AR, and ARV7 in PCa. Results: Docetaxel addition but not AMACR inhibition decreased the proliferation of 22Rv1 cells. The combination of AMACR inhibition and docetaxel treatment resulted in a maximum reduction of cell proliferation. The Western blotting analysis revealed that both AR and ARV7 expression were significantly decreased with the use of charcoal-stripped serum following AMACR inhibition and docetaxel treatment. AMACR inhibition and docetaxel treatment in the charcoal-stripped serum condition reduced the proliferation of 22Rv1, possibly via the downregulation of the heat shock protein 27. Conclusion: Using cell proliferation and Western blot analysis, we demonstrated that AMACR inhibition and docetaxel treatment, under androgen deprivation conditions, significantly reduced the proliferation of ARV7 positive cancer cells and decreased the levels of AR and ARV7 expression, possibly via downregulation of heat shock protein 27.

BACKGROUND: Regulatory T cells (Tregs) play important roles in the suppression of immune responses, including antitumor immune responses. C-C chemokine receptor 4 (CCR4) is highly expressed on effector Tregs, and anti-CCR4 antibody is attracting attention as a novel immunotherapeutic agent for solid tumors. This study aimed to evaluate the expression of CCR4-positive Tregs (CCR4+Tregs) in prostate cancer and estimate the clinical potential of CCR4-targeting therapy for prostate cancer. METHODS: A total of 15 radical prostatectomy (RP) specimens and 60 biopsy specimens from individuals diagnosed with prostate cancer were analyzed to evaluate the infiltration of CCR4+Tregs in prostate cancer. The relationships between the number of CCR4+Tregs and clinical parameters were investigated in RP and biopsy specimens. Moreover, the total number of Tregs, CCR4+Tregs, and T cells and the ratio of CCR4+Tregs to Tregs and T cells in biopsy specimens were compared between patients with poor prognosis who progressed to castration-resistant prostate cancer (CRPC) within 12 months (n = 13) and those with good prognosis who were stable with hormone-sensitive prostate cancer over 12 months (n = 47). Furthermore, biopsy specimens were divided into two groups: low and high CCR4+Treg expression groups and the prognosis was compared between them. RESULTS: There was a higher expression of CCR4+Tregs in RP specimens with a higher (≥8) Gleason score than in those with a lower (<8) Gleason score (P = .041). In biopsy specimens, 65.9% Tregs were positive for CCR4. The number of CCR4+Tregs positively correlated with clinical stage (P < .001) and Gleason score (P = .006). The total number of Tregs and CCR4+Tregs significantly increased in the poor prognosis group compared with that in the good prognosis group (P = .024 and .01, respectively). Furthermore, patients with lower CCR4+Treg expression levels showed a significantly longer time to progression to CRPC (not reached vs 27.3 months; P < .001) and median survival time (not reached vs 69.0 months; P = .014) than those with higher expression levels. CONCLUSIONS: CCR4+Tregs are highly infiltrated in the prostate tissue of patients with poor prognosis with potential to progress to CRPC. Furthermore, the degree of infiltration of CCR4+Tregs is related to the prognosis of prostate cancer.

Robot-assisted radical prostatectomy (RARP) is one of the most widely used procedures for localized prostate cancer (PCa). In the present study, the clinical and oncological outcomes of RARP with bilateral or unilateral nerve sparing (NS) for D'Amico high-risk PCa cases were assessed. Among the 767 cases who received RARP at Fujita Health University Hospital between August 2009 and December 2016, 230 high-risk PCa cases who were observed for >6 months comprised the retrospective study cohort. Bilateral NS was performed with the bilateral neurovascular bundle in eight, unilateral in 125 and none in 97 cases. Perioperative parameters [surgery time, console time, estimated blood loss, pathological stage, positive lymph node metastases [pN (+)], and surgical margin positivity] did not exhibit significant differences between the NS and non-NS cohorts. During a median follow-up time of 25 months, the 1- and 3-year biochemical recurrence (BCR)-free survival rates in the NS/non-NS cohorts were 84.4/86.0 and 72.7/75.0%, respectively. There were no significant differences identified between the two groups at each time period. According to multivariate analysis, the resection margin was an important factor for time to BCR, regardless of the NS technique used. The numbers of pads used daily at 3 and 6 months after RARP between the NS/non-NS cohorts were 1.1/1.5 and 0.6/1.0, respectively (P=0.045 and P=0.009), suggesting that the NS technique resulted in significantly improved outcomes regarding urinary continence recovery. In selected high-risk PCa cases, the NS technique resulted in equivalent oncological outcomes and improved urinary continence compared with the non-NS RARP group.

Docetaxel (DOC) is one of the most effective chemotherapeutic agents against castration‑resistant prostate cancer (CRPC). Despite an impressive initial clinical response, the majority of patients eventually develop resistance to DOC. In tumor metabolism, where tumors preferentially utilize anaerobic metabolism, lactate dehydrogenase (LDH) serves an important role. LDH controls the conversion of pyruvate to lactate, with LDH‑A, one of the predominant isoforms of LDH, controlling this metabolic process. In the present study, the role of LDH‑A in drug resistance of human prostate cancer (PC) was examined by analyzing 4 PC cell lines, including castration‑providing strains PC3, DU145, LNCaP and LN‑CSS (which is a hormone refractory cell line established from LNCaP). Sodium oxamate (SO) was used as a specific LDH‑A inhibitor. Changes in the expression level of LDH‑A were analyzed by western blotting. Cell growth and survival were evaluated with a WST‑1 assay. Cell cycle progression and apoptotic inducibility were evaluated by flow cytometry using propidium iodide and Annexin V staining. LDH expression was strongly associated with DOC sensitivity in PC cells. SO inhibited growth of PC cells, which was considered to be caused by the inhibition of LDH‑A expression. Synergistic cytotoxicity was observed by combining DOC and SO in LN‑CSS cells, but not in LNCaP cells. This combination treatment induced additive cytotoxic effects in PC‑3 and DU145 cells, caused cell cycle arrest in G2‑M phase and increased the number of cells in the sub‑G1 phase of cell cycle in LN‑CSS cells. SO promoted DOC induced apoptosis in LN‑CSS cells, which was partially caused by the inhibition of DOC‑induced increase in LDH‑A expression. The results strongly indicated that LDH‑A serves an important role in DOC resistance in advanced PC cells and inhibition of LDH‑A expression promotes susceptibility to DOC, particularly in CRPC cells. The present study may provide valuable information for developing targeted therapies for CRPC in the future.

Androgen receptor (AR) transcriptional activity contributes to prostate cancer development and castration resistance. The growth and survival pathways driven by AR remain incompletely defined. Here, we found PDCD4 to be a new target of AR signaling and a potent regulator of prostate cancer cell growth, survival, and castration resistance. The 3' untranslated region of PDCD4 is directly targeted by the androgen-induced miRNA, miR-21. Androgen treatment suppressed PDCD4 expression in a dose responsive and miR-21-dependent manner. Correspondingly, AR inhibition dose-responsively induced PDCD4 expression. Using data from prostate cancer tissue samples in The Cancer Genome Atlas (TCGA), we found a significant and inverse correlation between miR-21 and PDCD4 mRNA and protein levels. Higher Gleason grade tumors exhibited significantly higher levels of miR-21 and significantly lower levels of PDCD4 mRNA and protein. PDCD4 knockdown enhanced androgen-dependent cell proliferation and cell-cycle progression, inhibited apoptosis, and was sufficient to drive androgen-independent growth. On the other hand, PDCD4 overexpression inhibited miR-21-mediated growth and androgen independence. The stable knockdown of PDCD4 in androgen-dependent prostate cancer cells enhanced subcutaneous tumor take rate in vivo, accelerated tumor growth, and was sufficient for castration-resistant tumor growth. IMPLICATIONS: This study provides the first evidence that PDCD4 is an androgen-suppressed protein capable of regulating prostate cancer cell proliferation, apoptosis, and castration resistance. These results uncover miR-21 and PDCD4-regulated pathways as potential new targets for castration-resistant prostate cancer.

OBJECTIVES: To evaluate the impact of a novel biopsy instrument that extends the length of the side-notch on the detection of prostate cancer in transrectal needle biopsy. METHODS: We collaborated with a biopsy needle manufacturer and developed a novel biopsy instrument (PRIMECUT II long-notch type) with a 25-mm side-notch length and 28-mm stroke length to take longer tissue cores. The sampled core length, cancer detection rate, pain and complications of 489 patients who underwent transrectal biopsy using the long-notch needle were compared with those of 469 patients who underwent biopsy using a normal instrument with a 19-mm side-notch length and 22-mm stroke length. RESULTS: The mean length of tissue taken by the long-notch needle was significantly longer than that of tissue taken by the normal-notch needle (16.3 vs 22.4 mm, P < 0.001). The overall cancer detection rate was 42.0% for the normal-notch needle and 51.1% for the long-notch needle (P = 0.005). In patients with a prostate volume of 20-40 mL, the cancer detection rate for the long-notch needle was especially higher than that for the normal-notch needle (74.2% vs 47.5%, P < 0.001). Multivariate analysis showed that the long-notch needle improved cancer detection significantly (odds ratio 1.702, P < 0.001). There were no differences of pain during biopsy and complication between the two groups. CONCLUSIONS: The novel biopsy instrument with a 25-mm side-notch can take longer tissue samples safely and has a significantly higher rate of prostate cancer detection in transrectal biopsy.

The present study examined the clinical pharmacokinetics of pazufloxacin in prostate tissue and estimated the probability of target attainment for tissue-specific pharmacodynamic goals related to treating prostatitis using various intravenous dosing regimens. Patients with prostatic hypertrophy received prophylactic infusions of pazufloxacin (500 mg, n = 23; 1000 mg, n = 25) for 0.5 h prior to transurethral prostate resection. Drug concentrations in plasma (0.5-5 h) and prostate tissue (0.5-1.5 h) were measured by high-performance liquid chromatography and used for subsequent noncompartmental and three-compartmental analysis. Monte Carlo simulation was performed to evaluate the probability of target attainment of a specific minimum inhibitory concentration (MIC) in prostate tissue: the proportion that achieved both area under the drug concentration over time curve (AUC)/MIC = 100 and maximum concentration (Cmax)/MIC = 8. Prostatic penetration of pazufloxacin was good with mean Cmax ratios (prostate tissue/plasma) of 0.82-0.99 and for AUC, 0.80-0.98. The probability of reaching target MIC concentrations in prostate tissue was more than 90% for dosing schedules of 0.25 mg/L for 500 mg every 24 h (500 mg daily), 0.5 mg/L for 500 mg every 12 h (1000 mg daily), 1 mg/L for 1000 mg every 24 h (1000 mg daily), and 2 mg/L for 1000 mg every 12 h (2000 mg daily). Importantly, the 2000 mg daily regimen of pazufloxacin produced a profile sufficient to have an antibacterial effect in prostate tissue against clinical isolates of Escherichia coli and Klebsiella pneumonia with MIC values less than 2 mg/L.

OBJECTIVES: To compare various methods for measuring tumor extent in prostate biopsy specimens to identify small-volume prostate cancer. METHODS: A total of 100 radical prostatectomy specimens were retrospectively analyzed. Receiver operating characteristic analysis was used to compare the abilities of prostate-specific antigen density, and four measures of tumor extent in prostate biopsy specimens - positive core number, greatest percentage of cancer in a single core, greatest length of cancer in cores and total length of cancer in cores - to identify small volume prostate cancer. Four definitions of insignificant cancer volume were used in this analysis: index and total tumor volume <0.5 mL, index tumor volume <1.3 mL and total tumor volume <2.5 mL. Multivariate analysis was also used to evaluate variables for predicting small-volume prostate cancer. RESULTS: Total length of cancer in cores had the highest areas under the curve of all the measures defining small-volume prostate cancer: index tumor volume <0.5 mL (0.855), total tumor volume <0.5 mL (0.877), index tumor volume <1.3 mL (0.784) and total tumor volume <2.5 mL (0.818). On multivariate analysis total length of cancer in cores was an independent predictive factor for prostate cancers with index tumor volume <0.5 mL (P < 0.001), <1.3 mL (P < 0.001) and total tumor volume <0.5 mL (P < 0.001), respectively. CONCLUSION: Our data suggest that total length of cancer in cores is the optimal measure of tumor extent in prostate biopsy specimens for identifying small-volume prostate cancer.

Radiation therapy is a highly effective tool for treating all stages of prostate cancer, from curative approaches in localized disease to palliative care and enhanced survival for patients with distant bone metastases. The therapeutic index of these approaches may be enhanced with targeted radiation-sensitizing agents. Aptamers are promising nucleic acid delivery agents for short interfering RNAs (siRNA) and short hairpin RNAs (shRNA). We have previously developed a radiation-sensitizing RNA aptamer-shRNA chimera that selectively delivers DNA-PK targeting shRNAs to prostate-specific membrane antigen (PSMA) positive cells in the absence of transfection reagents. Although these chimera are effective, their synthesis requires in vitro transcription and their evaluation was limited to intratumoral administration. Here, we have developed a second-generation aptamer-siRNA chimera that can be assembled through the annealing of three separate chemically synthesized components. The resulting chimera knocked down DNA-PK in PSMA-positive prostate cancer cells, without the need of additional transfection reagents, and enhanced the efficacy of radiation-mediated cell death. Following intravenous injection, the chimera effectively knocked down DNA-PK in established subcutaneous PSMA-positive tumors. Systemic treatment with these radiation-sensitizing agents selectively enhanced the potency of external beam radiation therapy for established PSMA-positive tumors.

This study aimed to investigate the penetration of PIPC-TAZ into human prostate, and to assess effectiveness of PIPC-TAZ against prostatitis by evaluating site-specific PK-PD. Patients with prostatic hypertrophy (n = 47) prophylactically received a 0.5 h infusion of PIPC-TAZ (8:1.2-0.25 g or 4-0.5 g) before transurethral resection of the prostate. PIPC-TAZ concentrations in plasma (0.5-5 h) and prostate tissue (0.5-1.5 h) were analyzed with a three-compartment PK model. The estimated model parameters were, then used to estimate the drug exposure time above the minimum inhibitory concentration for bacteria (T > MIC, the PD indicator for antibacterial effects) in prostate tissue for six PIPC-TAZ regimens (2.25 or 4.5 g; once, twice, three times or four times daily; 0.5 h infusions). Prostate tissue/plasma ratio of PIPC was about 36% both for the maximum drug concentration (Cmax) and the area under the drug concentration-time curve (AUC). Against MIC distributions for isolates of Escherichia coli, Klebsiella species and Proteus species, regimens of 4.5 g twice daily and 2.25 g three times daily achieved a >90% probability of attaining the bacteriostatic target for PIPC (30% T > MIC) in prostate tissue; regimens of 4.5 g three times daily and 2.25 g four times daily achieved a >90% probability of attaining the bactericidal target for PIPC (50% T > MIC) in prostate tissue. However, against Pseudomonas aeruginosa isolates, none of the tested regimens achieved a >90% probability. PIPC-TAZ is appropriate for the treatment of prostatitis from the site-specific PK-PD perspective.

OBJECTIVES: To compare perioperative, oncological and functional outcomes of robot-assisted radical prostatectomy between experienced and novice open radical prostatectomy surgeons in a laparoscopically naïve center with a limited caseload. METHODS: Six surgeons carried out robot-assisted radical prostatectomy in 154 patients, which were divided into the following three groups: group 1 (n = 90), including patients operated on by a surgeon with experience in both open radical prostatectomy and robot-assisted radical prostatectomy; group 2 (n = 36), including patients operated on by two surgeons with experience in open radical prostatectomy only; and group 3 (n = 28), including patients operated on by three surgeons with limited experience in both open radical prostatectomy or robot-assisted radical prostatectomy. RESULTS: Groups 2 and 3 did not differ significantly in their median values of external blood loss (P = 0.165) or console time (P = 0.103). Positive surgical margin rates for pT2 patients were also similar in these two groups: 21.2% (7/33) in group 2 and 22.7% (5/22) in group 3 (P = 0.894). Kaplan-Meier analysis showed that 12 months after robot-assisted radical prostatectomy the prostate-specific antigen-free rate for pT2 patients was 96.0% in group 2 and 100% in group 3, but the pad-free continence rate was just 91.0% in group 1, 88.0% in group 2 and 75.5% in group 3 (group 1 vs group 3, P = 0.037; group 2 vs group 3, P = 0.239). The major complication rate after robot-assisted radical prostatectomy was 3.3% (3/90) in group 1, 11.1% (4/36) in group 2 and 17.9% (5/28) in group 3 (group 1 vs group 3, P = 0.008; group 2 vs group 3; P = 0.441). CONCLUSIONS: Robot-assisted radical prostatectomy offers satisfactory postoperative outcomes even when carried out by surgeons with limited experience in open radical prostatectomy.

We report a case of neuroendocrine carcinoma in a diverticulum of the bladder. A 65-year-old Japanese woman visited our hospital with the chief complaint of gross hematuria. Cystoscopy revealed a non-papillary broad-based tumor in a diverticulum of the posterior wall. She underwent transurethral resection of bladder tumor (TURBT) and subsequently total cystectomy with ileal conduit on the diagnosis of an invasive urothelial carcinoma. There was no residual tumor in the surgical specimen. Immunohistochemistry of TUR specimens showed positive synaptophysin, chromogranin A, CD56 and high ratio of positive Ki-67. Finally, it was diagnosed as a neuroendocrine carcinoma of the bladder. To our knowledge, this is the second case report of the neuroendocrine tumor or small cell carcinoma in a diverticulum of the urinary bladder in the Japanese literature.

Patients with progressive renal cell carcinoma who undergo sunitinib treatment, experience many adverse events (AEs), including thrombopenia and hypertension. Dose reduction or treatment discontinuation due to AEs makes it difficult to control the clinical condition. Therefore, patients' understanding regarding the basics of blood pressure (BP) measurement and how to deal with each AE are particularly important. Here we report whether or not pharmacist instructions help in order to increase patients' awareness of early AE management results in an improvement of treatment outcomes. The present study included 15 patients who were administered sunitinib. From the start of sunitinib treatment, pharmacists continuously provided drug administration guidance to the patients and confirmed their awareness and knowledge regarding AEs, symptom management, and drug adherence. The relative dose intensity (RDI) of 15 patients from week 1 to 24 after sunitinib treatment was calculated. Pharmaceutical interventions significantly improved patients' understanding of BP measurements and reference values, etc. Although the RDI was 67.3%-78.7%, there were no cases of discontinuation of administration or reduction of the dose caused by e.g. hypertension, hand and foot syndrome (HFS) and stomatitis. Pharmaceutical interventions improved patients' awareness of the management of AEs and adherence to sunitinib therapy. As a result, a high RDI was maintained, which may lead to prolonged survival. Therefore, our results suggest that early AE management provided by pharmacists is particularly important to assure the safety and efficacy of sunitinib therapy.

The aims of this study were to investigate the penetration of meropenem (MER) into human prostate tissue and to assess MER regimens for prostatitis by performing a site-specific pharmacokinetic/pharmacodynamic evaluation. Patients with prostatic hypertrophy (n=49) prophylactically received a 0.5-h infusion of MER (250 mg or 500 mg) before transurethral resection of the prostate. MER concentrations in plasma (0.5-5h) and prostate tissue (0.5-1.5h) were measured chromatographically. Concentration data were analysed pharmacokinetically with a three-compartment model and were used to estimate the drug exposure time above the minimum inhibitory concentration for bacteria (T>MIC, % of 24h) in prostate tissue, an indicator for antibacterial effects at the site of action. The prostate tissue/plasma ratio was 16.6% for the maximum drug concentration and 17.7% for the area under the drug concentration-time curve, irrespective of the dose. Against MIC distributions for clinical isolates of Escherichia coli, Klebsiella spp. and Proteus spp., 500 mg once daily achieved a >90% probability of attaining the bacteriostatic target (20% T>MIC) in prostate tissue, and 500 mg twice daily achieved a >90% probability of attaining the bactericidal target (40% T>MIC) in prostate tissue. However, against the Pseudomonas aeruginosa isolates, none of the tested regimens achieved a >90% probability of attaining the bacteriostatic or bactericidal targets.

Prostatic hypertrophy patients prophylactically received a 0.5-hour infusion of doripenem (250 or 500 mg) before transurethral resection of the prostate. Doripenem concentrations in plasma and prostate tissue were measured chromatographically, and analysed pharmacokinetically using a three-compartment model. The approved doripenem regimens were assessed based on the time above the minimum inhibitory concentration for bacteria (T>MIC, % of 24 hours), an indicator for antibacterial effects, at the prostate. The prostate tissue/plasma ratios were 17.3% for the maximum drug concentration and 18.7% for the area under the drug concentration-time curve, and they were irrespective of the dose. Against Escherichia coli and Klebsiella species isolates, 500 mg once daily achieved a >90% probability of attaining the bacteriostatic target (20% T>MIC) in prostate tissue, and 500 mg twice daily achieved a >90% probability of attaining the bactericidal target (40% T>MIC) in prostate tissue.

BACKGROUND: The aim was to retrospectively assess the results of treatment of upper urinary tract stones with the Sonolith vision manufactured by EDAP, and purchased in 2004. METHODS: The subjects were 226 Japanese patients who underwent extracorporeal shock wave lithotripsy (ESWL) alone as an initial treatment and could be followed up for at least 3 months, selected from 277 candidate patients who underwent this therapy between 2004 and 2006. Treatment effect was evaluated by kidney, ureter, and bladder X-ray or renal ultrasonography at 1 and 3 months after treatment. A stone-free status or status of stone fragmentation to 4 mm or smaller was considered to indicate effective treatment. RESULTS: At 3 months after treatment, the stone-free rate was 69.4% and the efficacy rate was 77.4% for renal stones, while these rates were 91.5 and 93.3%, respectively for ureteral stones. Assessment of treatment effect classified by the location of stones revealed a stone-free rate of 94.6% and an efficacy rate of 94.6% for lower ureteral stones (4.0 mm or smaller, 1 subject; 4.1-10.0 mm, 31 subjects; 10.1-20.0 mm, 5 subjects: number of treatment sessions, 1 or 2 sessions [mean: 1.03 sessions]). Complications of this therapy included renal subcapsular hematoma and pyelonephritis in 1 case each. CONCLUSIONS: ESWL with the Sonolith vision manufactured by EDAP produced a treatment effect equivalent to those achieved with other models of ESWL equipment. ESWL seems to be an effective first-line treatment also in patients who have lower ureteral stones 10 mm or larger but do not wish to undergo TUL, if measures such as suitable positioning of the patient during treatment are taken.

INTRODUCTION: It has been reported that immunoglobulin G4-related systemic disease can spread to nearly every organ, and often presents as an inflammatory mass or masses at those sites. In the kidney, this disease is often diagnosed after a radical or partial nephrectomy following the discovery of an inflammatory mass which is often suspected to be a malignant tumor. Here, we present a rare case of inflammatory pseudotumors of the kidney and the lung presenting as immunoglobulin G4-related disease, which were diagnosed by computed tomography-guided biopsies. CASE PRESENTATION: A 54-year-old Japanese man was referred to our hospital with suspected bilateral renal cancer, multiple lung metastases and autoimmune pancreatitis. His serum immunoglobulin G4 level was high. We used computed tomography-guided biopsies and histopathological examinations of the biopsied specimens to diagnose the tumors as immunoglobulin G4-related bilateral renal and lung inflammatory pseudotumors. Our patient was treated with oral prednisolone, and after one month of treatment, contrast-enhanced computed tomography demonstrated a general improvement, as noted by a reduction in size of the masses. CONCLUSION: Renal masses that are formed due to immunoglobulin G4-related disease require comprehensive diagnosis to prevent unnecessary surgical resections from being performed. Further consideration should be paid to immunoglobulin G4-related diseases in the future.

The aim of this study was to investigate the relationship between tissue concentrations and exposure times or therapeutic effect of an anthracycline anticancer drug, pirarubicin, in bladder cancer tissue after single intravesical administration against superficial bladder cancer. The concentrations of pirarubicin in tumor tissues and serum were measured at designated collection times after a single intravesical administration of pirarubicin (30 mg) in 22 patients with superficial bladder cancer. A wide range of concentrations of pirarubicin in bladder cancer tissue was observed (2.3-125 μg/g of tissue), although serum pirarubicin concentrations were not detected in any of the patients. Recurrence of superficial bladder cancer after transurethral resection of the bladder tumor (TUR-BT) was observed in 2 patients (9%). The concentration of pirarubicin in the tumor tissue tended to be higher as the exposure time increased. There was a weak relationship between the pirarubicin tissue concentration and tumor size. However, no significant relationship between tissue pirarubicin concentrations and the prophylactic effect against intravesical recurrence of bladder cancer after TUR-BT was observed. All patients had no adverse events, such as bladder irritation and local toxicity, caused by the treatment with pirarubicin. These findings suggest that prior to single intravesical administration of pirarubicin to patients with superficial bladder cancer the exposure time and tumor size should be considered.

Molecular targeting agents have become formidable anticancer weapons showing much promise against refractory tumors and functional peptides and are among the more desirable of these nanobio-tools. Intracellular delivery of multiple functional peptides forms the basis for a potent, non-invasive mode of delivery, providing distinctive therapeutic advantages. We examine the growth suppression efficiency of human renal cell carcinoma (RCC) by single-peptide targeting. We simultaneously introduced p16INK4a tumor suppressor peptides by Wr-T-mediated peptide delivery. Wr-T-mediated transport of p16INK4a functional peptide into 10 RCC lines, lacking expression of the p16INK4a molecule, reversed the specific loss of p16 function, thereby drastically inhibiting tumor growth in all but 3 lines by >95% within the first 96 h. In vivo analysis using SK-RC-7 RCC xenografts in nude mice demonstrated tumor growth inhibition by the p16INK4a peptide alone, however, inoculation of Wr-T and the p16INK4a functional peptide mixture, via the heart resulted in complete tumor regression. Thus, restoration of tumor suppressor function with Wr-T peptide delivery represents a powerful approach, with mechanistic implications for the development of efficacious molecular targeting therapeutics against intractable RCC.

It has not been elucidated whether certain types of M1b prostate cancer (M1b PC) are associated with a poor outcome. The present study retrospectively identified predictive factors related to the outcome of M1b PC. The subjects were 104 patients who attended our hospital and received a diagnosis of M1b PC. The observation period ranged from 4 to 122 months (median, 43 months). The parameters investigated were: T classification, N classification, Gleason score (GS), pretreatment prostate-specific antigen (PSA) level, extent of disease (EOD) grade, alkaline phosphatase (ALP), lactate dehydrogenase (LDH), calcium, and hemoglobin (Hb) levels, platelet count, and the status of HER-2 overexpression as determined with a Hercep Test(TM) Kit using initial needle biopsy specimens for diagnosis. Log-rank test and Cox univariate analysis identified the following factors with statistically significant differences: pretreatment PSA ≥ 192, N1, GS ≥ 8, EOD grade 3+4, high LDH, high ALP, low Hb, and HER-2 overexpression. Multivariate Cox proportional hazard analysis identified the factors GS ≥ 8, high LDH, and HER-2 overexpression with significant differences. The hazard ratio was 5.962, 2.465, and 2.907, respectively, and the probability value was P=0.0218, P=0.0207 and P=0.0090, respectively. When the subjects with GS ≥ 8, high LDH, and HER-2 over-expression were classified as the high-risk group, the 5-year cause-specific survival rate was 51.2, 29.6, and 20.0%, respectively. The present study showed that M1b PC patients with GS ≥ 8, high LDH, and HER-2 overexpression have a very poor outcome and thus, should be treated as a high-risk group requiring close follow-up.

BACKGROUND: We examined whether human epidermal growth factor-2(HER-2) overexpression could be a useful marker of outcome after hormone therapy in patients with M1b prostate cancer (PC). SUBJECTS AND METHODS: The subjects were 102 patients who were diagnosed with M1b PC at Aichi Medical University Hospital. HER-2 expression was determined by immunohistochemical (IHC) staining using initial needle biopsy specimens for diagnosis. The results were classified into four grades (0, 1+, 2+, 3+), and scores of 1+ or greater were considered overexpression and defined as positive. RESULTS: The results showed a rating of 0 in 72 subjects, 1+ in 10, 2+ in 14, and 3+ in 6; 30 subjects (29.4%) were classified as HER-2 positive. Comparison of clinical data of HER-2 positive and negative subjects obtained at baseline revealed many of the subjects with high-grade tumors by Gleason score were HER-2 positive (P = 0.030). The prostate-specific antigen (PSA) relapse was observed in 76 subjects and cause-specific death occurred in 44. A significant difference was observed only in the item HER-2 (negative vs. positive) by multivariate Cox proportional hazard analysis. The 5-year PSA relapse-free rate was 0% in subjects with HER-2 positive (26/30), and 43.9% in subjects with HER-2 negative (50/72, P = 0.0192). The 5-year cause-specific survival rate was 40.9% in subjects with HER-2 positive (30/102), and 67.3% in subjects with HER-2 negative (72/102, P = 0.0301). CONCLUSION: HER-2 overexpression as determined by IHC staining using needle biopsy specimens for diagnosis with M1b PC is a significant prognostic factor for PSA relapse after hormone therapy and unfavorable outcome.

It has not yet been determined whether certain types of prostate cancer with bone metastasis (M1b PC) are associated with a poor outcome. The present study retrospectively assessed the potential significance of various clinical data in predicting the outcome of M1b PC. The subjects were 104 patients who attended our hospital and received a diagnosis of M1b PC between January 1998 and December 2006. The age of the subjects ranged from 51 to 91 years (median 74). The observation period ranged from 4 to 122 months (median 43). The parameters investigated were T classification, N classification, Gleason score (GS), pre-treatment prostate-specific antigen (PSA) level, extent of disease (EOD) grade, alkaline phosphatase (ALP), lactate dehydrogenase (LDH), calcium and hemoglobin (Hb) levels and platelet count. The 5-year cause-specific survival rate was 56.6% and the 10-year cause-specific survival rate was 34.9%. Log-rank test and Cox univariate analysis identified the following factors with statistically significant differences: pre-treatment PSA level ≥192, N1, GS ≥8, EOD grade 3+4, high LDH, high ALP and low Hb. Multivariate Cox proportional hazard analysis identified the factors GS ≥8 and high LDH with significant differences. The hazard ratio was 4.967 and 2.728, respectively, and the probability value (P) was 0.029 and 0.004, respectively. When the subjects with GS ≥8 and high LDH were classified as the high-risk group, the 5-year cause-specific survival rate was 24.6%. The outcome was significantly poorer in this group (P<0.0001) than in the other group, which had a 5-year cause-specific survival rate of 67.7%. The present study showed that patients with M1b PC with GS ≥8 and high LDH have a very poor outcome and thus should be treated as a high-risk group requiring close follow-up.

Expression of HER-2 and COX-2 was determined to assess the potential of molecular-targeted therapy against human epidermal growth factor receptor-2 (HER-2) and cyclooxygenase-2 (COX-2) for the treatment of invasive bladder cancer. The subjects were 46 patients who attended Aichi Medical University Hospital between January 2001 and August 2008, underwent total cystectomy with a diagnosis of M0 bladder cancer, and received a pathological diagnosis of invasive transitional cell carcinoma of the urinary bladder (pT2-pT4). Expression of HER-2 and COX-2 was determined by immunohistochemical staining, and the results were interpreted by two pathologists by classifying HER-2 expression into four grades, and considering COX-2 positive when 10% or more of the tumor cells were stained. In HER-2 immunostaining, 10 subjects (21.7%) were positive, all of whom had a Grade 3 tumor. Staging classification identified 2 subjects (2/22, 9.1%) with pT2 stage, 3 (3/16, 18.8%) pT3 stage, and 5 (5/8, 62.5%) pT4 stage. There was a correlation between HER-2 positivity and tumor stage (P=0.007). Lymph node metastasis was detected in 13 subjects, 3 of them (3/8, 37.5%) with pN2 metastasis were HER-2 positive. The 5-year cause-specific survival rate was 51.4% for HER-2-positive subjects and 83.4% for HER-2-negative subjects. The outcome was poorer in HER-2-positive subjects, but the difference in survival rate was not statistically significant (P=0.218). In COX-2 immunostaining, 27 subjects (58.7%) were found to be positive. Three (3/4, 75.0%) showed a Grade 2 tumor and 24 (24/42, 57.1%) a Grade 3 tumor. Staging classification identified 13 subjects (13/22, 59.1%) with pT2 stage, 9 (9/16, 56.3%) pT3 stage, and 5 (5/8, 62.5%) pT4 stage. There was no correlation between COX-2 positivity and tumor grade or stage (P=0.488 and 0.089, respectively). Classification by the extent of lymph node metastasis revealed that 6 subjects (6/8, 75.0%) with pN2 were COX-2 positive. There was a correlation between COX-2 positivity and the extent (pN1 or pN2) of lymph node metastasis (P=0.008). The 5-year cause-specific survival rate was 84.0% for COX-2-positive subjects and 71.7% for COX-2-negative subjects. However, the difference in survival rate was not significant (P=0.407). Seven subjects (7/46, 15.2%) were positive for both HER-2 and COX-2, and there was no statistically significant correlation between the status of HER-2 expression and that of COX-2 expression (P=0.2195). The present study failed to show any association between HER-2 or COX-2 positivity and outcome in subjects with invasive bladder cancer. However, HER-2-positive subjects tended to have a poorer outcome. This finding suggests that molecular-targeted therapy against HER-2 could be an effective therapy. Further studies involving a larger number of subjects are required.

OBJECTIVE: We evaluated the efficacy and safety of M-VAC chemotherapy combined with mild hyperthermia, a new therapeutic strategy for advanced metastatic transitional cell carcinoma of the urothelium. SUBJECTS AND METHODS: The subjects were 12 patients diagnosed with advanced metastatic transitional cell carcinoma of the urothelium. For mild hyperthermia, the patients' oral temperature was elevated to about 38 degrees C by heating for 20 min and retaining the heat for 20 min with a far-infrared heater. The antitumor effect was evaluated according to the RECIST, while adverse drug reactions were assessed based on the NCI-CTC. RESULTS: The antitumor effect was rated as partial remission (PR) in 10 of the 12 patients and stable disease in 2 patients, with an efficacy rate of 83% (10/12). All 10 patients who had achieved PR received three courses of treatment. Of the 12 patients, 5 died during the observation period, with survival for 9-23 months (mean: 15.6 months). Adverse drug reactions included myelosuppression in all patients (Grade 3 in 4 patients, Grade 4 in 8), and gastrointestinal toxicity, such as nausea or vomiting, which was mild (Grade 0 in 2 patients, Grade 1 in 8, Grade 2 in 1, Grade 3 in 1). CONCLUSIONS: The results of the present study suggest that M-VAC chemotherapy combined with mild hyperthermia, which potentiates the anticancer effect and reduces adverse drug reactions such as gastrointestinal symptoms, is a useful and safe method for the treatment of advanced transitional cell carcinoma of the urothelium.

The standard operative procedure for ureteral transitional cell carcinoma is nephrouterectomy with partial cystectomy at the affected ureteral orifice. However, nephron-sparing surgery and endoscopic surgery and management have become common practice for low-grade and low-stage cases. We investigated the follow-up results of patients who underwent endoscopic surgery using the holmium:YAG laser, and evaluated its treatment effect. The patients were 4 men and 3 women aged from 68 to 87 years (mean: 74.7 years). Two were imperative cases and 5 were elective cases. The tumor size ranged from 8 to 25 mm (mean: 15.4 mm). Hydronephrosis was not found in any case, and urinary cytology was negative in all cases. Biopsy revealed 5 cases of grade 1, and 2 of grade 2. A Versa Pulse Select 80 laser generator, a 365-microm slim line laser fiber, and a rigid ureteroscope with 8F-point diameter were used. A 6F double J catheter was placed postoperatively for 3 weeks. Pulse energy was set at 0.5-1.0 J (mean: 0.8 J) with a frequency of 10 Hz. The total amount of energy was 0.9-11.22 KJ (mean: 2.89 KJ) and the operation time including ureteral stent placement was 20-97 min (mean: 66 min). Neither urinary tract perforation nor ureteral stricture associated with laser irradiation was observed. The postoperative follow-up period ranged from 23-88 months (mean: 67.8 months). Patients underwent urinary cytological examination once a month, and cystoscopy, retrograde pyelography and urethroscopy once every 3 months for 2 years, then once every 6 months thereafter. One patient developed tumor recurrence 23 months after surgery and received another laser treatment, but no recurrence has been observed in the other 6 patients (85.7%). Transurethral endoscopic surgery and management using the holmium:YAG laser is safe and effective nephron-sparing surgery for ureteral transitional cell carcinoma, and good long-term treatment results can be expected even in elective cases if the indications are carefully selected.