Dose modification in enzalutamide and abiraterone plus prednisolone for castration-resistant prostate cancer: A subanalysis from the ENABLE study for PCa.

BACKGROUND: A head-to-head comparison between enzalutamide (ENZ) and abiraterone plus prednisolone (ABI) revealed similar survival benefits for castration-resistant prostate cancer (CRPC) in the ENABLE study for PCa. Considering that a dose reduction of ENZ and ABI has demonstrated sufficient inhibitory ability of androgen receptor (AR) signaling, we analyzed the efficacy of modified doses of these agents in the ENABLE study for PCa. METHODS: This investigator-initiated, multicenter, randomized controlled trial that was conducted in Japan analyzed the prespecified survival endpoints, prostate-specific antigen (PSA) response rate ( ≥50% decline from baseline), and safety profile in patients treated with modified doses (ENZ ≤ 120 mg/day, ABI ≤ 750 mg/day) compared with those treated with a standard dose (ENZ 160 mg/day, ABI 1000 mg/day) as a starting dose. RESULTS: In total, 92 patients in each arm were treated and analyzed; 16 patients were treated with a modified dose in both the ENZ and ABI arms, respectively. Moreover, 32 patients treated with modified doses showed a significantly better time to PSA progression (TTPP) and overall survival (OS) compared with the 152 patients treated with a standard dose (HR 0.47, 95%CI 0.27-0.83, p = 0.0379, and HR 0.35, 95%CI 0.19-0.63, p = 0.0162). Despite a significantly longer TTPP in the modified ABI group than in the standard ABI group (HR 0.29, 95%CI 0.14-0.62, p = 0.0248), no significant difference was observed in the TTPP between the modified and standard ENZ groups (p = 0.5366). Furthermore, similar adverse event rates and grades were observed in each treatment dose group. CONCLUSIONS: The modified doses of ABI showed better TTPP than the standard dose of ABI and may be a potential treatment option for CRPC patients; however, its mechanism is still unclear, although its ability to suppress AR signaling is equivalent to that of a standard dose.

Longitudinal analysis of trifecta outcome in Japanese patients with prostate cancer following robot-assisted laparoscopic radical prostatectomy.

PURPOSE: To analyze the trifecta outcome (continence, potency, and cancer control) longitudinally using robot-assisted laparoscopic radical prostatectomy (RARP). METHOD: We prospectively obtained 1-year longitudinal Expanded Prostate Cancer Index Composite (EPIC) data (preoperative and at 3, 6, 9, and 12 months after RARP) from 291 patients who underwent RARP by a single surgeon. Continence was defined as the use of 'zero or one pads'. Potency was defined as the ability to achieve and maintain satisfactory erections firm enough for sexual activity or sexual intercourse. Continence and potency were subjectively determined from patient-reported outcomes (EPIC question nos. 5 and 18). The biochemical recurrence (BCR) rate was defined as two consecutive PSA levels of > 0.2 ng/mL after RARP. Outcomes of the pentafecta were complications and positive surgical margins combined with the trifecta outcomes. RESULTS: Trifecta was achieved in 4.6, 5.6, 8.1, and 9.6% of all patients at 3, 6, 9, and 12 months, respectively. Pentafecta rates were 2.3, 3.0, 5.1, and 6.1%, respectively. Trifecta rates in the nerve-sparing (NS) group were 12.5, 12.7, 18.9, and 23.6%, respectively. The BCR-free rates maintained a high level and were 94.4, 93.9, 93.9, and 90.9%, respectively. Continence rates were improved to 55.2, 75.5, 81.6, and 85.0%, while the potency rate was extremely low at 7.5, 7.8, 9.8, and 10.9%. Even in the NS group, potency rates remained low at 18.1, 18.6, 21.9, and 26.1%, respectively. CONCLUSION: This longitudinal analysis of trifecta outcomes may be beneficial and should be used when counseling patients with clinically localized PCa.

BUB1B Overexpression Is an Independent Prognostic Marker and Associated with CD44, p53, and PD-L1 in Renal Cell Carcinoma.

INTRODUCTION: BUB1 mitotic checkpoint serine/threonine kinase B encoded by BUB1B gene is a member of the spindle assembly checkpoint family. Several reports have demonstrated that overexpression of BUB1B is associated with cancer progression and prognosis. OBJECTIVE: This study aims to clarify the expression and function of BUB1B in renal cell carcinoma (RCC). METHODS: The expression of BUB1B was determined using immunohistochemistry and bioinformatics analysis in RCC. The effects of BUB1B knockdown on cell growth and invasion were evaluated. We analyzed the interaction between BUB1B, cancer stem cell markers, p53, and PD-L1 in RCC. RESULTS: In 121 cases of RCC, immunohistochemistry showed that 30 (25%) of the RCC cases were positive for BUB1B. High BUB1B expression was significantly correlated with high nuclear grade, T stage, and M stage. A Kaplan-Meier analysis showed that the high expression of BUB1B was associated with poor overall survival after nephrectomy. High BUB1B expression was associated with CD44, p53, and PD-L1 in RCC. Knockdown of BUB1B suppressed cell growth and invasion in RCC cell lines. Knockdown of BUB1B also suppressed the expression of CD44 and increased the expression of phospho-p53 (Ser15). In silico analysis showed that BUB1B was associated with inflamed CD8+, exhausted T-cell signature, IFN-γ signature, and the response to nivolumab. CONCLUSION: These results suggest that BUB1B plays an oncogenic role and may be a promising predictive biomarker for survival in RCC.

Longitudinal evaluation of the frequency of sexual intercourse and sexual activity in patients after nerve-sparing robot-assisted laparoscopic radical prostatectomy.

OBJECTIVE: To evaluate the frequency of sexual intercourse and sexual activity of patients after nerve-sparing (NS) robot-assisted laparoscopic radical prostatectomy (RARP). PATIENTS AND METHODS: We prospectively obtained 2-years longitudinal Expanded Prostate Cancer Index Composite (EPIC) and Sexual Health Inventory for Men (SHIM) score data from 99 patients. We classified the frequency of sexual intercourse and sexual activity as 'none', 'less than once a week', 'about once a week', 'several times a week', and 'daily'. RESULTS: The percentages of patients who took part in sexual activity before and at 3, 6, 9, 12, 18, and 24 months after NS RARP were 55.6%, 27.9%, 38.8%, 42.5%, 44.4%, 41.7%, and 42.1%, respectively. The percentages of patients who took part in sexual intercourse before and at 3, 6, 9, and 12, 18, and 24 months after NS RARP were 41.4%, 9.0%, 13.3%, 16.3%, 16.7%, 22.2%, and 23.7%, respectively. Preoperative sexual status was classified into two groups: those who had sexual intercourse or those who only had sexual activity except sexual intercourse. Sexual function (SF) was investigated longitudinally using the EPIC and SHIM data between the two groups. The SHIM data showed an improvement in SF in the sexual intercourse group, but did not do so in the sexual activity except sexual intercourse group. On the other hand, SF in the EPIC data might reflect the postoperative improvement of SF in the sexual activity except sexual intercourse group. CONCLUSION: There was a large discrepancy between the percentages of patients taking part in sexual intercourse and sexual activity; therefore, surveys of postoperative SF are recommended to include not only sexual intercourse but also sexual activity.

Recurrence- and progression-free survival in intermediate-risk non-muscle-invasive bladder cancer: the impact of conditional evaluation and subclassification.

OBJECTIVES: To assess the change in rates of recurrence-free survival (RFS) and progression-free survival (PFS) based on the duration of survival without recurrence or progression among patients with intermediate-risk (IR) non-muscle-invasive bladder cancer (NMIBC), and to examine the predictive factors for recurrence at different time points by assessing conditional RFS and PFS. PARTICIPANTS AND METHODS: A cohort of 602 patients treated with transurethral resection of bladder tumour and histopathologically diagnosed with IR NMIBC was included in this retrospective study. RESULTS: The conditional RFS rate at 1, 2, 3, 4 and 5 years improved with increased duration of RFS; however, the conditional PFS rate did not improve over time. Multivariable analyses showed that recurrent tumour, multiple tumours, tumour size (>3 cm), immediate postoperative instillation of chemotherapy, and administration of BCG were independent predictive factors for recurrence at baseline. The predictive ability of these factors disappeared with increasing recurrence-free survivorship. Subclassification of these patients with IR NMIBC into three groups using clinicopathological factors (recurrent tumour, multiple tumours, tumour size) demonstrated that the high IR group (two factors) had significantly worse RFS than the intermediate (one factor, P < 0.001) and low IR groups (no factor, P = 0.005) at baseline. This subclassification stratified conditional risk of RFS also at 1, 3 and 5 years, which provides the basis for distinct surveillance protocols among patients with IR NMIBC. CONCLUSION: Conditional survival analyses of patients with IR NMIBC demonstrate that RFS changes over time, while PFS does not change. These data support distinct surveillance protocols based on the subclassification of IR NMIBC.

Comparison of Chief Surgeons' and Assistants' Feelings of Fatigue Between Laparoendoscopic Single-site and Conventional Laparoscopic Adrenalectomy.

BACKGROUND: Our objective was to compare the surgical staff's feelings of fatigue between laparoendoscopic single-site adrenalectomy (LESS-A) and conventional laparoscopic adrenalectomy (CLA) before and after surgery. METHOD: Data were collected for surgical procedures performed between June 2011 and September 2017 (57 LESS-A and 37 CLA). Each procedure in both groups was performed by the same chief surgeon. The subjective fatigue feelings of the key members of the surgical team (chief surgeon, scopist, assistant surgeon) were assessed using the "Jikaku-sho shirabe" questionnaire, which contained questions about work-related feelings of fatigue. It consisted of 25 subjective items for 5 factors drawn from factor analysis (drowsiness, instability, uneasiness, local pain or dullness, and eyestrain). For each item, the participants were requested to estimate the intensity of their feelings using a five-point rating scale before and after surgery. RESULTS: There was no significant difference in operative time (p = 0.231) between the LESS-A and CLA procedure groups. For the chief surgeon, local pain or dullness (p = 0.603) and eyestrain (p = 0.086) were similar between the LESS-A and CLA procedures. The scopists and assistant surgeons in the LESS-A group did not suffer local pain or dullness (p = 0.793 and p = 0.240, respectively). They did, however, suffer more eyestrain than those in the CLA group (p = 0.001 and p = 0.001, respectively). CONCLUSION: Although LESS-A is generally considered to be a technically difficult procedure, the results of this study demonstrate that the feelings of physical fatigue are roughly equivalent between LESS-A and CLA procedures.

Tumor contact length of prostate cancer determined by a three-dimensional method on multiparametric magnetic resonance imaging predicts extraprostatic extension and biochemical recurrence.

OBJECTIVE: To evaluate the clinical benefit of tumor contact length as a predictor of pathological extraprostatic extension and biochemical recurrence in patients undergoing prostatectomy. METHODS: A total of 91 patients who underwent 3T multiparametric magnetic resonance imaging before prostatectomy from April 2014 to July 2019 were included. A total of 94 prostate cancer foci were analyzed retrospectively. We evaluated maximum tumor contact length, which was determined to be the maximum value in the three-dimensional directions, as a predictor of pathological extraprostatic extension and biochemical recurrence. RESULTS: A total of 19 lesions (20.2%) had positive pathological extraprostatic extension. Areas under the curves showed maximum tumor contact length to be a significantly better parameter to predict pathological extraprostatic extension than the Prostate Imaging Reporting and Data System (P = 0.002), tumor maximal diameter (P = 0.001), prostate-specific antigen (P = 0.020), Gleason score (P < 0.001), and clinical T stage (P < 0.001). Multivariate analysis showed maximum tumor contact length (P = 0.003) to be an independent risk factor for predicting biochemical recurrence. We classified the patients using preoperative factors (prostate-specific antigen >10, Gleason score >3 + 4 and maximum tumor contact length >10 mm) into three groups: (i) high-risk group (patients having all factors); (ii) intermediate-risk group (patients having two of three factors); and (iii) low-risk group (patients having only one or none of the factors). Kaplan-Meier curves showed that the high-risk group had significantly worse biochemical recurrence than the intermediate-risk group (P = 0.042) and low-risk group (P < 0.001). CONCLUSIONS: Our findings suggest that maximum tumor contact length is an independent predictor of pathological extraprostatic extension and biochemical recurrence. A risk stratification system using prostate-specific antigen, Gleason score and maximum tumor contact length might be useful for preoperative assessment of prostate cancer patients.

TUBB3 Is Associated with High-Grade Histology, Poor Prognosis, p53 Expression, and Cancer Stem Cell Markers in Clear Cell Renal Cell Carcinoma.

BACKGROUND: ßIII-Tubulin, encoded by the TUBB3 gene, is a microtubule protein. Several studies have shown that overexpression of TUBB3 is linked to poor prognosis and is involved in taxane resistance in some cancers. OBJECTIVE: The aim of this study was to analyze the expression and function of TUBB3 in clear cell renal cell carcinoma (ccRCC). METHODS: The expression of TUBB3 was determined using immuno-histochemistry in ccRCC specimens. The effects of TUBB3 knockdown on cell growth and invasion were evaluated in RCC cell lines. We analyzed the interaction between TUBB3, p53, cancer stem cell markers, and PD-L1. RESULTS: In 137 cases of ccRCC, immunohistochemistry showed that 28 (20%) of the ccRCC cases were positive for TUBB3. High TUBB3 expression was significantly correlated with high nuclear grade, high T stage, and N stage. A Kaplan-Meier analysis showed that high expression of TUBB3 was associated with poor overall survival after nephrectomy. In silico analysis also showed that high TUBB3 expression was correlated with overall survival. Knockdown of TUBB3 suppressed cell growth and invasion in 786-O and Caki-1 cells. High TUBB3 expression was associated with CD44, CD133, PD-L1, and p53 in ccRCC. We generated p53 knockout cells using the CRISPR-Cas9 system. Western blotting revealed that p53 knockout upregulated the expression of TUBB3. CONCLUSION: These results suggest that TUBB3 may play an oncogenic role and could be a potential therapeutic target in ccRCC.

Impact of radiological morphology of clinical T1 renal cell carcinoma on the prediction of upstaging to pathological T3.

OBJECTIVES: Previous studies have reported that cases with clinical T1 renal cell cancer upstaging to pathological T3 are a risk factor to predicting postoperative recurrence after partial nephrectomy. The aim of our study was to investigate the impact of the radiological morphology of the enhanced CT scan of clinical T1 renal cell cancer on predicting upstaging to pathological T3. METHODS: Three hundred sixty-seven cases with clinical T1 renal cell cancer diagnosed from enhanced CT scans were enrolled in this study. Based on the findings from the enhanced CT scan, the cases were classified into 'round', the margins of which were smooth and round; 'lobular', one or more findings of smooth dent and no spiky dent were identified on the margin of the tumor; and 'irregular', one or more spiky dent were identified on the margin of the tumor. The association of postoperative upstaging with these radiological morphology and other clinical characteristics of each case was analyzed. RESULTS: Eighteen cases (4.9%) pathologically upstaged to T3a. Two round case (0.7%), 3 lobular cases (10.0%) and 13 irregular cases (22.0%) pathologically upstaged (P < 0.001, round + lobular versus irregular). Four of 17 cases (23.5%) with hilar tumors pathologically upstaged, while 14 of 350 cases (4%) with tumors pathologically upstaged in other sites (P < 0.001). Multivariate analysis revealed that irregular case was an independent factor in predicting upstaging to pathological T3a (P < 0.001). CONCLUSIONS: Evaluation of the radiological morphology of clinical T1 renal cell cancer based on enhanced CT scans is useful for predicting pathological upstaging.

Impact of Adrenalectomy on Cortisol-Producing Adenoma: Longitudinal Evaluation of Health-Related Quality of Life following Laparoscopic Adrenalectomy.

INTRODUCTION: There is increasing interest in evaluating the quality of life of patients with cortisol-producing adrenocortical adenoma (CPA). Our objective was to assess patient-reported health-related quality of life (HRQOL) in patients with CPA compared to non-CPA. METHODS: Between January 2012 and September 2015, a total of 24 and 62 patients who had laparoscopic adrenalectomy with CPA and non-CPA, respectively, were included in the study. General HRQOL was evaluated on Short Form 8 (SF-8) questionnaire. The SF-8 questionnaire was administered at preoperative baseline and at 3, 6, 9, 12, 18, and 24 months after adrenalectomy. The impact of changing 2 measures of the summary score on the physical component summary (PCS) and mental component summary (MCS) score of SF-8 was evaluated in prospective and longitudinal studies. RESULTS: The baseline PCS score was significantly lower in the CPA than in the non-CPA group (43.6 vs. 49.0; p = 0.0075). Thereafter, the PCS score was significantly lower in the CPA group at 3, 6, 9, and 12 months postoperatively. The PCS score increased in the CPA group with no significant difference between both groups at 18 months (48.1 vs. 50.2; p = 0.1202) and 24 months (48.0 vs. 50.8; p = 0.3625) postoperatively. However, the baseline MCS score was not significantly different between the CPA and non-CPA group. The MCS score in both groups gradually increased with no significant differences between the groups at any time points after surgery. The PCS score was not significantly improved at all postoperative points than the baseline score in the CPA and non-CPA group. The MCS score was significantly improved than the baseline score from 6 months postoperatively only in the CPA group. CONCLUSION: Our research suggests that laparoscopic adrenalectomy may contribute to improving the physical and mental function in HRQOL.

Magnetic resonance imaging/transrectal ultrasonography fusion targeted prostate biopsy finds more significant prostate cancer in biopsy-naïve Japanese men compared with the standard biopsy.

OBJECTIVE: To assess the clinical benefits of magnetic resonance imaging/transrectal ultrasound fusion-targeted biopsy for biopsy-naïve Japanese men. METHODS: Between February 2017 and August 2018, 131 biopsy-naïve men who underwent targeted biopsy together with 10-core systematic biopsy at Hiroshima University Hospital were retrospectively investigated. Multiparametric magnetic resonance imaging findings were reported based on Prostate Imaging Reporting and Data System version 2. RESULTS: The overall cancer detection rates per patient were 69.5% in systematic biopsy + targeted biopsy cores, 61.1% in systematic biopsy cores and 61.1% in targeted biopsy cores. The detection rates for clinically significant prostate cancer were 43.5% in targeted biopsy cores and 35.9% in systematic biopsy cores (P = 0.04), whereas the detection rates for clinically insignificant prostate cancer were 17.6% and 25.2% respectively (P = 0.04). Lesions in the peripheral zone were diagnosed more with clinically significant prostate cancer (54.8% vs 20.7%, P < 0.001) and International Society of Urological Pathology grade (3.2 vs 2.7, P = 0.02) than that in the inner gland. Just 4.2% (3/71) of Prostate Imaging Reporting and Data System category 2 and 3 lesions in the middle or base of the inner gland were found to have clinically significant prostate cancer. The cancer detection rate per core was 42.3% in targeted biopsy cores, whereas it was 17.9% in systematic biopsy cores (P < 0.001). CONCLUSIONS: Targeted biopsy is able to improve the diagnostic accuracy of biopsy in detection of clinically significant prostate cancer by reducing the number of clinically insignificant prostate cancer detections compared with 10-core systematic biopsy in biopsy-naïve Japanese men. In addition, the present findings suggest that patients with Prostate Imaging Reporting and Data System category 2 or 3 lesions at the middle or base of the inner gland might avoid biopsies.

Current status of prognostic factors in patients with metastatic renal cell carcinoma.

In recent years, the induction of novel agents, including molecular-targeted agents and immune checkpoint inhibitors, have dramatically changed therapeutic options and their outcomes for metastatic renal cell carcinoma. Several prognostic models based on the data of patients with metastatic renal cell carcinoma treated with targeted agents or cytokine therapy have been useful in real clinical practice. Serum or peripheral blood markers related to inflammatory response have been reported to be associated with their prognosis or therapeutic efficacy. In addition to them, investigation for novel predictive factors that represent the efficacy of agents, the risk of adverse events and the prognosis are required for the advance of therapeutic strategies. The present review discusses the conventional prognostic models and clinical factors, and recent advances of the identification of some of the most promising molecules as novel biomarkers for metastatic renal cell carcinoma.

TUBB3 Reverses Resistance to Docetaxel and Cabazitaxel in Prostate Cancer.

Recent studies have reported that TUBB3 overexpression is involved in docetaxel (DTX) resistance in prostate cancer (PCa). The aim of this study was to clarify the role of TUBB3 in DTX and cabazitaxel (CBZ) resistance, and cross-resistance between DTX and CBZ in PCa. We analyzed the effect of TUBB3 knockdown on DTX and CBZ resistance and examined the interaction between TUBB3 and PTEN. We also investigated the role of phosphoinositide 3-kinases (PI3K) inhibitor (LY294002) in DTX and CBZ resistance. TUBB3 expression was upregulated in DTX-resistant and CBZ-resistant cells. TUBB3 knockdown re-sensitized DTX-resistant cells to DTX and CBZ-resistant cells to CBZ. Additionally, TUBB3 knockdown re-sensitized DTX-resistant cell lines to CBZ, indicating that TUBB3 mediates cross-resistance between DTX and CBZ. Knockdown of TUBB3 enhanced PTEN expression, and PTEN knockout enhanced TUBB3 expression. LY294002 suppressed TUBB3 expression in DTX-resistant and CBZ-resistant cell lines. LY294002 re-sensitized DTX-resistant cell lines to DTX and CBZ-resistant cell lines to CBZ. These results suggest that TUBB3 is involved in DTX resistance and CBZ resistance. A combination of LY294002/DTX and that of LY294002/CBZ could be potential strategies for PCa treatment.

Preoperative risk classification using neutrophil-lymphocyte ratio and hydronephrosis for upper tract urothelial carcinoma.

BACKGROUND: To improve the prediction of outcomes in patients who will undergo radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC), we examined the preoperative prognostic factors and established a risk classification model. METHODS: A total of 148 patients who underwent RNU without history of neo-adjuvant chemotherapy between 1999 and 2016 in Hiroshima University Hospital were retrospectively reviewed. Associations between preoperative/clinicopathological factors and outcomes including cancer-specific survival (CSS) and recurrence-free survival (RFS) were assessed. We specifically looked at neutrophil-lymphocyte ratio (NLR) due to growing evidence on its predictive role in cancer prognosis prediction. RESULTS: Preoperative elevated neutrophil-lymphocyte ratio (pre-op NLR, ≥3.0) and hydronephrosis (≥grade 2) were associated with advanced pathological stage; and were identified as independent predictive factors of shorter CSS and RFS in univariate and multivariate analysis. We classified the patients in three groups using preoperative factors and found that the 5-year CSS was 94.5, 75.9 and 44.7% and the 5-year RFS was 74.3, 57.6 and 28.7% in the low-risk group (neither pre-op NLR nor hydronephrosis), intermediate-risk group (either pre-op NLR or hydronephrosis) and high-risk group (pre-op NLR and hydronephrosis), respectively. High-risk group had significantly worse CSS (P = 0.0172) and RFS (P = 0.0014) than intermediate-risk group and low-risk group (CSS (P < 0.0001) and RFS (P < 0.0001)). CONCLUSIONS: Elevated pre-op NLR and hydronephrosis were identified as independent prognostic factors in patients with UTUC. These simple preoperative factors can stratify three prognostic groups and may help urologists in clinical decision-making before RNU.

Enzalutamide versus abiraterone as a first-line endocrine therapy for castration-resistant prostate cancer (ENABLE study for PCa): a study protocol for a multicenter randomized phase III trial.

BACKGROUND: Both enzalutamide and abiraterone have demonstrated improved radiographic progression-free and overall survival for castration-resistant prostate cancer (CRPC) compared with placebo controls before docetaxel treatment in phase III studies. These oral agents target androgen and androgen receptor signaling and are thought to be less toxic than chemotherapy. Cross-resistance to these agents was recently reported because of their similar mechanism of action, and it is important to assess which agent is more effective to use initially for CRPC. METHODS/DESIGN: The present study is a phase III, investigator-initiated, multicenter, head-to-head, randomized controlled trial investigating enzalutamide vs. abiraterone as a first-line treatment for CRPC patients. Patients will be randomly assigned to an enzalutamide or an abiraterone treatment group. The primary endpoint is the time to prostate-specific antigen progression. The target sample size is set at 100 patients per group (total, 200 patients). The study duration is 5 years, and the duration for recruitment is 2 years and 6 months. DISCUSSION: Thus far, there have been no prospective head-to-head studies comparing enzalutamide and abiraterone. This ENABLE study will clarify which agent should be prioritized for CRPC patients and enable clinicians to decide the appropriate treatment before chemotherapy. TRIAL REGISTRATION: University hospital Medical Information Network (UMIN) Center identifier UMIN000015529 . Registrated 11/1/2014.

Laparoendoscopic single-site surgeries: A multicenter experience of 469 cases in Japan.

OBJECTIVE: To report on a multi-institutional series of non-robotic urological laparoendoscopic single-site surgery in Japan. METHODS: Consecutive cases of laparoendoscopic single-site surgery carried out between February 2009 and December 2012 at nine academic institutions were included. We examined the surgical outcomes, including conversion and complications rates. RESULTS: Four hundred and sixty-nine cases were included in the analysis. The most common procedure was adrenalectomy (n = 177) and the second most common procedure was radical nephrectomy (n = 143). The procedures also included nephroureterectomy (n = 40), living donor nephrectomy (n = 40), pyeloplasty (n = 30), urachal remnant excision (n = 9), simple nephrectomy (n = 7), radical prostatectomy (n = 6) and others (n = 17). The access sites included umbilicus (n = 248, 53%) and other sites (n = 221, 47%). A transperitoneal approach was used in 385 cases (82%), and retroperitoneal approach in 84 cases (18%). The median operation time of all procedures was 198 min. Conversion to reduced port surgery, conventional laparoscopy, or open surgery was noted in 27 cases (5.8%), 12 cases (2.6%), and two cases (0.4%), respectively, with an overall conversion rate of 8.7%. Intraoperative complications occurred in 10 cases (2.1%). Post-operative complications were noted in 29 cases (6.2%), including five major complications (1.1%). No mortality was recorded in this series. CONCLUSIONS: Non-robotic laparoendoscopic single-site surgery is technically feasible and safe for various urologic diseases in Japan. Furthermore, urological laparoendoscopic single-site surgery is a promising minimally invasive surgical option that is feasible for experienced urological surgeons in intermediate-volume centers as well as high-volume centers.

The impact of change in serum C-reactive protein level on the prediction of effects of molecular targeted therapy in patients with metastatic renal cell carcinoma.

OBJECTIVES: To investigate the impact of pretreatment serum C-reactive protein (CRP) level and its change after targeted therapy on the anti-tumour effect of targeted agents in patients with metastatic renal cell carcinoma (mRCC). PATIENTS AND METHODS: The serum CRP level in 190 cases of molecular targeted therapy for mRCC was measured before starting the prescription of molecular targeted agents and when computed tomography showed the maximum effect. Patients in which the pretreatment CRP level was ≥0.5 mg/dL were classified into a 'higher-CRP' group and others into a 'lower-CRP' group. The higher-CRP group was further classified into two subgroups, i.e. those whose serum CRP level decreased after molecular targeted therapy ('decreased-CRP' subgroup), and those whose level did not decrease after therapy ('non-decreased-CRP' subgroup). All patients were also classified according to their other clinical details and progression-free survival (PFS) rates of each subgroup were compared. RESULTS: Of the 190 patients, 97 were categorised as lower CRP and 93 as higher CRP, with 50 and 43 patients in the higher-CRP group further categorised as decreased- and non-decreased-CRP subgroups, respectively. For the maximum effects of the targeted therapy, determined based on the Response Evaluation Criteria In Solid Tumors (RECIST) criteria, in the lower-CRP group, significantly more patients had a complete response (CR) and partial response (PR) (P = 0.002) and significantly fewer had progressive disease (PD) (P < 0.001) vs the higher-CRP group. In the higher-CRP group, significantly fewer patients had PD in the decreased-CRP subgroup (P < 0.001) than those in the non-decreased-CRP subgroup. The 2-year PFS rate for the lower-CRP group (39.1%) was significantly better vs the decreased-CRP subgroup (21.2%; P = 0.013) and significantly better vs the non-decreased CRP subgroup (0%; P < 0.001). Multivariate analyses in the higher-CRP group revealed that decreased CRP was an independent predictive factor for PFS (P = 0.002, hazard ratio 2.454, 95% confidence interval 1.404-4.290). CONCLUSION: A decrease of CRP and pretreatment CRP levels show promise as a novel predictive factor for anti-tumour effects in patients treated with molecular targeted therapy.

[Prostate cancer and metabolic syndrome].

The prevalence of metabolic syndrome (MS) is increasing in Japan because of westernization of diet and lifestyle. Previous epidemiological studies have demonstrated MS to relate with the malignant potential of prostate cancer (PCa) while its relationship to the risk of PCa has been still controversial. Several pathologies involved in MS, such as insulin resistance, abnormality of secreted adipokines, chronic inflammation, alteration of sex hormones, have been reported to affect the progression of PCa. Based on these evidences, clinical studies for PCa patients have been tried for suppressing the progression of PCa through the management of MS.

FGF19 promotes progression of prostate cancer.

BACKGROUND: Fibroblast growth factor (FGF) signaling pathways have been reported to play important roles in prostate cancer (PCa) progression. FGF19 is one of a subfamily of FGFs that circulate in serum and act in an endocrine manner. Our objective was to investigate its role in the progression of PCa. METHODS: The effect of FGF19 on the proliferation and epithelial-mesenchymal transition of LNCaP and PC3 cells was examined using MTT assay and Western blotting. Serum concentration of FGF19 was measured by ELISA in 209 patients with PCa, and the association between clinicopathological features and the presence of FGF19-positive cells in tissues derived from 155 patients who undergone radical prostatectomy was investigated. RESULTS: Under androgen-deprived conditions achieved by incubation in medium with FGF19, the expression of N-cadherin in LNCaP cells was enhanced, that of E-cadherin and caspase 3 was suppressed, and the viability of LNCaP and PC3 cells was significantly enhanced. Significantly higher levels of PSA were recorded in the group determined by immunohistochemistry staining to be FGF19-positive (P = 0.0046). The 5-year biochemical recurrence-free survival rate after radical prostatectomy was 46.4% in the FGF19-positive group and 70.0% in the FGF19-negative group (P = 0.0027). In multivariate analysis, the presence of FGF19-positive tissues was an independent factor for worse prognosis after radical prostatectomy (P = 0.0052). Serum FGF19 levels in high Gleason grade group were higher than that in low Gleason grade group (P = 0.0009). CONCLUSIONS: FGF19 might be associated with biochemical recurrence after radical prostatectomy by promoting cell proliferation and epithelial-mesenchymal transition of PCa.

Rat cavernous nerve reconstruction with CD133+ cells derived from human bone marrow.

INTRODUCTION: Erectile dysfunction remains a major complication after surgery of pelvic organs, especially after radical prostatectomy. AIM: The aim of this study was to assess the effect of endothelial progenitor cells on the regeneration of cavernous nerves in a rat injury model. METHODS: A 2 mm length of the right and left cavernous nerves of 8-week-old male nude rats were excised. Alginate gel sponge sheets supplemented with 1 × 10(4) CD133+ cells derived from human bone marrow were then placed over the gaps on both sides (CD group). The same experiments were performed on sham-operated rats (SH group), rats with only the nerve excision (EX group), and rats with alginate gel sheets placed on the injured nerves (AL group). MAIN OUTCOME MEASURES: Immunofluorescence staining and molecular evaluation were performed 4 days later. Functional and histological evaluations were performed 12 weeks later. RESULTS: The intracavernous pressure elicited by electrical stimulation and the neuronal nitric oxide synthase-positive area in surrounding tissues of the prostate was significantly greater in the CD group. Immunofluorescence microscopy showed that CD133+ cells were assimilated as vascular endothelial cells, and the real-time polymerase chain reaction showed upregulation of nerve growth factor and vascular endothelial growth factor in the alginate gel sponge sheets of the CD group. CONCLUSIONS: Transplantation of CD133+ cells accelerated the functional and histological recovery in this cavernous nerve injury model, and the recovery mechanism is thought to be angiogenesis and upregulation of growth factors. CD133+ cells could be an optional treatment for cavernous nerve injury after prostatectomy in clinical settings.