Auraptene Enhances AMP-Activated Protein Kinase Phosphorylation and Thereby Inhibits the Proliferation, Migration and Expression of Androgen Receptors and Prostate-Specific Antigens in Prostate Cancer Cells.

Citrus hassaku extract reportedly activates AMPK. Because this extract contains an abundance of auraptene, we investigated whether pure auraptene activates AMPK and inhibits proliferation using prostate cancer cell lines. Indeed, auraptene inhibited the proliferation and migration of LNCaP cells and induced phosphorylation of AMPK or its downstream ACC in LNCaP, PC3, and HEK-293 cells, but not in DU145 cells not expressing LKB1. In addition, the mTOR-S6K pathway, located downstream from activated AMPK, was also markedly suppressed by auraptene treatment. Importantly, it was shown that auraptene reduced androgen receptor (AR) and prostate-specific antigen (PSA) expressions at both the protein and the mRNA level. This auraptene-induced downregulation of PSA was partially but significantly reversed by treatment with AMPK siRNA or the AMPK inhibitor compound C, suggesting AMPK activation to, at least partially, be causative. Finally, in DU145 cells lacking the LKB1 gene, exogenously induced LKB1 expression restored AMPK phosphorylation by auraptene, indicating the essential role of LKB1. In summary, auraptene is a potent AMPK activator that acts by elevating the AMP/ATP ratio, thereby potentially suppressing prostate cancer progression, via at least three molecular mechanisms, including suppression of the mTOR-S6K pathway, reduced lipid synthesis, and AR downregulation caused by AMPK activation.

Significance of timing of therapeutic line on effectiveness of nivolumab for metastatic renal cell carcinoma.

Objectives: This study aimed to clarify the significance of therapeutic timing on the effectiveness of nivolumab for treating metastatic renal cell carcinoma. Marterials and methods: Fifty-eight patients with metastatic renal cell carcinoma treated with nivolumab monotherapy were retrospectively studied. Patients who were treated with nivolumab as second-line therapy were included in the second-line group, while the others were included in the later-line group. The clinicopathological characteristics, effects of nivolumab, and prognoses of these groups were compared. Results: Twenty and thirty-eight patients were included in the second-line and later-line groups, respectively. There were no significant differences in the distribution of International Metastatic Renal Cell Carcinoma Database Consotium risk and other clinicopathological characteristics between the 2 groups. The proportion of patients whose objective best response was progressive disease in the second-line group was significantly lower than that in the later-line group (15% vs. 50%, p = 0.0090). The 50% progression-free survival with nivolumab in the second-line group was significantly better than that in the later-line group (not reached and 5 months, p = 0.0018). Multivariate analysis showed that the second-line setting was an independent predictive factor for better progression-free survival (p = 0.0028, hazard ratio = 0.108). The 50% overall survival after starting nivolumab in the second-line and later-line groups was not reached and 27.8 months, respectively (p = 0.2652). Conclusions: The therapeutic efficacy of nivolumab as second-line therapy is expected to be better than that of later therapy.

ANXA10 Expression Is Inversely Associated with Tumor Stage, Grade, and TP53 Expression in Upper and Lower Urothelial Carcinoma.

INTRODUCTION: Urothelial carcinoma (UC) is a common type of malignant disease, but little is known about the diagnostic and prognostic markers of upper urinary tract urothelial cancer (UTUC) because of its rarity. To clarify the significance of ANXA10 in UTUC, we studied ANXA10 expression with immunohistochemistry (IHC). METHODS: The expression of ANXA10 was analyzed in the upper and lower urinary tract of UC by IHC in combination with The Cancer Genome Atlas (TCGA) data analysis. The association between ANXA10 expression and representative cancer-related molecules was also evaluated. RESULTS: ANXA10 expression was weak in normal upper tract urothelium but was positive in 39/117 (33%) UTUCs. ANXA10 was more frequently positive in tumors with pure UC (36%, p < 0.05), papillary morphology (50%, p < 0.01), low grade (G1/2: 57%, p < 0.01), and pTa/is/1 stage (55%, p < 0.01) than in those with histological variants (0%), nodular morphology (9%), G3 (16%), and pT2/3/4 (13%), respectively. ANXA10-positive patients showed better cancer-specific survival and progression-free survival than ANXA10-negative patients (p < 0.05). IHC showed that ANXA10 positivity was detected more in cases with the low expression of TP53 (p < 0.01) and Ki-67 labeling index <20% (p < 0.01). In TCGA dataset of muscle-invasive bladder cancer, higher ANXA10 expression correlated with papillary morphology, lower grade/stage, luminal papillary subtype, wild-type TP53, and FGFR3 gene mutation. CONCLUSION: We revealed that ANXA10 expression was increased during carcinogenesis and was observed more frequently in papillary UC of lower grade and stage. However, its expression decreased as cancer progressed. Therefore, the ANXA10 expression in UTUC might be clinically useful for decision-making.

Par14 interacts with the androgen receptor, augmenting both its transcriptional activity and prostate cancer proliferation.

BACKGROUND: Prostate cancer (PCa) is a major cause of cancer morbidity and mortality for men globally, and androgen signaling clearly drives its onset and progression. Androgen receptor (AR) regulation is complex and remains elusive, despite several studies tackling these issues. Therefore, elucidating the mechanism(s) underlying AR regulation is a potentially promising approach to suppressing PCa. METHODS: We report that Par14, one isoform of the prolyl isomerases homologous to Pin1, is a critical regulator of AR transcriptional activity and is essential for PCa cell growth. RESULTS: Par14 was shown to be overexpressed in PCa, based on analyses of deposited data. Importantly, overexpression of Par14 significantly enhanced androgen-sensitive LNCap cell growth. In contrast, silencing of Par14 dramatically decreased cell growth in LNCap cells by causing cell cycle arrest. Mechanistically, silencing of the Par14 gene dramatically induced cyclin-dependent kinase inhibitor p21 at both the mRNA and the protein level through modulating the localization of p53. In addition, suppression of Par14 in LNCap cells was shown to downregulate the expressions of androgen response genes, at both the mRNA and the protein level, induced by dihydrotestosterone. Par14 was shown to directly associate with AR in nuclei via its DNA-binding domain and augment AR transcriptional activity. CONCLUSION: Thus, Par14 plays a critical role in PCa progression, and its enhancing effects on AR signaling are likely to be involved in the underlying molecular mechanisms. These findings suggest Par14 to be a promising therapeutic target for PCa.

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.

Clinicopathological significance of claspin overexpression and its efficacy as a novel biomarker for the diagnosis of urothelial carcinoma.

We previously reported that claspin is a key regulator in the progression of gastric cancer and renal cell carcinoma. However, the clinicopathological significance of claspin in urothelial carcinoma (UC) has not been investigated. We analyzed the expression and distribution of claspin in UC cases by immunohistochemistry. In the non-neoplastic urothelium, the expression of claspin was either weak or absent, whereas UC tissues showed nuclear staining. The expression of claspin was detected in 58 (42%) of a total of 138 upper tract UC cases treated by radical nephroureterectomy without neoadjuvant chemotherapy. Claspin-positive UC cases were associated with nodular/flat morphology, variant histology, high tumor grade, high pathological T grade, and lymphatic and venous invasion. The expression of claspin was significantly associated with decreased progression-free survival and cancer-specific survival. In addition, claspin was co-expressed with Ki-67, PD-L1, HER2, EGFR, and p53 in consecutive tumor sections of UC. An immunohistochemical analysis of claspin in biopsy specimens revealed that strong to moderate claspin staining was more frequently observed in carcinoma in situ in comparison to dysplasia or the benign urothelium. Furthermore, immunocytochemistry for claspin on urine cytology slides demonstrated that the proportion of claspin-positive cells was significantly greater in high-grade UC than in benign cases. These results suggest that claspin may be a novel prognostic marker and a possible therapeutic target molecule for UC. Moreover, claspin could be a useful diagnostic biomarker of urothelial neoplasia.

Overexpression of claspin promotes docetaxel resistance and is associated with prostate-specific antigen recurrence in prostate cancer.

Although docetaxel (DTX) confers significant survival benefits in patients with castration-resistant prostate cancer (CRPC), resistance to DTX inevitably occurs. Therefore, clarifying the mechanisms of DTX resistance may improve survival in patients with CRPC. Claspin plays a pivotal role in DNA replication stress and damage responses and is an essential regulator for the S-phase checkpoint. CLSPN is an oncogenic gene that contributes to tumor proliferation in several human solid tumors. However, the clinical significance of claspin in prostate cancer (PCa) has not been examined. The present study aimed to elucidate the role of claspin and its relationship with DTX resistance in PCa. We immunohistochemically analyzed the expression of claspin in 89 PCa cases, of which 31 (35%) were positive for claspin. Claspin-positive cases were associated with higher Gleason score, venous invasion, and perineural invasion. Kaplan-Meier analysis showed that high claspin expression was related to poor prostate-specific antigen (PSA) relapse-free prognosis. In a public database, high CLSPN expression was associated with poor PSA relapse-free prognosis, Gleason score, T stage, lymph node metastasis, CRPC, and metastatic PCa. Claspin knockdown by siRNA decreased cell proliferation, upregulated DTX sensitivity, and suppressed the expression of Akt, Erk1/2, and CHK1 phosphorylation in DU145 and PC3 cell lines. Furthermore, claspin expression was much more upregulated in DTX-resistant DU145 (DU145-DR) than in parental DU145 cells. Claspin knockdown significantly upregulated the sensitivity to DTX in DU145-DR cells. These results suggest that claspin plays an important role in PCa tumor progression and DTX resistance.

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.

Change of preoperative symptoms of the late-onset hypogonadism syndrome after robot-assisted radical prostatectomy.

BACKGROUND: As prostate cancer (PCa) is a common cancer among older men, patients with PCa often show aging male symptoms (AMSs). This study aimed to investigate the preoperative AMSs of the late-onset hypogonadism (LOH) syndrome and the effects on them after robot-assisted radical prostatectomy (RARP). MATERIALS AND METHODS: One hundred eighty-eight patients who underwent RARP without androgen deprivation therapy were measured for serum free and serum total testosterone, and were preoperatively assessed for symptoms of the LOH syndrome using a questionnaire containing an AMS score. Patients with a preoperative AMS score higher than 37 and a serum free testosterone level lower than 8.5 pg/mL were classified as Group A, with the remaining classified as Group B. AMS scores were measured at 1, 3, 6, 9, and 12 months after surgery. RESULTS: Of the 188 patients, 49 and 139 patients were classified as Groups A and B, respectively. Preoperative AMS scores were 44.5 ±â€Š8.2 in Group A and 28.6 ±â€Š5.3 in Group B (p < 0.0001). AMS scores in Group A significantly improved 1 month after RARP (30.6 ±â€Š8.4, p < 0.0001) compared with their preoperative scores and remained at the same level from 3 to 12 months postoperatively, whereas those in Group B became significantly worse (32.0 ±â€Š7.8, p < 0.0001) than their preoperative ones. There were no differences between AMS scores in Groups A and B at every postoperative period (p = 0.3259, 0.2730, 0.2429, 0.4629, 0.1771 at 1, 3, 6, 9, and 12 months after surgery, respectively). CONCLUSIONS: Our results indicate that AMSs in PCa patients with the LOH syndrome can expect the same level of improvement as patients without it.

TUBB3 is associated with PTEN, neuroendocrine differentiation, and castration resistance in prostate cancer.

BACKGROUND: Tubulin-ß3 encoded by the Tubulin-ß3 (TUBB3) gene is a microtubule protein. Previous studies have shown that TUBB3 expression is upregulated in castration-resistant prostate cancer (CaP) and is involved in taxane resistance. However, the biological mechanism of TUBB3 involvement in the progression to castration-resistant CaP is not fully elucidated. This study aimed to analyze the expression and function of TUBB3 in localized and metastatic CaP. METHODS: TUBB3 expression was determined using immunohistochemistry in localized and metastatic CaP. We also investigated the association between TUBB3, phosphatase and tensin homolog (PTEN), and neuroendocrine differentiation and examined the involvement of TUBB3 in new antiandrogen drugs (enzalutamide and apalutamide) resistance in metastatic CaP. RESULTS: In 155 cases of localized CaP, immunohistochemistry showed that 5 (3.2%) of the CaP cases were positive for tubulin-ß3. Kaplan-Meier analysis showed that high expression of tubulin-ß3 was associated with poor prostate-specific antigen recurrence-free survival after radical prostatectomy. In 57 cases of metastatic CaP, immunohistochemistry showed that 14 (25%) cases were positive for tubulin-ß3. Tubulin-ß3 expression was higher in metastatic CaP than in localized CaP. High tubulin-ß3 expression was correlated with negative PTEN expression. TUBB3 expression was increased in neuroendocrine CaP based on several public databases. PTEN knockout decreased the sensitivity to enzalutamide and apalutamide in 22Rv-1 cells. TUBB3 knockdown reversed the sensitivity to enzalutamide and apalutamide in PTEN-CRISPR 22Rv-1 cells. High expression of tubulin-ß3 and negative expression of PTEN were significantly associated with poor overall survival in metastatic CaP treated with androgen deprivation therapy. CONCLUSIONS: These results suggest that TUBB3 may be a useful predictive biomarker for survival and play an essential role in antiandrogen resistance in CaP.

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.

Impact of postoperative acute kidney injury on predicting the upstaging of chronic kidney disease after robot-assisted partial nephrectomy.

INTRODUCTION: The aim of our study was to assess the impact of acute kidney injury (AKI) on postoperative upstaging of chronic kidney disease (CKD) after robot-assisted partial nephrectomy (RAPN). METHODS: This study consisted of 110 patients who had undergone RAPN and were followed up for at least 6 months after surgery. Patients were classified as AKI or non-AKI based on their serum creatinine level and estimated glomerular filtration rate within 7 days after surgery. Patient characteristics, outcome of RAPN and estimated glomerular filtration rate, and CKD upstage 6 months after surgery were compared between the AKI and non-AKI groups. RESULTS: A total of 26 patients (23.6%) experienced AKI after surgery. RENAL (radius, exophytic/endophitic properties, nearness of the tumor to the collecting system or sinus, anterior/posterior, location relative to the polar lines) nephrometry scores were ≥7 for 22 (84.6%) in the AKI group and 39 (46.4%) in the non-AKI group (P = .0006). A significantly smaller proportion of patients in the AKI group than in the non-AKI group recovered 90% of baseline function (38.5% vs 81.0%, P < .0001). CKD upstaging occurred in a total of 27 patients 24.5%) and in a significantly larger proportion of patients in the AKI group than in the non-AKI group (42.3% vs 19.0%, P = .0160). There was no significant difference in characteristics and perioperative outcomes between the patients with and without CKD, except for in those experiencing AKI. CONCLUSION: After RAPN, AKI can be associated with CKD upstaging.

Indwelling catheterization, renal stones, and hydronephrosis are risk factors for symptomatic Staphylococcus aureus-related urinary tract infection.

PURPOSE: Staphylococcus aureus is a relatively uncommon causative agent of urinary tract infection (UTI). However, the clinical features of S. aureus-related UTI are unclear. Thus, we aimed to clarify how patients with S. aureus bacteriuria develop UTI and determine the features and clinical risk factors of symptomatic S. aureus-related UTI. METHODS: We performed a retrospective study of patients at the Hiroshima University Hospital for whom S. aureus had been isolated from urine culture from January 2010 to December 2017. The characteristics (age, sex, body mass index, indwelling catheterization, renal stones, hydronephrosis, anticancer drug use, diabetes mellitus, steroid use, serum albumin, antibiotic use in the past 1 month, estimated glomerular filtration rate, benign prostate hyperplasia, and neurogenic bladder) of patients with UTI and those without UTI were compared, and the risk factors for S. aureus-related UTI were identified by multiple logistic regression model. RESULTS: A total of 286 patients with S. aureus bacteriuria were analyzed; 33 patients developed UTI. The causative pathogens were methicillin-sensitive S. aureus and methicillin-resistant S. aureus (MRSA) in 14 and 19 patients, respectively, who developed UTI. This study demonstrated that indwelling catheterization, hydronephrosis, and renal stones are significantly associated with S. aureus-related UTI (p = 0.01, odds ratio = 3.1; and p < 0.01, odds ratio = 7.0; and p = 0.02, odds ratio = 1.2; respectively) and hypoalbuminemia in MRSA-related UTI (p < 0.01). CONCLUSION: Paying attention to risk factors, specifically indwelling catheterization, renal stones, and hydronephrosis, will be an effective strategy for prevention of S. aureus-related UTI with persistent staphylococcal bacteriuria.

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.

Prediction of early progression of metastatic renal cell carcinoma treated with first-line tyrosine kinase inhibitor.

BACKGROUND: There are various alternative first-line therapeutic options besides tyrosine kinase inhibitors (TKIs) for metastatic renal cell carcinoma (mRCC). To inform therapeutic decision-making for such patients, this study aimed to identify predictive factors for resistance to TKI. MATERIALS AND METHODS: A total of 239 cases of mRCC patients who received first-line TKI therapy were retrospectively studied. Patients with a radiologic diagnosis of progressive disease within 3 months after initiating therapy were classified as primary refractory cases; the others were classified as non-primary refractory cases. The association between primary refractory cases and age, gender, pathology findings, serum c-reactive protein (CRP) level, metastatic organ status, and 6 parameters defined by the International Metastatic Renal Cell Carcinoma Database Consortium were analyzed. RESULTS: Of 239 cases, 32 (13.3%) received a radiologic diagnosis of progressive disease within 3 months after initiating therapy. The rates of sarcomatoid differentiation, hypercalcemia, a serum CRP level of 0.3 mg/dL or higher, presence of liver metastasis, anemia, and time from diagnosis to treatment interval of less than a year were significantly higher in the primary refractory group. Multivariate analysis showed that sarcomatoid differentiation, hypercalcemia, a serum CRP level of 0.3 mg/dL or higher, and liver metastasis were independently associated with primary refractory disease. A risk-stratified model based upon the number of patients with these factors indicated rates of primary refractory disease of 4.0%, 10.1%, and 45.0% for patients with 0, 1, and 2 or more factors, respectively. CONCLUSIONS: Sarcomatoid differentiation, hypercalcemia, an elevated serum CRP level, and presence of liver metastasis were associated with primary refractory disease in mRCC patients receiving first-line TKI therapy. These results provide clinicians with useful information when selecting a first-line therapeutic option for mRCC patients.

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.

The influence of reviewer's occupation on the skill assessment of urethrovesical anastomosis in robot-assisted radical prostatectomy.

INTRODUCTION: In recent years, crowd-sourced assessments have been reported as a timesaving, cost-efficient, and practicable method of surgical skill evaluation. However, the differences in the assessment of surgical skills by the individual reviewers cannot be further examined in terms of characteristics of the reviewers because they are usually anonymously and randomly selected. This study aimed to reveal the effects of reviewers' occupations on their assessment of a surgeon's skill. METHODS: In total, 42 urologists, 19 paramedics, 73 medical students, and 28 non-medical personnel used the Global Evaluative Assessment of Robotic Skills (GEARS) validated robotic surgery rating tool to assess the surgical skill of surgeons in nine edited video clips of complete urethrovesical anastomosis during a robot-assisted radical prostatectomy. The total GEARS scores of the four groups of reviewers were compared, and the similarities and the differences between the ratings of the urologists group and those of the other three groups were subsequently investigated. RESULTS: The rankings of video clips in the order of GEARS scores were very similar in each group, and a strong positive correlation (R2 values >0.8) was observed between the scores assigned by the urologists group and those assigned by the other three groups. CONCLUSION: Our findings indicate that the crude evaluation of robot-assisted urethrovesical anastomosis is not affected by the reviewers' occupations. Non-medical personnel may be able to provide a rudimentary screening evaluation of surgical skill.

Retzius-sparing robot-assisted radical prostatectomy: early learning curve experience in three continents.

OBJECTIVE: To assess the effect of surgical experience on peri-operative, functional and oncological outcomes during the first 50 Retzius-sparing robot-assisted radical prostatectomy (RsRARP) cases performed by surgeons naïve to this novel approach. MATERIALS AND METHODS: We retrospectively evaluated the initial cases operated by 14 surgeons in 12 different international centres. Pre-, peri- and postoperative features of the first 50 patients operated by each surgeon in all the participating centres were collected. The effect of surgical experience on peri-operative, functional and oncological outcomes was firstly evaluated after stratification by level of surgical experience (initial [≤25 cases] and expert [>25 cases]) and after using locally weighted scatterplot smoothing to graphically explore the relationship between surgical experience and the outcomes of interest. RESULTS: We evaluated 626 patients. The median follow-up was 13 months in the initial group and 9 months in the expert group (P = 0.002). Preoperative features overlapped between the two groups. Shorter console time (140 vs 120 min; P = 0.001) and a trend towards lower complications rates (13 vs 5.5%; P = 0.038) were observed in the expert group. The relationship between surgical experience and console time, immediate urinary continence recovery and Clavien-Dindo grade ≥2 complications was linear, without reaching a plateau, after 50 cases. Conversely, a non-linear relationship was observed between surgical experience and positive surgical margins (PSMs). CONCLUSIONS: In this first report of a multicentre experience of RsRARP during the learning curve, we found that console time, immediate urinary continence recovery and postoperative complications are optimal from the beginning and further quickly improve during the learning process, while PSM rates did not clearly improve over the first 50 cases.

Effect of penile rehabilitation with low intensity extracorporeal shock wave therapy on erectile function recovery following robot-assisted laparoscopic prostatectomy.

BACKGROUNDS: Considering the natural course of cavernous nerve recovery after robot-assisted laparoscopic prostatectomy (RALP), early intervention of low intensity extracorporeal shock wave therapy (LIESWT) would be more effective for enhancing overall recovery of sexual function (SF). Our objective of this study is to analyze longitudinally the alterations of SF in patients after RALP, with a focus on the effect of early and delayed intervention with LIESWT. METHODS: A total of 5 and 11 patients underwent early and delayed intervention with LIESWT, respectively. SF was assessed with the Expanded Prostate Cancer Index Composite (EPIC). The same surgeon performed RALP on 178 patients, and these patients were assigned to the non-LIESWT group to establish a control group. The SF score of EPIC was investigated longitudinally before RALP and 3, 6, 9, and 12 months after RALP. RESULTS: Our results show that penile rehabilitation with LIESWT immediately before urethral catheter removal improved SF scores. In the baseline, the SF score was significantly higher in the early LIESWT group (P=0.0001). The SF score was significantly lower at postoperative 6 months (early 19.2, delayed 17.9, and non-LIESWT 8.1; P=0.0171), 9 months (20.9, 25.8, and 10.2; P=0.0188), and 12 months (28.0, 21.3, and 9.5; P=0.0051) in the non-LIESWT group. We regret that there was no significant difference in the recovery of SF between the early and delayed protocol with LIESWT at all points. In keeping with our results, LIESWT demonstrated the potential to be efficacious in treatment options for severe post-radical prostatectomy (RP) erectile dysfunction (ED) as it may indirectly support its promotion of nerve regeneration in severe ED due to RP. CONCLUSIONS: This is the first study in which LIESWT has been shown to deliver a clinical benefit on its early or delayed intervention to patients after RALP to penile rehabilitation in terms of restoring SF. Our preliminary results suggest that LIESWT could be used as a treatment option in penile rehabilitation.

Refractory fistula of bladder repaired with transurethral cystoscopic injection of N-butyl-2-cyanoacrylate.

INTRODUCTION: Refractory fistulas of the bladder are not rare, but they can rarely be closed naturally. Bladder fistulas can be treated in various ways. We report the case of an old woman who had a refractory fistula of the bladder that was able to be repaired with transurethral cystoscopic injection of N-butyl-2-cyanoacrylate. CASE PRESENTATION: For decades after being treated for cervical cancer in 1970s, the woman frequently suffered from fevers. A computed tomography scan showed pelvic abscess at the left side of her bladder, and cystography showed urine leakage at the wall. Thus, we diagnosed her with a pelvic abscess due to a bladder fistula after radiation. Then, we treated her with drainage, antibiotic agents, and N-butyl-2-cyanoacrylate. After that, she no longer had fevers, and cystography showed no leakage of urine. CONCLUSION: This result indicates transurethral cystoscopic injection of N-butyl-2-cyanoacrylate may treat bladder fistulas safely, minimally invasively, and quickly.