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.

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.

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.

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.

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.

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.

Claspin overexpression is associated with high-grade histology and poor prognosis in renal cell carcinoma.

Renal cell carcinoma (RCC) is one of the most common human cancers. We previously reported that claspin is a key regulator in the progression of gastric cancer, and it likely plays an important role in cancer stem cells of gastric cancer. However, the significance of claspin in RCC has not been examined. First, we analyzed the expression and distribution of claspin in 95 RCC cases by immunohistochemistry. In the nonneoplastic kidney, the staining of claspin was either weak or absent, whereas RCC tissue showed nuclear staining. In total, claspin expression was detected in 45 (47%) of 95 RCC cases. The claspin staining appeared relatively stronger in high nuclear grade RCC than in low nuclear grade RCC. Claspin-positive RCC cases were associated with higher T grade, tumor stage, nuclear grade, vein invasion, and poorer prognosis. CLSPN siRNA treatment decreased RCC cell proliferation. The levels of phosphorylated Erk and Akt were lower in CLSPN siRNA-transfected RCC cells than in control cells. In addition, claspin was coexpressed with CD44, epidermal growth factor receptor, p53, and programmed death ligand-1. These results suggest that claspin plays an important role in tumor progression in RCC and might be a prognostic marker and novel therapeutic target molecule.

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.

The third national Japanese antimicrobial susceptibility pattern surveillance program: Bacterial isolates from complicated urinary tract infection patients.

The antimicrobial susceptibility patterns of bacterial pathogens isolated from patients with complicated urinary tract infections were analyzed using national surveillance data. The data consisted of 881 bacterial strains from eight clinically relevant species. The data were collected for the third national surveillance project from January 2015 to March 2016 by the Japanese Society of Chemotherapy, the Japanese Association for Infectious Disease, and the Japanese Society of Clinical Microbiology. Surveillance was undertaken with the cooperation of 41 medical institutions throughout Japan. Fluoroquinolone required a MIC90 of 2-64 mg/L to inhibit the 325 Escherichia coli strains tested and the proportion of levofloxacin resistant E. coli strains increased to 38.5% from 29.6% in 2011 and 28.6% in 2008. The proportion of levofloxacin resistant strains of Pseudomonas aeruginosa and Enterococcus faecalis decreased from previous reports and the proportion of multidrug-resistant P. aeruginosa and carbapenem-resistant Enterobacteriaceae remained low. Among methicillin-resistant Staphylococcus aureus (MRSA) strains, strains with reduced susceptibility to vancomycin (minimum inhibitory concentration, 2 µg/mL) increased to 14.7% from 5.5%. Bacterial strains that produced extended-spectrum ß-lactamase included E. coli (79 of 325 strains, 24.3%), Klebsiella pneumoniae (9 of 177 strains, 7.7%), and Proteus mirabilis (6 of 55 strains, 10.9%). The proportion of extended-spectrum ß-lactamase producing E. coli and K. pneumoniae strains increased from previous surveillance reports.

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.

Protocadherin B9 promotes resistance to bicalutamide and is associated with the survival of prostate cancer patients.

Background Prostate cancer (PCa) is a common malignancy worldwide and is the second leading cause of cancer death in men. The standard therapy for advanced PCa is androgen deprivation therapy (ADT). Although ADT, including bicalutamide treatment, is initially effective, resistance to bicalutamide frequently occurs and leads to the development of castration-resistant PCa. Thus, clarifying the mechanisms of bicalutamide resistance is urgently needed. We designed this study to assess the expression and function of PCDHB9, which encodes the protocadherin B9 protein. Methods The expression of PCDHB9 was determined using immunohistochemistry and a qRT-PCR. The effects of the overexpression or knockdown of PCDHB9 on cell growth, migration, adhesion were evaluated. To evaluate the PCDHB9-mediated effects in PCa, we performed a gene expression analysis using DU145 transfected with PCDHB9. We examined the effects of PCDHB9 inhibition on bicalutamide resistance. Results The qRT-PCR revealed that the expression of PCDHB9 was much higher in PCa than that in non-neoplastic prostate tissues. In 152 clinically localized PCa cases immunohistochemistry showed that 59% of PCa cases were positive for protocadherin B9. A Kaplan-Meier analysis showed that the high expression of protocadherin B9 was associated with PSA recurrence after radical prostatectomy. A functional analysis showed that PCDHB9 modulated cell migration and adhesion. We also found that PCDHB9 induced the expression of ITGB6 based on a gene expression analysis. The effect of PCDHB9 inhibition on bicalutamide sensitivity was examined using MTT assays. The IC50 value of PCDHB9 siRNA-transfected PCa cells was significantly lower than that of negative control siRNA-transfected cells. Furthermore, immunohistochemical staining of protocadherin B9 in 74 PCa patients who were treated with androgen depletion therapy, including bicalutamide treatment, demonstrated that the high expression of protocadherin B9 was significantly associated with poor overall survival. Conclusions PCDHB9 plays an important role in the progression of PCa and bicalutamide resistance. Collectively, our results suggest that PCDHB9 targeted therapy may be more effective than bicalutamide alone.

miR-130b Promotes Sunitinib Resistance through Regulation of PTEN in Renal Cell Carcinoma.

BACKGROUND: MicroRNAs are a class of small noncoding RNAs that play an important role in progression and drug resistance in cancer. Several reports have shown that miR-130b modulates cell growth and drug resistance in some cancers. However, the expression and biological role of miR-130b in renal cell carcinoma (RCC) remain poorly understood. This study aimed to examine the expression and functional role of miR-130b and to analyze the association between miR-130b and sunitinib resistance in RCC. METHODS: The expression of miR-130b in 32 RCC tissues and their corresponding normal kidney tissues was determined by quantitative reverse transcription polymerase chain reaction (qRT-PCR). We performed a 4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide (MTT) assay in RCC cell lines transfected with miR-130b inhibitor or miR-130b mimics. We evaluated the relationship between miR-130b and PTEN and also analyzed the effect of miR-130b on sunitinib resistance. RESULTS: qRT-PCR analysis showed that the expression of miR-130b was higher in RCC tissues than in corresponding normal kidney tissues. The MTT assay revealed that miR-130b modulated cell growth. qRT-PCR revealed an inverse correlation between miR-130b and PTEN in RCC. Western blotting demonstrated that miR-130b regulated the expression of PTEN in the RCC cell line. Additionally, miR-130b was associated with sunitinib resistance through regulation of PTEN. We established the sunitinib-resistant Caki-1 (Caki-1-SR) cells and observed that the expression of miR-130b was elevated in Caki-1-SR cells compared with parental Caki-1 cells. Knockdown of miR-130b improved sunitinib resistance in Caki-1-SR cells. CONCLUSION: The expression of miR-130b was upregulated in RCC. miR-130b promoted cell growth and was associated with sunitinib resistance through regulating PTEN expression. Collectively, these results suggest that miR-130b may play an oncogenic role and be a promising therapeutic target.

SEC11A Expression Is Associated with Basal-Like Bladder Cancer and Predicts Patient Survival.

OBJECTIVES: Bladder cancer (BC) is a common malignancy worldwide. Signal peptidase complex 18 (SPC18) protein, which is encoded by the SEC11A gene, is one of the subunits of the signal peptidase complex and induces transforming growth factor-α secretion. In the present study, we analyzed the expression and function of SPC18 protein in human BC. METHODS: Expression of SPC18 was analyzed by immunohistochemistry. RNA interference was used to inhibit SEC11A expression in BC cell lines. For constitutive expression of the SEC11A gene, a SEC11A expression vector was transfected into BC cell lines. To examine cell viability, we performed 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. Modified Boyden chamber assays were used to examine cell invasiveness. RESULTS: SPC18 was upregulated in 54% of 81 BC cases. SPC18 expression served as an independent prognostic classifier of patients with BC. SPC18-positive BC cases frequently expressed cytokeratin 5/6, a marker of basal-like BC. Cell growth and invasiveness were inhibited by SEC11A knockdown and enhanced by forced expression of SEC11A. CONCLUSION: These results indicate that SPC18 plays an important role in the progression of BC. Specific inhibitors of SPC18 may be promising anticancer drugs for patients with basal-like BC.

Second nationwide surveillance of bacterial pathogens in patients with acute uncomplicated cystitis conducted by Japanese Surveillance Committee from 2015 to 2016: antimicrobial susceptibility of Escherichia coli, Klebsiella pneumoniae, and Staphylococcus saprophyticus.

The Japanese Surveillance Committee conducted a second nationwide surveillance of antimicrobial susceptibility patterns of uropathogens responsible for acute uncomplicated cystitis (AUC) in premenopausal patients aged 16-40 years old at 31 hospitals throughout Japan from March 2015 to February 2016. In this study, the susceptibility of causative bacteria (Escherichia coli, Klebsiella pneumoniae, Staphylococcus saprophyticus) for various antimicrobial agents was investigated by isolation and culturing of organisms obtained from urine samples. In total, 324 strains were isolated from 361 patients, including E. coli (n = 220, 67.9%), S. saprophyticus (n = 36, 11.1%), and K. pneumoniae (n = 7, 2.2%). The minimum inhibitory concentrations (MICs) of 20 antibacterial agents for these strains were determined according to the Clinical and Laboratory Standards Institute (CLSI) manual. At least 93% of the E. coli isolates showed susceptibility to fluoroquinolones and cephalosporins, whereas 100% of the S. saprophyticus isolates showed susceptibility to fluoroquinolones and aminoglycosides. The proportions of fluoroquinolone-resistant and extended-spectrum ß-lactamase (ESBL)-producing E. coli strains were 6.4% (13/220) and 4.1% (9/220), respectively. The antimicrobial susceptibility of K. pneumoniae was retained during the surveillance period, while no multidrug-resistant strains were identified. In summary, antimicrobial susceptibility results of our second nationwide surveillance did not differ significantly from those of the first surveillance. Especially the numbers of fluoroquinolone-resistant and ESBL-producing E. coli strains were not increased in premenopausal patients with AUC in Japan.

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.