Urinary tract infection after radiation therapy or radical prostatectomy on the prognosis of patients with prostate cancer: a population-based study.

BACKGROUND: We aimed to assess the trends in urinary tract infections (UTIs) and prognosis of patients with prostate cancer after radical prostatectomy (RP) and radiation therapy (RT) as definitive treatment options. METHODS: The data of patients diagnosed with prostate cancer between 2007 and 2016 were collected from the National Health Insurance Service database. The incidence of UTIs was evaluated in patients treated with RT, open/laparoscopic RP, and robot-assisted RP. The proportional hazard assumption test was performed using the scaled Schoenfeld residuals based on a multivariable Cox proportional hazard model. Kaplan-Meier analysis were performed to assess survival. RESULTS: A total of 28,887 patients were treated with definitive treatment. In the acute phase (< 3 months), UTIs were more frequent in RP than in RT; in the chronic phase (> 12 months), UTIs were more frequent in RT than in RP. In the early follow-up period, the risk of UTIs was higher in the open/laparoscopic RP group (aHR, 1.63; 95% CI, 1.44-1.83; p < 0.001) and the robot-assisted RP group (aHR, 1.26; 95% CI, 1.11-1.43; p < 0.001), compared to the RT group. The robot-assisted RP group had a lower risk of UTIs than the open/laparoscopic RP group in the early (aHR, 0.77; 95% CI, 0.77-0.78; p < 0.001) and late (aHR, 0.90; 95% CI, 0.89-0.91; p < 0.001) follow-up periods. In patients with UTI, Charlson Comorbidity Index score, primary treatment, age at UTI diagnosis, type of UTI, hospitalization, and sepsis from UTI were risk factors for overall survival. CONCLUSIONS: In patients treated with RP or RT, the incidence of UTIs was higher than that in the general population. RP posed a higher risk of UTIs than RT did in early follow-up period. Robot-assisted RP had a lower risk of UTIs than open/laparoscopic RP group in total period. UTI characteristics might be related to poor prognosis.

Shifting role of cytoreductive nephrectomy according to type of systemic therapy: A nationwide cohort study.

PURPOSE: The best protocol of cytoreductive nephrectomy (CN) and systemic therapy (ST) in the treatment of metastatic renal cell carcinoma (mRCC) remains unclear. We sought to evaluate overall survival (OS) in patients with mRCC treated with ST with or without CN. METHODS: We collected data from the National Health Insurance Service database. We excluded 2 years of washout period, 2 years of follow-up period, other cancer diagnoses within 2 years, and ≥4 months interval between ST and CN. The patients were divided into two groups according to whether CN was performed. Kaplan-Meier, propensity score matching, Cox regression model, and incremental survival analyses were conducted. Additionally, we performed subgroup analysis according to whether cytokine therapy or targeted therapy was used as first-line ST. RESULTS: Of 6478 patients, 1707 (26.4%) underwent CN. The CN group showed significantly better OS than the no CN group (p < 0.001). In the cytokine therapy subgroup, patients who underwent CN had significantly higher OS than those who did not (p < 0.001). In the targeted therapy subgroup, no significant difference was found (p = 0.867). In multivariate analysis, CN was associated with better OS in the total cohort (hazard ratio 0.819, p < 0.001). The incremental OS benefit of CN ranged from +0.98 in patients who survived for <24 months to +2.13 in those who survived during all periods. CONCLUSION: About a quarter patients with mRCC from a nationwide database were treated with CN and ST. CN was beneficial in specific patients with mRCC. Patient selection is crucial for obtaining the benefits of CN.

Renomedullary Interstitial Cell Tumor Mimicking Renal Cell Carcinoma: A Case Report.

Renomedullary interstitial cell tumors are often incidentally identified either upon autopsy or kidney resection for other reasons. However, rare renomedullary interstitial cell tumor cases resulting in a clinical symptomatic mass have been reported. We present a case of renomedullary interstitial cell tumor that was manifested as an incidentally detected renal mass and mimicked renal cell carcinoma on the imaging features.

Neoadjuvant versus adjuvant chemotherapy in upper tract urothelial carcinoma: A nationwide cohort study.

PURPOSE: This study aimed to evaluate the trend of adjuvant chemotherapy (AC) and neoadjuvant chemotherapy (NAC) in patients who underwent radical nephroureterectomy with bladder cuff excision (NUx) for upper tract urothelial carcinoma (UTUC) to compare the perioperative outcomes and overall survival (OS) between AC and NAC using nationwide population-based data. MATERIALS AND METHODS: We collected data on patients diagnosed with UTUC and treated with NUx between 2004 and 2016 using the National Health Insurance Service database, and evaluated the overall treatment trends. The AC and NAC groups were propensity score-matched. Cox proportional hazard and Kaplan-Meier analyses were used to assess survival. RESULTS: Of the 8,705 enrolled patients, 6,627 underwent NUx only, 94 underwent NAC, and 1,984 underwent AC. The rate of NUx without perioperative chemotherapy increased from 70.8 to 78.2% (R2 = 0.632; p < 0.001). The rates of dialysis (p = 0.398), TUR-BT (p = 1.000), and radiotherapy (p = 0.497) after NUx were similar. In the Kaplan-Meier curve, the NAC and AC groups showed no significant difference (p = 0.480). In multivariate analysis, treatment with AC or NAC was not associated with OS (hazard ratio 0.83, 95% confidence interval 0.49-1.40, p = 0.477). CONCLUSION: The use of NUx without perioperative chemotherapy has tended to increase in South Korea. Dialysis, TUR-BT, and radiotherapy rates after NUx were similar between the NAC and AC groups. There was no significant difference in OS between the NAC and AC groups. Proper perioperative chemotherapy according to patient and tumor conditions should be determined by obtaining more evidence of UTUC.

Low-dose versus standard-dose bacille Calmette-Guérin for non-muscle-invasive bladder cancer: Systematic review and meta-analysis of randomized controlled trials.

PURPOSE: Intravesical BCG (bacille Calmette-Guérin) instillation in patients with non-muscle-invasive bladder cancer decreases the risk for tumor recurrence and progression. After one BCG product was discontinued, a chronic global BCG shortage occurred. We focused on identifying a reduced dose of BCG that could maintain efficacy and reduce adverse effects. MATERIALS AND METHODS: We conducted a comprehensive literature search of PubMed, Embase, the Cochrane Library, CINAHL, Web of Science, and Scopus to identify randomized controlled trials through April 2021. The odds ratios (ORs) and 95% confidence intervals (CIs) for the low and standard doses in nine studies were compared. A low dose was defined as a low volume of BCG compared with the standard BCG dose (Armand Frappier, 120 mg; Connaught, 81 mg; Danish 1331, 120 mg; modified Danish 1331, 120 mg; Tokyo 172, 80 mg). RESULTS: The low-dose group experienced aggravated recurrence (OR, 1.45; 95% CI, 1.09-1.94; p=0.01) but similar progression (OR, 1.11; 95% CI, 0.76-1.62; p=0.59), similar cancer-specific survival (OR, 1.02; 95% CI, 0.60-1.75; p=0.93), similar overall survival (OR, 1.09; 95% CI, 0.76-1.56; p=0.65), favorable adverse effects (OR, 0.41; 95% CI, 0.28-0.62; p<0.0001), and favorable withdrawal (OR, 0.42; 95% CI, 0.25-0.71; p=0.001). CONCLUSIONS: Low-dose BCG had more unfavorable outcomes than did standard-dose BCG in terms of recurrence. Tumor progression, cancer-specific survival, and overall survival were similar between the doses. Low-dose BCG improved adverse effects and withdrawal. In the setting of BCG shortage, low-dose BCG may have strong potential as an alternative.

Neoadjuvant versus adjuvant chemotherapy in bladder cancer: a nationwide cohort study.

PURPOSE: Radical cystectomy is the standard of care for muscle-invasive bladder cancer. However, the 5-year survival rate is only about 50%. Therefore, additional treatments are needed. We compared the perioperative outcomes, overall survival, and treatment trends in patients with bladder cancer who underwent radical cystectomy and either neoadjuvant or adjuvant chemotherapy using nationwide population-based data. MATERIALS AND METHODS: We collected the data of patients diagnosed with bladder cancer treated with radical cystectomy between 2004 and 2016 using the National Health Insurance Service database. We evaluated overall treatment trends. The neoadjuvant chemotherapy and adjuvant chemotherapy groups were matched by propensity score. Cox proportional hazard analysis and Kaplan-Meier analysis were used to assess survival. RESULTS: Of 6134 patients, 1379 underwent adjuvant chemotherapy and 389 underwent neoadjuvant chemotherapy. The utilization rate of neoadjuvant chemotherapy increased from 6.4 to 12.2% from 2004 to 2016 (p = 0.018). The administration rate and number of granulocyte colony-stimulating factor cycles were lower in the neoadjuvant chemotherapy group than in the adjuvant chemotherapy group (p < 0.001 and p = 0.027, respectively). After propensity score matching, the neoadjuvant chemotherapy group had significantly better overall survival than the adjuvant chemotherapy group (p = 0.004). In multivariate analysis, neoadjuvant chemotherapy was associated with better overall survival (hazard ratio 0.77, 95% confidence interval 0.65-0.92, p = 0.003). CONCLUSIONS: Neoadjuvant chemotherapy was associated with lower granulocyte colony-stimulating factor administration and better overall survival than adjuvant chemotherapy. Neoadjuvant chemotherapy should be considered for patients with bladder cancer who undergo radical cystectomy.

The curative effect of androgen deprivation therapy alone is insufficient in high-risk prostate cancer.

ABSTRACT: To compare the outcomes of patients with high-risk prostate cancer treated by primary radical prostatectomy (RP) and primary androgen deprivation therapy (ADT).The study included patients with high-risk or very high-risk prostate cancer. Patients treated with definitive radiation therapy and those with clinical N1 and M1 disease were excluded. The RP group was divided into sub-cohorts of patients treated with ADT and those who received ADT after biochemical recurrence post-RP. Cancer-specific survival (CSS) and overall survival (OS) were analyzed using the Kaplan-Meier method and the Cox proportional hazards model.The study analyzed 859 patients divided into the RP group (n = 654) and ADT group (n = 205). Castration-resistant prostate cancer was detected in 23 (3.5%) patients in the RP group and 43 (21.0%) patients in the ADT group. Mortality cases included 63 (9.6%) patients in the RP group and 91 (44.4%) patients in the ADT group. CSS (P = .0002) and OS (P < .0001) were significantly higher in the RP group than in the ADT group. In the sub-cohort, CSS did not differ significantly between the RP and ADT groups, whereas OS was significantly higher in the RP group than in the ADT group (P < .0001). In the multivariate analysis, primary ADT increased CSS (hazard ratio, 2.068; P = .0498) and OS (hazard ratio, 3.218; P < .0001) compared with RP.In clinically localized high-risk prostate cancer patients, primary RP was associated with better CSS and OS than primary ADT. Comprehensive counseling in this cohort of patients will help the selection of treatment.

Hybrid ileal pouch with concomitant anti-refluxing and refluxing ureteroileal anastomosis.

PURPOSE: We report our preliminary experience of using a hybrid ileal pouch, assessing oncologic outcomes, complications, voiding, and renal function. METHODS: The study included 25 patients with bladder cancer treated with radical cystectomy with a hybrid ileal pouch with concomitant anti-refluxing and refluxing anastomosis, performed by a single surgeon. The patients were divided into two groups (first and last cases) according to the surgery date. Postoperative complications, separate renal function by renal scan, voiding function by uroflowmetry with residual urine, and oncologic outcomes were assessed. RESULTS: The surgery duration was shorter in the last cases than the first cases. The voiding volume increased with time. There were 23 cases of grade 3 complication in 12 patients and one case of grade 4 complication (sepsis). In the first cases, ureterovesical stenosis occurred in five cases, whereas in the last cases, there were no cases of stenosis. In separate renal function, there was no difference between the left and right side or between the first and last cases. CONCLUSIONS: The hybrid ileal pouch showed acceptable oncologic and functional outcomes and complications; therefore, it can be used according to the appropriate surgical situation with a relatively short bowel segment during neobladder construction.

Efficacy and tolerability of metallic stent in patients with malignant prostatic obstruction secondary to prostatic cancer.

OBJECTIVE: To evaluate the efficacy and tolerability of a self-expandable covered metallic stent in patients with malignant prostatic obstruction secondary to prostate cancer (PC). METHODS: We reviewed 22 cases of insertion of self-expandable covered metallic stents with barbs. Data were collected about PC status. Uroflowmetry variables, residual urine volume, International Prostate Symptom Score (IPSS), quality of life (QOL), and duration from stent insertion to removal were surveyed. These clinical parameters were compared before and after stent insertion. RESULTS: The patients with PC showed a mean age of 75.5 ± 6.5 years and mean 5.1 ± 1.9 Charlson comorbidity index. The average flow rate (2.4 ± 1.9 vs 5.9 ± 2.4 mL/s, P = .005), peak flow rate (6.9 ± 6.2 vs 14.1 ± 5.5 mL/s, P = .003), flow time (54.6 ± 29.1 vs 23.6 ± 13.7 s, P = .002), residual urine volume (178.7 ± 195.5 vs 7.0 ± 7.1 mL, P = .004), IPSS (26.2 ± 8.1 vs 8.0 ± 6.5 points, P = .001), and QOL (4.7 ± 1.3 vs 2.4 ± 2.1 points, P = .030) improved between before and after stent insertion, respectively. Pain was the most common complication, but 60% of the patients were managed without any intervention. There were hematuria, urinary retention, urinary frequency, obstruction, and urinary incontinence. However, there was no urinary tract infection due to the stent. The median time to stent removal was 5.7 months. CONCLUSIONS: The stent was maintained for about 6 months with improved objective and subjective outcomes. The patients with PC, who had a poor comorbidity index and advanced PC status showed a tolerable maintenance period. Self-expandable covered metallic stents can be used for PC patients with a short life expectancy and unsuitability for general anesthesia.

Urothelial-phase thin-section MDCT of the bladder in patients with hematuria: added value of multiplanar reformatted images.

PURPOSE: To evaluate the diagnostic performance of MDCT with axial images and multiplanar reformatted (MPR) images from the urothelial phase of the bladder in patients with hematuria using cystoscopy as the reference standard. MATERIALS AND METHODS: Our IRB for human investigation approved this study, and informed consent was waived. We included 192 patients (121 men, 71 women; age range 17-90 years; mean age ± SD: 60 ± 14 years) who underwent contrast-enhanced MDCT (scan delay: 70 s; section thickness: 2 mm) and conventional cystoscopy examination for painless gross hematuria or recurrent microscopic hematuria. Two radiologists in consensus interpreted the images for the presence or absence of bladder lesions. Using the kappa statistic, the patient-based agreement was determined between the CT and cystoscopic findings. We compared the diagnostic performance of axial images to those with coronal and sagittal reformations to detect bladder lesions. RESULTS: MDCT showed excellent agreement between cystoscopy-axial scans (κ = 0.896) and axial with reformatted images (κ = 0.948). The sensitivity, specificity, and accuracy of MDCT were 94%, 96%, and 95% in the axial scans and 98%, 97%, and 97% in the axial with reformatted images, respectively. All statistical parameters of diagnostic performance were similar between the axial and the reformatted images (p > .05). CONCLUSION: Axial MDCT imaging demonstrates high diagnostic performance in detecting bladder lesions, but additional reformatted images can improve diagnostic accuracy.

Does intraoperative frozen section really predict significant positive surgical margins after robot-assisted laparoscopic prostatectomy? A retrospective study.

We investigated the relationship between positive surgical margin (PSM)-related factors and biochemical recurrence (BCR) and the ability of intraoperative frozen sections to predict significant PSM in patients with prostate cancer. The study included 271 patients who underwent robot-assisted laparoscopic prostatectomy with bilateral nerve sparing and maximal urethral preservation. Intraoperative frozen sections of the periurethra, dorsal vein, and bladder neck were analyzed. The ability of PSM-related factors to predict BCR and significant PSM was assessed by logistic regression. Of 271 patients, 108 (39.9%) had PSM and 163 (60.1%) had negative margins. Pathologic Gleason score ≥8 (18.9% vs 7.5%, P = 0.015) and T stage ≥T3a (51.9%vs 24.6%, P < 0.001) were significantly more frequent in the PSM group. Multivariate analysis showed that Gleason pattern ≥4 (vs <4; hazard ratio: 4.386; P = 0.0004) was the only significant predictor of BCR in the PSM cohort. Periurethral frozen sections had a sensitivity of 83.3% and a specificity of 84.2% in detecting PSM with Gleason pattern ≥4. Multivariate analysis showed that membranous urethra length (odds ratio [OR]: 0.79, P = 0.0376) and extracapsular extension of the apex (OR: 4.58, P = 0.0226) on magnetic resonance imaging (MRI) and positive periurethral tissue (OR: 17.85, P < 0.0001) were associated with PSM of the apex. PSM with Gleason pattern ≥4 is significantly predictive of BCR. Intraoperative frozen sections of periurethral tissue can independently predict PSM, whereas sections of the bladder neck and dorsal vein could not. Pathologic examination of these samples may help predict significant PSM in patients undergoing robot-assisted laparoscopic prostatectomy with preservation of functional outcomes.

Robot-Assisted Partial Nephrectomy for Treatment of Juxtaglomerular Cell Tumor of the Kidney: A Case Report.

Background: A juxtaglomerular cell tumor (JGCT), or a reninoma, is a rare renal tumor that can cause secondary hypertension. This is the first reported JGCT that was resected through robotic surgery. Case: We present a case of a 27-year-old female patient with 1.35-cm-sized JGCT in the lower pole of the right kidney. We effectively removed a JGCT through robot-assisted partial nephrectomy without any complications. Conclusion: The robot-assisted partial nephrectomy procedure could be a suitable choice for JGCT resection.

Luteinizing Hormone Levels Relate to the Unfavorable Pathology of Prostate Cancer.

PURPOSE: This study analyzed the association between sex hormone concentrations and stage/condition in patients with prostate cancer. MATERIALS AND METHODS: The concentrations of sex hormones, including testosterone (total, free, and bioavailable), sex hormone-binding globulin (SHBG), luteinizing hormone (LH), and follicle-stimulating hormone (FSH), were measured in 415 patients diagnosed with prostate cancer. Differences in serum hormone concentrations after receiving androgen deprivation therapy (ADT) and after withdrawal from ADT were evaluated. Pathologic characteristics were assessed in the 225 patients unexposed to ADT with a history of radical prostatectomy. Logistic regression analysis was performed to identify factors predictive of unfavorable pathology (Grade ≥3, ≥T3a, or N1). RESULTS: Of the 415 prostate cancer patients, 130 (31.3%) were assessed before treatment, 171 (41.2%) after surgery, 35 (8.4%) after biochemical recurrence, and 59 (14.2%) during ADT, whereas 20 (4.8%) had castration-resistant prostate cancer. FSH was significantly lower after compared to before prostatectomy (3.229 ± 4.486 vs. 5.941 ± 7.044 mIU/mL, p < 0.001). LH, FSH, and testosterone decreased significantly 3 months after starting ADT, but increased 3 months after ADT withdrawal, whereas SHBG was unchanged. Multivariate analysis showed that high LH (odds ratio [OR]: 1.59, 95% confidence interval [CI]: 1.03-2.47, p = 0.0376) and prostate-specific antigen (PSA) (OR: 1.13, 95% CI: 1.03-1.24, p = 0.0133) concentrations were significantly associated with a high risk of unfavorable pathology. CONCLUSIONS: Sex hormones, including LH, FSH, and testosterone, were affected by ADT. The FSH level decreased after radical prostatectomy. High baseline LH concentration in patients unexposed to ADT was associated with an unfavorable pathology.

Percent tumor volume vs American Joint Committee on Cancer staging system subclassification for predicting biochemical recurrence in patients with pathologic T2 prostate cancer.

PURPOSE: Here, we re-checked the American Joint Committee on Cancer 7th edition subclassification and confirmed the possibility of percent tumor volume as a prognostic factor for biochemical recurrence in the 8th edition subclassification. METHODS: A total of 1073 patients with pathologic T2 stage disease who underwent radical prostatectomy were included. Exclusion criteria were neoadjuvant therapy and pathologic T3 and N1 disease. Biochemical recurrence-free survival was estimated using the Kaplan-Meier method. Cox hazard regression was used to predict biochemical recurrence. RESULTS: According to the 7th edition subclassification, 141 patients (13.1%) had T2a, 43 (4.0%) had T2b, and 889 (82.9%) had T2c disease. The 7th edition subclassification did not differ significantly on Kaplan-Meier analysis (p = 0.502). Mean percent tumor volume was 8.7 ± 8.0% (interquartile range, 5-10%). Percent tumor volume was positively correlated with initial prostate-specific antigen, grade group, surgical margin, and T2 subclassification (all p < 0.001). The 7th edition subclassification was not a significant factor, whereas percent tumor volume was (hazard ratio, 1.023; 95% confidence interval, 1.005-1.041; p = 0.0128) on multivariate analysis. On Kaplan-Meier analysis, percent tumor volume (> 7.5% vs ≤ 7.5%) differed significantly for biochemical recurrence-free survival (p < 0.001). CONCLUSIONS: The 7th edition pathologic T2 subclassification had poor prognostic value for biochemical recurrence in our cohort. Elimination of the 8th edition subclassification was suitable. Percent tumor volume classified biochemical recurrence prognosis in pathologic T2 stage. Therefore, percent tumor volume can be a candidate factor for the next T2 subclassification.

Structure establishment of three-dimensional (3D) cell culture printing model for bladder cancer.

PURPOSE: Two-dimensional (2D) cell culture is a valuable method for cell-based research but can provide unpredictable, misleading data about in vivo responses. In this study, we created a three-dimensional (3D) cell culture environment to mimic tumor characteristics and cell-cell interactions to better characterize the tumor formation response to chemotherapy. MATERIALS AND METHODS: We fabricated the 3D cell culture samples using a 3D cell bio printer and the bladder cancer cell line 5637. T24 cells were used for 2D cell culture. Then, rapamycin and Bacillus Calmette-Guérin (BCG) were used to examine their cancer inhibition effects using the two bladder cancer cell lines. Cell-cell interaction was measured by measuring e-cadherin and n-cadherin secreted via the epithelial-mesenchymal transition (EMT). RESULTS: We constructed a 3D cell scaffold using gelatin methacryloyl (GelMA) and compared cell survival in 3D and 2D cell cultures. 3D cell cultures showed higher cancer cell proliferation rates than 2D cell cultures, and the 3D cell culture environment showed higher cell-to-cell interactions through the secretion of E-cadherin and N-cadherin. Assessment of the effects of drugs for bladder cancer such as rapamycin and BCG showed that the effect in the 2D cell culture environment was more exaggerated than that in the 3D cell culture environment. CONCLUSIONS: We fabricated 3D scaffolds with bladder cancer cells using a 3D bio printer, and the 3D scaffolds were similar to bladder cancer tissue. This technique can be used to create a cancer cell-like environment for a drug screening platform.

Depletion of NBR1 in urothelial carcinoma cells enhances rapamycin-induced apoptosis through impaired autophagy and mitochondrial dysfunction.

Rapamycin is well-recognized in the clinical therapeutic intervention for patients with cancer by specifically targeting mammalian target of rapamycin (mTOR) kinase. Rapamycin regulates general autophagy to clear damaged cells. Previously, we identified increased expression of messenger RNA levels of NBR1 (the neighbor of BRCA1 gene; autophagy cargo receptor) in human urothelial cancer (URCa) cells, which were not exhibited in response to rapamycin treatment for cell growth inhibition. Autophagy plays an important role in cellular physiology and offers protection against chemotherapeutic agents as an adaptive response required for maintaining cellular energy. Here, we hypothesized that loss of NBR1 sensitizes human URCa cells to growth inhibition induced by rapamycin treatment, leading to interruption of protective autophagic activation. Also, the potential role of mitochondria in regulating autophagy was tested to clarify the mechanism by which rapamycin induces apoptosis in NBR1-knockdown URCa cells. NBR1-knockdown URCa cells exhibited enhanced sensitivity to rapamycin associated with the suppression of autophagosomal elongation and mitochondrial defects. Loss of NBR1 expression altered the cellular responses to rapamycin treatment, resulting in impaired ATP homeostasis and an increase in reactive oxygen species (ROS). Although rapamycin treatment-induced autophagy by adenosine monophosphate-activated protein kinase (AMPK) phosphorylation in NBR1-knockdown cells, it did not process the conjugated form of LC3B-II after activation by unc-51 like autophagy-activating kinase 1 (ULK1). NBR1-knockdown URCa cells exhibited rather profound mitochondrial dysfunctions in response to rapamycin treatment as evidenced by Δψm collapse, ATP depletion, ROS accumulation, and apoptosis activation. Therefore, our findings provide a rationale for rapamycin treatment of NBR1-knockdown human urothelial cancer through the regulation of autophagy and mitochondrial dysfunction by regulating the AMPK/mTOR signaling pathway, indicating that NBR1 can be a potential therapeutic target of human urothelial cancer.

Human Neural Stem Cells Overexpressing a Carboxylesterase Inhibit Bladder Tumor Growth.

Bladder cancer is a significant clinical and economic problem. Despite intravesical chemotherapy and immunotherapy, up to 80% of patients with non-muscle-invasive bladder cancer develop recurrent tumors, of which 20% to 30% evolve into more aggressive, potentially lethal tumors. Recently, bladder cancer cells are considered to be mediators of resistance to current therapies and therefore represent strong candidates as biologic targets. No effective chemotherapy has yet been developed for advanced bladder cancer. It is desirable that a drug can be delivered directly and specifically to bladder cancer cells. Stem cells have selective migration ability toward cancer cells, and therapeutic genes can be easily transduced into stem cells. In suicide gene therapy for cancer, stem cells carry a gene encoding a carboxylesterase (CE) enzyme that transforms an inert CPT-11 prodrug into a toxic SN-38 product, a topoisomerase 1 inhibitor. In immunodeficient mice, systemically transplanted HB1.F3.CE stem cells migrated toward the tumor implanted by the TCCSUP bladder cancer cell line, and, in combination with CPT-11, the volume of tumors was significantly reduced. These findings may contribute to the development of a new selective chemotherapeutic strategy against bladder cancer. Mol Cancer Ther; 15(6); 1201-7. ©2016 AACR.

P70S6K and Elf4E dual inhibition is essential to control bladder tumor growth and progression in orthotopic mouse non-muscle invasive bladder tumor model.

We investigated how the dual inhibition of the molecular mechanism of the mammalian target of the rapamycin (mTOR) downstreams, P70S6 kinase (P70S6K) and eukaryotic initiation factor 4E (eIF4E), can lead to a suppression of the proliferation and progression of urothelial carcinoma (UC) in an orthotopic mouse non-muscle invasive bladder tumor (NMIBT) model. A KU-7-luc cell intravesically instilled orthotopic mouse NMIBC model was monitored using bioluminescence imaging (BLI) in vivo by interfering with different molecular components using rapamycin and siRNA technology. We then analyzed the effects on molecular activation status, cell growth, proliferation, and progression. A high concentration of rapamycin (10 µM) blocked both P70S6K and elF4E phosphorylation and inhibited cell proliferation in the KU-7-luc cells. It also reduced cell viability and proliferation more than the transfection of siRNA against p70S6K or elF4E. The groups with dual p70S6K and elF4E siRNA, and rapamycin reduced tumor volume and lamina propria invasion more than the groups with p70S6K or elF4E siRNA instillation, although all groups reduced photon density compared to the control. These findings suggest that both the mTOR pathway downstream of eIF4E and p70S6K can be successfully inhibited by high dose rapamycin only, and p70S6K and Elf4E dual inhibition is essential to control bladder tumor growth and progression.

Modulating the internalization of bacille Calmette-Guérin by cathelicidin in bladder cancer cells.

OBJECTIVE: To confirm the role of cathelicidin (LL-37) in the internalization of bacille Calmette-Guérin (BCG) into bladder cancer cells. METHODS: Enzyme-linked immunosorbent assay and reverse transcription polymerase chain reaction analysis evaluated the changes in protein and messenger ribonucleic acid (RNA) expression with BCG incubation after LL-37 pretreatment in 5637 and T24 human bladder cancer cells. The internalization rate was evaluated by a double immunofluorescence assay, and confocal microscopy confirmed the function of LL-37 in BCG internalization. We also investigated the difference in internalization rates and cell viability between LL-37, anti-LL-37 antibody, and LL-37 plus anti-LL-37 antibody. RESULTS: The levels of LL-37 increased after BCG exposure in bladder cancer cells in dose- and time-dependent manners. Increasing LL-37 levels using recombinant LL-37 protein further dose dependently decreased BCG internalization in both cell lines. The internalization rates of BCG after LL-37 instillation were lower compared with the controls, and the internalization rate of BCG after anti-LL-37 antibody instillation was significantly higher compared with the controls in both cell lines (P <.05). Viability of LL-37 plus BCG group was higher compared with the BCG-alone group. The anti-LL-37 antibody plus BCG group had decreased cell viability compared with the BCG-alone group in both cell lines. CONCLUSION: Bladder cancer cells produce cathelicidin when infected with BCG and upregulate cathelicidin to defend against BCG by inhibiting its internalization. Blocking the action of cathelicidin may increase the internalization and effectiveness of BCG in reducing bladder cancer cell proliferation.

Murine ß-defensin-2 may regulate the effect of bacillus Calmette-Guérin (BCG) in normal mouse bladder.

PURPOSE: We investigated whether bacillus Calmette-Guérin (BCG)-induced secretion of murine ß-defensin-2 (mBD2) and determined whether mBD2 regulated BCG effects in the normal mouse bladder. MATERIALS AND METHODS: A total of 140 C57BL/6 female mice were divided into 28 groups, and the experiment was performed over 3 steps. In the first step (20 groups), mice bladders were stimulated with different doses of BCG (multiplicity of infection [MOI] 0, 1, 10, 30, and 100) and histological analysis was conducted in bladder specimens isolated at different times (0, 4, 8, and 24h after instillation) to determine optimal dose and time point of BCG internalization and urine mBD2 and cytokine concentration. In the second step (4 groups), BCG internalization and urine cytokine levels were measured after pretreatment of different recombinant mBD2 (rmBD2) (0, 1, 2.5, and 5 ng/ml) at optimal dose and time point. In the third step (4 groups), BCG internalization and urine cytokine levels were compared between pretreatment conditions (control, rmBD2, anti-mBD2 Ab, and rmBD2+anti-mBD2 Ab). Urine was collected for estimating mBD2 levels and a multiplex analysis for 9 cytokines. Real-time polymerase chain reaction assay was used for estimating the relative BCG cell number in mice bladder tissue. RESULTS: Bladder edema was induced by BCG (MOI 30 and 100), which progressed to an inflammatory infiltrate composed primarily of neutrophils and increased mBD2 secretion at 4 hours after instillation. Relative BCG cell number and urinary cytokine levels (interferon-γ and interleukins [IL]-2, -4, -6, and -10) response pattern was characterized by a peak at 4 hours after instillation followed by rapid decline. The levels of interferon-γ, and IL-1ß, -2, -4, -6, and -10 and relative BCG cell numbers decreased in a dose-dependent manner according to pretreatment with rmBD2 protein, and the responses were potentiated in the anti-mBD2 pretreatment group at 4 hours after BCG (MOI 30) instillation. CONCLUSION: The present results suggest that the mouse urothelium produces mBD2 in response to intravesicular BCG as a defense mechanism against BCG, and blocking mBD2 by an anti-mBD2 antibody increased the effectiveness of BCG.