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.

Dose Optimization Using a Deep Learning Tool in Various CT Protocols for Urolithiasis: A Physical Human Phantom Study.

Background and Objectives: We attempted to determine the optimal radiation dose to maintain image quality using a deep learning application in a physical human phantom. Materials and Methods: Three 5 × 5 × 5 mm3 uric acid stones were placed in a physical human phantom in various locations. Three tube voltages (120, 100, and 80 kV) and four current-time products (100, 70, 30, and 15 mAs) were implemented in 12 scans. Each scan was reconstructed with filtered back projection (FBP), statistical iterative reconstruction (IR, iDose), and knowledge-based iterative model reconstruction (IMR). By applying deep learning to each image, we took 12 more scans. Objective image assessments were calculated using the standard deviation of the Hounsfield unit (HU). Subjective image assessments were performed by one radiologist and one urologist. Two radiologists assessed the subjective assessment and found the stone under the absence of information. We used this data to calculate the diagnostic accuracy. Results: Objective image noise was decreased after applying a deep learning tool in all images of FBP, iDose, and IMR. There was no statistical difference between iDose and deep learning-applied FBP images (10.1 ± 11.9, 9.5 ± 18.5 HU, p = 0.583, respectively). At a 100 kV-30 mAs setting, deep learning-applied FBP obtained a similar objective noise in approximately one third of the radiation doses compared to FBP. In radiation doses with settings lower than 100 kV-30 mAs, the subject image assessment (image quality, confidence level, and noise) showed deteriorated scores. Diagnostic accuracy was increased when the deep learning setting was lower than 100 kV-30 mAs, except for at 80 kV-15 mAs. Conclusions: At the setting of 100 kV-30 mAs or higher, deep learning-applied FBP did not differ in image quality compared to IR. At the setting of 100 kV-30 mAs, the radiation dose can decrease by about one third while maintaining objective noise.

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.

Establishment of Three-Dimensional Bioprinted Bladder Cancer-on-a-Chip with a Microfluidic System Using Bacillus Calmette-Guérin.

Immunotherapy of bladder cancer is known to have favorable effects, although it is difficult to determine which patients will show a good response because of the different tumor microenvironments (TME). Here, we developed a bladder cancer-on-a-chip (BCOC) to mimic the TME using three-dimensional (3D) bioprinting and microfluidic technology. We fabricated a T24 and a 5637-cell line-based BCOC that also incorporated MRC-5, HUVEC, and THP-1 cells. We evaluated the effects of TME and assessed the immunologic reactions in response to different concentrations of Bacillus Calmette-Guérin (BCG) via live/dead assay and THP-1 monocytic migration, and concentrations of growth factors and cytokines. The results show that cell viability was maintained at 15% filling density in circle-shaped cell constructs at 20 µL/min microfluidic flow rate. A 3D co-culture increased the proliferation of BCOCs. We found that the appropriate time to evaluate the viability of BCOC, concentration of cytokines, and migration of monocytes was 6 h, 24 h, and three days after BGC treatment. Lastly, the immunotherapeutic effects of BCOC increased according to BCG dosage. To predict effects of immunotherapeutic agent in bladder cancer, we constructed a 3D bioprinted BCOC model. The BCOC was validated with BCG, which has been proven to be effective in the immunotherapy of bladder cancer.

Rapamycin enhances growth inhibition on urothelial carcinoma cells through LKB1 deficiency-mediated mitochondrial dysregulation.

Rapamycin, a mammalian target of rapamycin (mTOR) inhibitor, has significant potential for application in the treatment of urothelial carcinoma (URCa) of the bladder. Previous studies have shown that regulation of the AMP-activated serine/threonine protein kinase (AMPK)-mTOR signaling pathway enhances apoptosis by inducing autophagy or mitophagy in bladder cancer. Alteration of liver kinase B1 (LKB1)-AMPK signaling leads to mitochondrial dysfunction and the accumulation of autophagy-related proteins as a result of mitophagy, resulting in enhanced cell sensitivity to drug treatments. Therefore, we hypothesized that LKB1 deficiency in URCa cells could lead to increased sensitivity to rapamycin by inducing mitochondrial defect-mediated mitophagy. To test this, we established stable LKBI-knockdown URCa cells and analyzed the effects of rapamycin on their growth. Rapamycin enhanced growth inhibition and apoptosis in stable LKB1-knockdown URCa cells and in a xenograft mouse model. In spite of the stable downregulation of LKB1 expression, rapamycin induced AMPK activation in URCa cells, causing loss of the mitochondrial membrane potential, ATP depletion, and ROS accumulation, indicating an alteration of mitochondrial biogenesis. Our findings suggest that the absence of LKB1 can be targeted to induce dysregulated mitochondrial biogenesis by rapamycin treatment in the design of novel therapeutic strategies for bladder cancer.

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.

The immunotherapeutic effects of recombinant Bacillus Calmette-Guérin resistant to antimicrobial peptides on bladder cancer cells.

PURPOSE: Although Mycobacterium bovis Bacillus Calmette-Guérin (BCG) is the most widely used bladder cancer immunotherapy, innate immune responses involving antimicrobial peptides (AMPs) cause BCG failure and unwanted side effects. Here, we generated genetically modified BCG strains with improved immunotherapeutic effects by adding genes that confer evasion of AMPs. MATERIALS AND METHODS: We constructed recombinant BCG (rBCG) strains expressing Streptococcal inhibitor of complement (Sic), which confers resistance to human α-defensin-1 and cathelicidin, and d-alanyl carrier protein ligase (dltA), which confers resistance to cationic AMPs. Sic and dltA were separately cloned into the pMV306 plasmid and introduced into BCG via electroporation. Then, the efficacy of the rBCGs was tested in a growth inhibition assay using two bladder cancer cell lines (5637, T24). RESULTS: We confirmed the presence of cDNA segments corresponding to the Sic and dltA genes in total mRNA of the rBCG strains containing Sic (rBCG-Sic) and dltA (rBCG-dltA), and these rBCGs showed higher survival against AMPs. The growth inhibitory effects of rBCGs on bladder cancer cells were significantly enhanced compared to those of the parent BCG, and THP-1 migration also increased. After 8 h of infection, the levels of internalization were higher in rBCG-infected bladder cancer cells than in BCG-infected cells, and cells infected with rBCGs showed increased release of antitumor cytokines, such as IL-6/12, TNF-α, and INF-γ, resulting in inhibition of bacterial killing and immune modulation via antimicrobial peptides. CONCLUSIONS: rBCG-Sic and rBCG-dltA can effectively evade BCG-stimulated AMPs, and may be significantly improved immunotherapeutic tools to treat bladder cancer.

Targeting the Hepatocyte Growth Factor and c-Met Signaling Axis in Bone Metastases.

Bone metastasis is the terminal stage disease of prostate, breast, renal, and lung cancers, and currently no therapeutic approach effectively cures or prevents its progression to bone metastasis. One of the hurdles to the development of new drugs for bone metastasis is the complexity and heterogeneity of the cellular components in the metastatic bone microenvironment. For example, bone cells, including osteoblasts, osteoclasts, and osteocytes, and the bone marrow cells of diverse hematopoietic lineages interact with each other via numerous cytokines and receptors. c-Met tyrosine kinase receptor and its sole ligand hepatocyte growth factor (HGF) are enriched in the bone microenvironment, and their expression correlates with the progression of bone metastasis. However, no drugs or antibodies targeting the c-Met/HGF signaling axis are currently available in bone metastatic patients. This significant discrepancy should be overcome by further investigation of the roles and regulation of c-Met and HGF in the metastatic bone microenvironment. This review paper summarizes the key findings of c-Met and HGF in the development of novel therapeutic approaches for bone metastasis.

Combined Poly(Lactide-Co-Glycolide) Microspheres Containing Diphtheria Toxoid for a Single-shot Immunization.

To develop a single-shot vaccine containing diphtheria toxoid (DT) with a sufficient immune response, poly(lactide-co-glycolide) (PLGA) microspheres were prepared by water-in-oil-in-water double emulsification and solvent extraction techniques using low or high-molecular-weight PLGA (LMW-MS or HMW-MS). Stearic acid (SA) was introduced to HMW-MS (HMW/SA-MS) as a release modulator. Mean particle sizes (dvs, µm) varied between the prepared microspheres, with LMW-MS, HMW-MS, and HMW/SA-MS having the sizes of 29.83, 110.59, and 69.5 µm, respectively; however, the protein entrapment and loading efficiency did not vary, with values of 15.2-16.8 µg/mg and 61-75%, respectively. LMW-MS showed slower initial release (~ 2 weeks) but faster and higher release of antigen during weeks 3~7 than did HMW-MS. HMW/SA-MS showed rapid initial release followed by a continuous release over an extended period of time (~ 12 weeks). Mixed PLGA microspheres (MIX-MS), a combination of HMW/SA-MS and LMW-MS (1:1), demonstrated a sufficient initial antigen release and a subsequent boost release in a pulsatile manner. Serum antibody levels were measured by ELISA after DT immunization of Balb/c mice, and showed a greater response to MIX-MS than to alum-adsorbed DT (control). A lethal toxin challenge test with MIX-MS (a DT dose of 18 Lf) using Balb/c mice revealed complete protection, indicating a good candidate delivery system for a single-shot immunization.

Daily Mean Temperature and Urolithiasis Presentation in Six Cities in Korea: Time-Series Analysis.

Seasonal variation in urinary stone presentation is well described in the literature. However, previous studies have some limitations. To explore overall cumulative exposure-response and the heterogeneity in the relationships between daily meteorological factors and urolithiasis incidence in 6 major Korean cities, we analyzed data on 687,833 urolithiasis patients from 2009 to 2013 for 6 large cities in Korea: Seoul, Incheon, Daejeon, Gwangju, Daegu, and Busan. Using a time-series design and distributing lag nonlinear methods, we estimated the relative risk (RR) of mean daily urolithiasis incidence (MDUI) associated with mean daily meteorological factors, including the cumulative RR for a 20-day period. The estimated location-specific associations were then pooled using multivariate meta-regression models. A positive association was confirmed between MDUI and mean daily temperature (MDT), and a negative association was shown between MDUI and mean daily relative humidity (MDRH) in all cities. The lag effect was within 5 days. The multivariate Cochran Q test for heterogeneity at MDT was 12.35 (P = 0.136), and the related I² statistic accounted for 35.2% of the variability. Additionally, the Cochran Q test for heterogeneity and I² statistic at MDHR were 26.73 (P value = 0.148) and 24.7% of variability in the total group. Association was confirmed between daily temperature, relative humidity and urolithiasis incidence, and the differences in urolithiasis incidence might have been partially attributable to the different frequencies and the ranges in temperature and humidity between cities in Korea.

Identification of Downstream Genes of the mTOR Pathway that Predict Recurrence and Progression in Non-Muscle Invasive High-Grade Urothelial Carcinoma of the Bladder.

Microarray analysis was used to investigate the lack of identified mammalian target of rapamycin (mTOR) pathway downstream genes to overcome cross-talk at non-muscle invasive high-grade (HG)-urothelial carcinoma (UC) of the bladder, gene expression patterns, gene ontology, and gene clustering by triple (p70S6K, S6K, and eIF4E) small interfering RNAs (siRNAs) or rapamycin in 5637 and T24 cell lines. We selected mTOR pathway downstream genes that were suppressed by siRNAs more than 2-fold, or were up-regulated or down-regulated by rapamycin more than 2-fold. We validated mTOR downstream genes with immunohistochemistry using a tissue microarray (TMA) of 125 non-muscle invasive HG-UC patients and knockout study to evaluate the synergistic effect with rapamycin. The microarray analysis selected mTOR pathway downstream genes consisting of 4 rapamycin up-regulated genes (FABP4, H19, ANXA10, and UPK3A) and 4 rapamycin down-regulated genes (FOXD3, ATP7A, plexin D1, and ADAMTS5). In the TMA, FABP4, and ATP7A were more expressed at T1 and FOXD3 was at Ta. ANXA10 and ADAMTS5 were more expressed in tumors ≤ 3 cm in diameter. In a multivariate Cox regression model, ANXA10 was a significant predictor of recurrence and ATP7A was a significant predictor of progression in non-muscle invasive HG-UC of the bladder. In an ATP7A knock-out model, rapamycin treatment synergistically inhibited cell viability, wound healing, and invasion ability compared to rapamycin only. Activity of the ANXA10 and ATP7A mTOR pathway downstream genes might predict recurrence and progression in non-muscle invasive HG-UC of the bladder. ATP7A knockout overcomes rapamycin cross-talk.

Daily Mean Temperature Affects Urolithiasis Presentation in Seoul: a Time-series Analysis.

This study aimed to investigate the overall cumulative exposure-response and the lag response relationships between daily temperature and urolithiasis presentation in Seoul. Using a time-series design and distributing lag nonlinear methods, we estimated the relative risk (RR) of urolithiasis presentation associated with mean daily temperature, including the cumulative RR for a 20 days period, and RR for individual daily lag through 20 days. We analyzed data from 14,518 patients of 4 hospitals emergency department who sought medical evaluation or treatment of urolithiasis from 2005-2013 in Seoul. RR was estimated according to sex and age. Associations between mean daily temperature and urolithiasis presentation were not monotonic. Furthermore, there was variation in the exposure-response curve shapes and the strength of association at different temperatures, although in most cases RRs increased for temperatures above the 13°C reference value. The RRs for urolothiasis at 29°C vs. 13°C were 2.54 in all patients (95% confidence interval [CI]: 1.67-3.87), 2.59 in male (95% CI, 1.56-4.32), 2.42 in female (95% CI, 1.15-5.07), 3.83 in male less than 40 years old (95% CI, 1.78-8.26), and 2.47 in male between 40 and 60 years old (95% CI, 1.15-5.34). Consistent trends of increasing RR of urolithiasis presentation were observed within 5 days of high temperatures across all groups. Urolithiasis presentation increased with high temperature with higher daily mean temperatures, with the strongest associations estimated for lags of only a few days, in Seoul, a metropolitan city in Korea.

CT for evaluation of urolithiasis: image quality of ultralow-dose (Sub mSv) CT with knowledge-based iterative reconstruction and diagnostic performance of low-dose CT with statistical iterative reconstruction.

PURPOSE: To compare radiation dose and image quality in regular, low, and ultralow-dose CT protocols, and to evaluate diagnostic performance of low-dose CT for urolithiasis. MATERIALS AND METHODS: Sixty-five patients with suspected urolithiasis underwent three different scans under the regular, low, and ultralow-dose protocols. The regular dose scans were reconstructed using filtered back projection and the low-dose scans were reconstructed using a statistical iterative reconstruction. The ultralow-dose scans were reconstructed using both techniques in addition to a knowledge-based IR. Effective radiation doses were compared. Objective image noise was assessed by measuring standard deviation of HU and subjective image assessment was performed with a 3- or 5-point scale. Diagnostic performance of the low-dose image was evaluated, using the regular dose image as a standard reference and the interobserver agreement between two reviewers with different levels of experience was calculated. RESULTS: The effective radiation dose was significantly different in each protocol (p < 0.001) and estimated dose reduction of the low-dose and ultralow-dose protocols was 76.4% and 89.8%, respectively. The knowledge-based iterative reconstruction algorithm showed poorer subjective image quality than the regular and low-dose protocols, but it also had the least objective image noise. Overall, the low-dose image set showed a greater than 84% concordance rate and 100% in ureter stones larger than 3 mm. Interobserver agreement was substantial (kappa value = 0.61). CONCLUSIONS: The knowledge-based IR can provide a better quality image while reducing radiation exposure under the same protocol. Furthermore, the diagnostic performance of the low-dose CT protocol is comparable to the regular dose scan.

Establishment of Reference Ranges for Prostate Volume and Annual Prostate Volume Change Rate in Korean Adult Men: Analyses of a Nationwide Screening Population.

We aimed to determine normal reference ranges for prostate volume (PV) and annual PV change rate in a Korean nationwide screening population. Data from men who underwent a routine health check-up were collected from 13 university hospitals. The cohort comprised men aged ≥40 yr who had undergone 2 or more serial transrectal ultrasonographies. Men with initial PV>100 mL; serum PSA level>10 ng/mL; PV reduction>20% compared with initial PV, or who had history of prostate cancer or prostate surgery, were excluded. Linear regression and mixed effects regression analyses were used to predict mean PV and longitudinal change in PV over time. A total of 2,967 men formed the study cohort. Age, body mass index (BMI), and serum prostate-specific antigen (PSA) level were found to be significant predictors of PV. A predicted PV table, with a 95% confidence interval (CIs), was developed after adjusting for these 3 variables. Annual PV change rate was 0.51 mL/year (95% CI, 0.47-0.55). Annual PV change rate according to age was 0.68 mL/year, 0.84 mL/year, 1.09 mL/year, and 0.50 mL/year for subjects in their 40s, 50s, 60s, and ≥70 yr, respectively. Predicted annual PV change rate differed depending on age, BMI, serum PSA level and baseline PV. From a nationwide screening database, we established age-, PSA-, and BMI-specific reference ranges for PV and annual PV change rate in Korean men. Our newly established reference ranges for PV and annual PV change rate will be valuable in interpreting PV data in Korean men.

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.

Effect of obesity-related plasma hemodilution on serum tumor marker concentration in women.

AIM: We determined to investigate the effect of plasma hemodilution on tumor marker concentration in obese women. METHODS: We collected the data for tumor markers (cancer-associated antigen 125 [CA125], carbohydrate antigen 19-9 [CA19-9], carcinoembryonic antigen [CEA] and α-fetoprotein) from 6917 healthy women who visited the health promotion center at the Chung-Ang University Hospital from 2003 to 2011. We used multivariate linear regression analysis and χ(2) -test for linear-by-linear association adjusting for age, alanine aminotransferase and creatinine to determine the association between the serum tumor marker concentrations, plasma volume, tumor marker mass, and body mass index (BMI). RESULTS: Higher BMI was significantly associated with higher plasma volume (P < 0.001 for trend). The lower concentrations of CA125 and CA19-9 were significantly associated with increasing BMI (P < 0.001). Serum concentration and mass of CEA and α-fetoprotein were increased with higher BMI in obese women (P < 0.001). CEA in women had the opposite result to that in men due to visceral fat in women. CONCLUSION: This study shows that we should consider the hemodilution effect in Asian obese women when interpreting serum tumor marker concentration in cancer screening.

Establishment of an orthotopic mouse non-muscle invasive bladder cancer model expressing the mammalian target of rapamycin signaling pathway.

We established an orthotopic non-muscle invasive bladder cancer (NMIBC) mouse model expressing the mammalian target of the rapamycin (mTOR) signaling pathway. After intravesical instillation of KU-7-lucs (day 0), animals were subsequently monitored by bioluminescence imaging (BLI) on days 4, 7, 14, and 21, and performed histopathological examination. We also validated the orthotopic mouse model expressing the mTOR signaling pathway immunohistochemically. In vitro BLI photon density was correlated with KU-7-luc cell number (r (2) = 0.97, P < 0.01) and in vivo BLI photon densities increased steadily with time after intravesical instillation. The tumor take rate was 84.2%, formed initially on day 4 and remained NMIBC up to day 21. T1 photon densities were significantly higher than Ta (P < 0.01), and histological tumor volume was positively correlated with BLI photon density (r (2) = 0.87, P < 0.01). The mTOR signaling pathway-related proteins were expressed in the bladder, and were correlated with the western blot results. Our results suggest successful establishment of an orthotopic mouse NMIBC model expressing the mTOR signaling pathway using KU-7-luc cells. This model is expected to be helpful to evaluate preclinical testing of intravesical therapy based on the mTOR signaling pathway against NMIBC.

A prospective Korean multicenter study for infectious complications in patients undergoing prostate surgery: risk factors and efficacy of antibiotic prophylaxis.

This multicenter study was undertaken to determine the efficacy of antibiotic prophylaxis and identify the risk factors for infectious complications after prostate surgery in Korean patients. A total of 424 patients who underwent surgery of the prostate were reviewed. All patients underwent urinalysis and urine culture preoperatively and postoperatively. Efficacy of antibiotic prophylaxis and risk factors for infectious complications were investigated. Infectious complications were observed in 34.9% of all patients. Factors independently associated with infectious complications were diabetes mellitus (adjusted OR, 1.99; 95% CI, 1.09-3.65, P=0.025) and operation time (adjusted OR, 1.08; 95% CI, 1.03-1.13, P=0.004). Clinicians should be aware of the high risk of infectious complications in patients with diabetes and those who undergo a prolonged operation time. Neither the type nor duration of prophylactic antibiotics resulted in differences in infectious complications.

Histopathological differences between prostate cancer foci that are detected and missed using multiparametric magnetic resonance imaging in Korean patients.

OBJECTIVES: We investigated whether multiparametric magnetic resonance imaging is appropriate to localize prostate cancer foci in Koreans. METHODS: A total of 141 prostate cancer foci in 115 prostate specimens from patients who had undergone radical prostatectomy with preoperative 3 Tesla multiparametric magnetic resonance imaging including T2-weighted imaging, diffusion weighted imaging and magnetic resonance spectroscopy. Differences in the histopathological findings between detected and undetected prostate cancer foci on multiparametric magnetic resonance imaging were investigated. RESULTS: The mean tumor size was 1.9 cm, and 31.9%, 48.9%, and 19.9% of the patients had Gleason scores of 6, 7, or ≥8, respectively. The detection rates of prostate cancer foci were 54.6%, 57.4%, 55.3%, and 45.4% on multiparametric magnetic resonance imaging, T2-weighted imaging, diffusion weighted imaging, and magnetic resonance spectroscopy, respectively. On multivariate analysis, tumor size ≥1.5 cm (odds ratio 3.1; 95% confidence interval 1.31­7.49), Gleason score >7 (4 + 3; odds ratio 2.9; 95% confidence interval 1.05­8.05), and a malignant epithelium/stroma ratio of ≥60% (odds ratio 2.9; 95% confidence interval 1.14­7.20) were significant independent predictors of prostate cancer foci detection on multiparametric magnetic resonance imaging and diffusion weighted imaging. In a multivariate linear model analysis, the apparent diffusion coefficient value was inversely associated with maximum tumor diameter (ß = −0.242, P < 0.05), Gleason score (ß = −0.234, P < 0.05)and high malignant epithelium/stroma ratio (ß = −0.229, P < 0.05). CONCLUSIONS: Distinct histological differences between prostate cancer foci that were detected and missed by multiparametric magnetic resonance imaging can be identified. Despite limitations, multiparametric magnetic resonance imaging seems useful for determining prostate cancer in Korean patients, particularly with Gleason score >7 and tumor diameter>1.5 cm.

Prostate cancer therapy using immune checkpoint molecules to target recombinant dendritic cells.

PURPOSE: We developed immune checkpoint molecules to target recombinant dendritic cells (DCs) and verified their anti-tumor efficacy and immune response against prostate cancer. MATERIALS AND METHODS: DCs were generated from mononuclear cells in the tibia and femur bone marrow of mice. We knocked down the programmed death ligand 1 (PD-L1) on monocyte-derived DCs through siRNA PD-L1. Cell surface antigens were immune fluorescently stained through flow cytometry to analyze cultured cell phenotypes. Furthermore, we evaluated the efficacy of monocyte-derived DCs and recombinant DCs in a prostate cancer mouse model with subcutaneous TRAMP-C1 cells. Lastly, DC-induced mixed lymphocyte and lymphocyte-only proliferations were compared to determine cultured DCs' function. RESULTS: Compared to the control group, siRNA PD-L1 therapeutic DC-treated mice exhibited significantly inhibited tumor volume and increased tumor cell apoptosis. Remarkably, this treatment substantially augmented interferon-gamma and interleukin-2 production by stimulating T-cells in an allogeneic mixed lymphocyte reaction. Moreover, we demonstrated that PD-L1 gene silencing improved cell proliferation and cytokine production. CONCLUSIONS: We developed monocyte-derived DCs transfected with PD-L1 siRNA from mouse bone marrow. Our study highlights that PD-L1 inhibition in DCs increases antigen-specific immune responses, corroborating previous immunotherapy methodology findings regarding castration-resistant prostate cancer.