Alix-normalized exosomal programmed death-ligand 1 analysis in urine enables precision monitoring of urothelial cancer.

Anti-programmed death-ligand 1 (PD-L1) Ab-based therapies have demonstrated potential for treating metastatic urothelial cancer with high PD-L1 expression. Urinary exosomes are promising biomarkers for liquid biopsy, but urine's high variability requires normalization for accurate analysis. This study proposes using the PD-L1/Alix ratio to normalize exosomal PD-L1 signal intensity with Alix, an internal exosomal protein less susceptible to heterogeneity concerns than surface protein markers. Extracellular vesicles were isolated using ExoDisc and characterized using various methods, including ExoView to analyze tetraspanins, PD-L1, and Alix on individual exosomes. On-disc ELISA was used to evaluate PD-L1 and Alix-normalized PD-L1 in 15 urothelial cancer patients during the initial treatment cycle with Tecentriq. Results showed that Alix signal range was relatively uniform, whereas tetraspanin marker intensity varied for individual exosome particles. On-disc ELISA was more reliable for detecting exosomal PD-L1 expression than standard plate ELISA-based measurement. Using exosomal Alix expression for normalization is a more reliable approach than conventional methods for monitoring patient status. Overall, the study provides a practical and reliable method for detecting exosomal PD-L1 in urine samples from patients with urothelial cancer.

Rate of benign histology after resection of suspected renal cell carcinoma: multicenter comparison between Korea and the United States.

BACKGROUND: In the United States, the rate of benign histology among resected renal tumors suspected to be malignant is increasing. We evaluated the rates in the Republic of Korea and assessed the racial effect using recent multi-institutional Korean-United States data. METHODS: We conducted a multi-institutional retrospective study of 11,529 patients (8,812 from The Republic of Korea and 2,717 from the United States) and compared the rates of benign histology between the two countries. To evaluate the racial effect, we divided the patients into Korean, Asian in the US, and Non-Asian in the US. RESULTS: The rates of benign histology and small renal masses in Korean patients were significantly lower than that in United States patients (6.3% vs. 14.3%, p < 0.001) and (≤ 4 cm, 7.6% vs. 19.5%, p < 0.001), respectively. Women, incidentaloma, partial nephrectomy, minimally invasive surgery, and recent surgery were associated with a higher rate of benign histology than others. CONCLUSIONS: In Korea, the rate of benign histology among resected renal tumors was significantly lower than that in the United States. This disparity could be caused by environmental or cultural differences rather than racial differences. Our findings suggest that re-evaluating current context-specific standards of care is necessary to avoid overtreatment.

Regulation of Epithelial-Mesenchymal Transition of A549 Cells by Prostaglandin D2.

BACKGROUND/AIMS: Despite significant advances in diagnostic and operative techniques, lung cancer remains one of the most lethal malignancies worldwide. Since prostaglandins such as prostaglandin D2 (PGD2) is involved in various pathophysiological process, including inflammation and tumorigenesis, this study aims to investigate the role of PGD2 during the process of epithelial-mesenchymal transition (EMT) in A549 cells. METHODS: A549 cells were stimulated with PGD2 and expression of EMT markers was analyzed by immunoblotting and immunofluorescence. EMT-related gene, Slug expression was evaluated using quantitative real-time polymerase chain reaction (qPCR). Migration and invasion abilities of A549 cells were determined in chemotaxis and Matrigel invasion assays, respectively. We also inhibited the TGF/Smad signaling pathway using a receptor inhibitor or silencing of TGF-ß1 and TGFß type I receptor (TGFßRI), and protein expression was assessed by immunoblotting and immunofluorescence. RESULTS: Here, we found that stimulation of A549 cells with PGD2 resulted in morphological changes into a mesenchymal-like phenotype under low serum conditions. Stimulation of A549 cells with PGD2 resulted in a significant reduction in proliferation, whereas invasion and migration were enhanced. The expression of E-cadherin was markedly downregulated, while Vimentin expression was upregulated after treatment of A549 cells with PGD2. Slug expression was markedly upregulated by stimulating A549 cells with PGD2, and stimulation of A549 cells with PGD2 significantly enhanced TGF-ß1 expression, and silencing of TGF-ß1 significantly blocked PGD2-induced EMT and Smad2 phosphorylation. In addition, PGD2-induced Smad2 phosphorylation and EMT were significantly abrogated by either pharmacological inhibition or silencing of TGFßRI. PGD2-induced expression of Slug and EMT were significantly augmented in low nutrient and low serum conditions. Finally, the subsequent culture of mesenchymal type of A549 cells under normal culture conditions reverted the cell's phenotype to an epithelial type. CONCLUSION: Given these results, we suggest that tumor microenvironmental factors such as PGD2, nutrition, and growth factors could be possible therapeutic targets for treating metastatic cancers.

Targeted therapy response in early versus late recurrence of renal cell carcinoma after surgical treatment: A propensity score-matched study using the Korean Renal Cancer Study Group database.

OBJECTIVES: To investigate the clinicopathological features and outcomes of targeted therapy in patients with recurrence of renal cell carcinoma in <5 years or ≥5 years after the surgical treatment for renal cell carcinoma. METHODS: Patients with metastatic renal cell carcinoma treated with targeted therapy in a multicenter database were retrospectively characterized according to time from surgery to recurrence. Early recurrence was defined as recurrence within 5 years after surgery, and late recurrence was defined as occurring ≥5 years after surgery. The propensity scores for recurrence status were calculated, and patients with late recurrence were matched to patients with early recurrence at a 1:3 ratio. The oncological outcomes of targeted therapy in both groups were compared. RESULTS: Among 716 patients, 512 (71.5%) experienced early recurrence and 204 (28.5%) experienced late recurrence. The patients with late recurrence presented with younger age at surgery, lower tumor stages and Fuhrman grade, and fewer sarcomatoid features and lymphovascular invasion (all P < 0.005). All differences in clinicopathological characteristics before targeted therapy disappeared after matching. Patients with late recurrence had significantly longer median overall survival (56 months vs 36 months; P < 0.0001) and median first-line progression-free survival (12 months vs 8 months; P = 0.031). The early recurrence status was a significantly worse predictor for overall survival and first-line progression-free survival (hazard ratio 1.30, P = 0.007; and hazard ratio 1.76, P < 0.001, respectively). CONCLUSIONS: Late recurrence might have prognostic value in terms of oncological outcomes in metastatic renal cell carcinoma treated with targeted therapy.

Clinical factors that influence the occurrence of symptomatic pseudoaneurysms and arteriovenous fistulas after partial nephrectomy: multi-institutional study of renal function outcomes after one year of selective arterial embolization.

PURPOSE: Renal artery pseudoaneurysms (RAPs) and arteriovenous fistulas (AVFs) are rare but potentially life-threatening complications after partial nephrectomy (PN). Selective arterial embolization (SAE) is an effective method for controlling RAPs/AVFs. We assessed the clinical factors affecting the occurrence of RAPs/AVFs after PN and the effects of SAE on postsurgical renal function. MATERIALS AND METHODS: Four hundred ninety-three patients who underwent PN were retrospectively reviewed. They were placed in either the SAE or the non-SAE group. The effects of clinical factors, including R.E.N.A.L. scores, on the occurrence of RAPs/AVFs were analyzed. The influence of SAE on the estimated glomerular filtration rate (eGFR) during the first postoperative year was evaluated. RESULTS: Thirty-three (6.7%) patients experienced RAPs/AVFs within 8 days of the median interval between PN and SAE. The SAE group had significantly higher R.E.N.A.L. scores, higher N component scores, and higher L component scores (all, p <0.05). In the multivariate analysis, higher N component scores were associated with the occurrence of RAPs/AVFs (Odds ratio: 1.96, p=0.039). In the SAE group, the mean 3-day postembolization eGFR was significantly lower than the mean 3-day postoperative eGFR (p <0.01). This difference in the eGFRs was still present 1 year later. CONCLUSIONS: Renal tumors located near the renal sinus and collecting system were associated with a higher risk for RAPs/AVFs after PN. Although SAE was an effective method for controlling symptomatic RAPs/AVFs after PN, a procedure-related impairment of renal function after SAE could occur and still be present at the end of the first postoperative year.

EV-Ident: Identifying Tumor-Specific Extracellular Vesicles by Size Fractionation and Single-Vesicle Analysis.

Tumor-derived extracellular vesicles (EVs) have emerged as a promising source of circulating biomarkers for liquid biopsies. However, understanding the heterogeneous physical and biochemical properties of EVs originating from multiple complex biogenesis pathways remains a major challenge. Here, we introduce EV-Ident for preparation of subpopulations of EVs in three different size fractions: large EVs (EV200 nm; 200-1 000 nm), medium EVs (EV100 nm; 100-200 nm), and small EVs (EV20 nm; 20-100 nm). Furthermore, this technology enables the in situ labeling of fluorescence markers for the protein profiling of individual EVs. As a proof-of-concept, we analyzed the presence of human epidermal growth factor receptor 2 (HER2) and prostate-specific membrane antigen (PSMA) in breast cancer and prostate cancer cell-derived EVs, respectively, using three different size fractions at the single-EV level. By reducing the complexity of EV heterogeneity in each size fraction, we found that HER2-positive breast cancer cells showed the greatest expression of HER2 in EV20 nm, whereas PSMA expression was the highest in EV200 nm derived from PSMA-expressing prostate cancer cells. This increase in HER2 expression in EV20 nm and PSMA expression in EV200 nm was further confirmed in plasma-derived nanoparticles (PNPs) obtained from breast and prostate cancer patients, respectively. Our study demonstrates that single-EV analysis using EV-Ident provides a practical way to understand EV heterogeneity and to successfully identify potent subpopulation of EVs for breast and prostate cancer, which has promising translational implications for cancer theranostics. Furthermore, these findings have the potential to address fundamental questions surrounding the biology and clinical applications of EVs.

Vesical Imaging-Reporting and Data System for Multiparametric MRI to Predict the Presence of Muscle Invasion for Bladder Cancer.

BACKGROUND: The Vesical Imaging-Reporting and Data System (VI-RADS) is a newly developed system of bladder cancer staging with multiparametric MRI (mpMRI), which can be used to predict the presence of muscle invasion for bladder cancer. PURPOSE: To evaluate the accuracy of three mpMRI series (T2 WI, diffusion-weighted imaging [DWI], and dynamic contrast-enhanced image [DCEI]) and VI-RADS for diagnosing the muscle invasive bladder cancer (MIBC). STUDY TYPE: Retrospective. POPULATION: In all, 66 pathologically proven bladder cancers in 32 patients. FIELD STRENGTH/SEQUENCE: Before the diagnostic MRI with an intramuscular antispasmodic agent, optimal bladder distension was confirmed. 3.0T MRI with T2 WI, DWI, and DCEI. ASSESSMENT: Three reviewers independently assessed and scored the bladder cancers in T2 WI, DWI, and DCEI using a five-point score system. Based on the scores in the three sequences, reviewers scored each bladder cancer with reference to VI-RADS categories. We evaluated the diagnostic performance of each of three mpMRI sequences and the final VI-RADS categorization for diagnosing MIBC. STATISTICAL TESTS: Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and the area under the curve (AUC) of each of three sequences separately and VI-RADS categorization for diagnosing the MIBC. RESULTS: The diagnostic performances of each of the three mpMRI series and VI-RADS for diagnosing MIBC were excellent. Especially using the optimal cutoff score >3 for predicting MIBC on DWI, DCEI, and VI-RADS, the sensitivity, specificity, PPV, NPV, and AUC values were 90% (95% confidence interval [CI]: 0.56, 1.00), 100% (95% CI: 0.94, 1.00), 100% (95% CI: 0.66. 1.00), 98.3% (95% CI: 0.91, 1.00), and 0.95, respectively. DATA CONCLUSION: mpMRI based on VI-RADS can stratify patients with bladder cancer according to the presence of muscle invasion. LEVEL OF EVIDENCE: 3. TECHNICAL EFFICACY STAGE: 2. J. Magn. Reson. Imaging 2020;52:1249-1256.

RNA-Seq identifies condition-specific biological signatures of ischemia-reperfusion injury in the human kidney.

BACKGROUND: Acute kidney injury (AKI) is defined as a sudden event of kidney failure or kidney damage within a short period. Ischemia-reperfusion injury (IRI) is a critical factor associated with severe AKI and end-stage kidney disease (ESKD). However, the biological mechanisms underlying ischemia and reperfusion are incompletely understood, owing to the complexity of these pathophysiological processes. We aimed to investigate the key biological pathways individually affected by ischemia and reperfusion at the transcriptome level. RESULTS: We analyzed the steady-state gene expression pattern of human kidney tissues from normal (pre-ischemia), ischemia, and reperfusion conditions using RNA-sequencing. Conventional differential expression and self-organizing map (SOM) clustering analyses followed by pathway analysis were performed. Differential expression analysis revealed the metabolic pathways dysregulated in ischemia. Cellular assembly, development and migration, and immune response-related pathways were dysregulated in reperfusion. SOM clustering analysis highlighted the ischemia-mediated significant dysregulation in metabolism, apoptosis, and fibrosis-related pathways, while cell growth, migration, and immune response-related pathways were highly dysregulated by reperfusion after ischemia. The expression of pro-apoptotic genes and death receptors was downregulated during ischemia, indicating the existence of a protective mechanism against ischemic injury. Reperfusion induced alterations in the expression of the genes associated with immune response such as inflammasome and antigen representing genes. Further, the genes related to cell growth and migration, such as AKT, KRAS, and those related to Rho signaling, were downregulated, suggestive of injury responses during reperfusion. Semaphorin 4D and plexin B1 levels were also downregulated. CONCLUSIONS: We show that specific biological pathways were distinctively involved in ischemia and reperfusion during IRI, indicating that condition-specific therapeutic strategies may be imperative to prevent severe kidney damage after IRI in the clinical setting.

Is it worth carrying out ultrasound-magnetic resonance imaging fusion targeted biopsy on Prostate Imaging Reporting and Data System score 3 prostate lesions?

OBJECTIVES: To evaluate the use of ultrasound-magnetic resonance imaging fusion targeted biopsy for Prostate Imaging Reporting and Data System 3 prostate lesions. METHODS: We identified 227 patients with prostate-specific antigen levels ≥4 ng/mL who underwent concurrent transrectal ultrasound-guided systemic biopsy and fusion biopsy. Suspicious prostatic lesions were assessed in accordance with Prostate Imaging Reporting and Data System version 2.0. We compared ultrasound-magnetic resonance imaging fusion targeted biopsy and ultrasound-guided biopsy cancer detection rates in Prostate Imaging Reporting and Data System 3 lesions with those in other Prostate Imaging Reporting and Data System score lesions. In Prostate Imaging Reporting and Data System 3 patients, we identified clinically significant prostate cancer risk factors by logistic regression analysis. RESULTS: In total, 2770 transrectal ultrasound-guided and 867 fusion biopsy cores were obtained; where 332 (12.0%) and 194 (22.4%) cores were prostate cancer-positive, respectively (P < 0.001). The fusion biopsy cancer detection rate (8.0%) in Prostate Imaging Reporting and Data System 3 lesions was similar to that in Prostate Imaging Reporting and Data System 1-2 lesions, but was lower than that of Prostate Imaging Reporting and Data System 4 (30.0%; P < 0.001) and 5 lesions (65.2%; P < 0.001), and ultrasound-guided biopsy (12.0%; P = 0.023). For clinically significant prostate cancer detection, fusion biopsy in Prostate Imaging Reporting and Data System 3 lesions was inferior to that in Prostate Imaging Reporting and Data System 4 and 5 lesions, and non-superior to ultrasound-guided biopsy. Cancer detection rate trends were similar in biopsy-naïve patients. In Prostate Imaging Reporting and Data System 3 patients, prostate-specific antigen density was the only significant predictor of clinically significant prostate cancer. CONCLUSIONS: The present findings do not support the use of ultrasound-magnetic resonance imaging fusion targeted biopsy for Prostate Imaging Reporting and Data System 3 lesions. Thus, we recommend the use of transrectal ultrasound-guided systemic biopsy for patients with Prostate Imaging Reporting and Data System 3 index lesions.

Three novel methods to measure the postoperative displacement of lower urinary tract structures following radical prostatectomy in a sample of Korean patients.

BACKGROUND: There is a change in the position of the remaining anatomical structures of the lower urinary tract system following radical prostatectomy. The aims of this investigation were to describe three novel methods used to measure the displacement of i) the vesico-urethral junction (VUJ), proximal membranous urethra (PMU) and anorectal junction (ARJ) and ii) the VUJ angle of displacement in men following radical prostatectomy and determine their intra- and interrater reliability. METHODS: Retrospective comparative measurement of twenty pre- and postoperative MRI scans was undertaken by one observer on two separate occasions and on one occasion by another observer. Three standardized midsagittal pelvimetry reference lines were used to describe three X, Y axis measurement systems. The displacement (mm) of the VUJ, PMU and ARJ, and the angle of displacement (degrees) of the VUJ was measured for each of the three methods. Interrater reliability of VUJ, PMU and ARJ displacement and the VUJ angle of displacement measurements was assessed using a two-way mixed-effects agreement intra-class correlation coefficient (ICC) with 95% confidence intervals (CI). Test-retest (intrarater) reliability was calculated using a two-way random effects consistency ICC with 95% CI for all displacement measures of the VUJ, PMU and ARJ for one observer between two days. RESULTS: The pubococcygeal line (PCL) axis measurement system demonstrated good to excellent intrarater and interrater reliability (ICC 95% interval lower bound > 0.75) for the VUJ and PMU displacement and the VUJ angle of displacement measurements. Other measurement systems were less reliable and more variable. CONCLUSIONS: In this sample of 20 Korean patients with median prostate volume 27.5 mL and maximum volume 70 mL, the measurement methodology using the PCL consistently demonstrated good to excellent reliability and the lowest variability for the measurement of the displacement of the VUJ and PMU and the VUJ angle of displacement. The PCL methodology is recommended as the method of choice. Further studies should validate these results in patients with large prostate volumes.

Diagnostic Performance of Radiolabeled Prostate-Specific Membrane Antigen Positron Emission Tomography/Computed Tomography for Primary Lymph Node Staging in Newly Diagnosed Intermediate to High-Risk Prostate Cancer Patients: A Systematic Review and Meta-Analysis.

INTRODUCTION: We aimed to assess the diagnostic accuracy of radiolabeled prostate-specific membrane antigen positron emission tomography (PSMA PET) or positron emission tomography/computed tomography (PET/CT) for primary lymph node (LN) staging in newly diagnosed intermediate to high-risk prostate cancer (PCa) patients. MATERIAL AND METHODS: The MEDLINE, PubMed, EMBASE, and Cochrane Library database from the earliest available date of indexing through May 31, 2018, were searched for studies evaluating the diagnostic performance of radiolabeled PSMA PET or PET/CT for primary LN staging in newly diagnosed intermediate to high-risk PCa. We determined the sensitivities and specificities across studies, calculated positive and negative likelihood ratios (LR+ and LR-), and constructed summary receiver operating characteristic curves. RESULTS: Across 6 studies (298 patients), the pooled sensitivity was 0.71 (95% CI 0.59-0.81) and a pooled specificity of 0.95 (95% CI 0.87-0.99). Likelihood ratio (LR) syntheses gave an overall positive likelihood ratio (LR+) of 15.6 (95% CI 5.6-43.0) and negative likelihood ratio (LR-) of 0.30 (95% CI 0.21-0.43). The pooled diagnostic odds ratio (DOR) was 51 (95% CI 21-126). CONCLUSION: Radiolabeled PSMA PET/CT shows a moderate sensitivity and high specificity for the detection of metastatic LNs in patients with newly diagnosed intermediate to high-risk PCa.

The cumulative incidence and risk factors of postoperative inguinal hernia in patients undergoing radical prostatectomy.

BACKGROUND: The aim of this study is to investigate the cumulative incidence and risk factors of postoperative inguinal hernia (PIH) in patients undergoing radical prostatectomy, i.e., laparoscopic prostatectomy (LRP) and robot-assisted laparoscopic prostatectomy (RARP). METHODS: This study included 1124 patients who had undergone radical prostatectomy or transurethral resection of bladder tumor from 2011-2016. We compared the cumulative incidence of PIH in the radical prostatectomy groups (460; LRP 341, RARP 119) and the control group (664; transurethral resection of bladder tumor), and we then analyzed the risk factors (age, operative methods, previous abdominal operative history, thickness and width of external oblique muscle and rectus muscle, thickness of abdominal subcutaneous fat layer at Hesselbach's triangle level, body mass index, prostate-specific antigen, operative time, specimen weight, Gleason score, and pathology T-stage) of PIH in the radical prostatectomy groups. RESULTS: The median follow-up period in this study was 39.6 months. In Kaplan-Meier curve analysis, the cumulative incidence of PIH was 5.3, 4.2, and 0.5% for the LRP, RARP, and control groups, respectively (p < 0.001). Multiple logistic regressions showed that thickness of external oblique muscle and width of rectus muscle were significant risk factors (p < 0.001 and p = 0.027). CONCLUSIONS: PIH is considered to be one of the complications of LRP and RARP. Moreover, we suggest that if the thickness of the muscle is <7.3 mm, thoughtful surgical manipulation is needed for radical prostatectomy, and care should be taken to determine whether hernia occurs during follow-up.

The two isoforms of matrix metalloproteinase- 2 have distinct renal spatial and temporal distributions in murine models of types 1 and 2 diabetes mellitus.

BACKGROUND: We recently reported on the enhanced tubular expression of two discrete isoforms of the MMP-2 (full length and N-terminal truncated, FL-MMP-2, NTT-MMP-2) in a murine model and human diabetic kidneys. In the present study, we examined in more detail the temporal and spatial distributions of MMP-2 isoform expression in murine models of Type 1 and Type 2 diabetes mellitus. METHODS: Diabetic models were streptozotocin (STZ)-induced diabetes (Type 1 diabetes mellitus) and db/db mice (Type 2 diabetes mellitus). We quantified the abundance of two isoforms of MMP-2 transcripts by qPCR. A spatial distribution of two isoforms of MMP-2 was analyzed semi-quantitatively according to time after injection of STZ and with increasing age of db/db mice. Furthermore, immunohistochemistry for nitrotyrosine was performed to examine a potential association between oxidative stress and MMP-2 isoform expression. RESULTS: Both isoforms of MMP-2 were upregulated in whole kidneys from STZ and db/db mice. In the case of FL-MMP-2, mRNA levels significantly increased at 12 and 24 weeks in STZ mice, while the isoform expression was significantly increased only at 16 weeks, in the db/db mice. FL-MMP-2 protein levels increased in the cortices and outer medullae of both STZ and db/db mice as a function of the duration of diabetes. For NTT-MMP-2, mRNA levels increased earlier at 4 weeks in STZ mice and at 10 weeks of age in db/db mice. The expression of NTT-MMP-2 also increased, primarily in the cortices of STZ and db/db mice, as a function of the duration of diabetes. Quantitatively, these findings were consistent with the qPCR results in the case of NTT-MMP-2, respectively (STZ 24 weeks, 3.24 ± 3.70 fold; 16 weeks db/db, 4.49 ± 0.55 fold). In addition, nitrotyrosine was expressed primarily in cortex as compared to medulla as a function of the duration of diabetes similar to NTT-MMP-2 expression. CONCLUSIONS: Two isoforms of MMP-2 are highly inducible in two diabetic murine models and become more abundant as a function of time. As the expression patterns were not the same in the two isoforms of MMP-2, it is possible that each isoform has a discrete role in the development of diabetic renal injury.

Transcript Levels of Androgen Receptor Variant 7 and Ubiquitin-Conjugating Enzyme 2C in Hormone Sensitive Prostate Cancer and Castration-Resistant Prostate Cancer.

PURPOSE: This study is designed to identify the androgen receptor variant 7 (AR-V7) status, clinical significance of AR-V7 in hormone sensitive prostate cancer (HSPC). Then, we evaluated AR-V7 and changes of its target gene, ubiquitin-conjugating enzyme E2C (UBE2C) which is an anaphase-promoting complex/cyclosome (APC/C)-specific ubiquitin-conjugating enzyme, in castration-resistant prostate cancer (CRPC) in serial tumor biopsies from patients receiving androgen deprivation therapy. METHODS: We used RT-PCR and Q-PCR assay to evaluate AR-V7, androgen receptor full length (AR-FL), and UBE2C in tumor biopsies from patients with HSPC and CRPC. We examined associations between mRNA expression of AR-V7 and clinicopathologic factors. Furthermore, to identify other potential genes involved in the development of CRPC, RNA sequencing was conducted, using paired prostate cancer (PCa) tissues obtained immediately prior to treatment and at the time of therapeutic resistance. RESULTS: A total of 13 HSPC patients and three CRPC patients were enrolled. Neither a high Gleason score (score of 8 and 9) nor a high risk of PCa (a high risk of locally advanced PCa according to NCCN guidelines) was correlated with mRNA expression of AR-V7 in HSPC (P = 0.153 and P = 0.215). The mRNA expression of AR-FL, but not AR-V7, was significantly associated with the mRNA expression of UBE2C level in HSPC (P = 0.007). However, increased expression of AR-V7, not AR-FL, paralleled increased expression of UBE2C in the CRPC specimens (P = 0.03). AR-V7 expression status before ADT was likely related to shorter CRPC development in patients treating ADT. The result of the RNA-sequencing analysis using serial samples from the same patient before and after castration demonstrated an increased level of the PI3K regulatory subunit 1 (P = 0.018). CONCLUSION: Our study revealed the role of UBE2C as a marker of the androgen signaling pathway in PCa. Differential gene expression analysis using serial samples from the same patient before and after castration revealed potential genes and pathways involved in development of CRPC. Further studies are needed to determine whether these genes and pathways are potential therapeutic target for CRPC. Prostate 77:60-71, 2017. © 2016 Wiley Periodicals, Inc.

Clinical application of calculated split renal volume using computed tomography-based renal volumetry after partial nephrectomy: Correlation with technetium-99m dimercaptosuccinic acid renal scan data.

OBJECTIVE: To evaluate the clinical application of computed tomography-based measurement of renal cortical volume and split renal volume as a single tool to assess the anatomy and renal function in patients with renal tumors before and after partial nephrectomy, and to compare the findings with technetium-99m dimercaptosuccinic acid renal scan. METHODS: The data of 51 patients with a unilateral renal tumor managed by partial nephrectomy were retrospectively analyzed. The renal cortical volume of tumor-bearing and contralateral kidneys was measured using ImageJ software. Split estimated glomerular filtration rate and split renal volume calculated using this renal cortical volume were compared with the split renal function measured with technetium-99m dimercaptosuccinic acid renal scan. RESULTS: A strong correlation between split renal function and split renal volume of the tumor-bearing kidney was observed before and after surgery (r = 0.89, P < 0.001 and r = 0.94, P < 0.001). The preoperative and postoperative split estimated glomerular filtration rate of the operated kidney showed a moderate correlation with split renal function (r = 0.39, P = 0.004 and r = 0.49, P < 0.001). The correlation between reductions in split renal function and split renal volume of the operated kidney (r = 0.87, P < 0.001) was stronger than that between split renal function and percent reduction in split estimated glomerular filtration rate (r = 0.64, P < 0.001). CONCLUSIONS: The split renal volume calculated using computed tomography-based renal volumetry had a strong correlation with the split renal function measured using technetium-99m dimercaptosuccinic acid renal scan. Computed tomography-based split renal volume measurement before and after partial nephrectomy can be used as a single modality for anatomical and functional assessment of the tumor-bearing kidney.

Androgen Receptor-dependent Expression of Low-density Lipoprotein Receptor-related Protein 6 is Necessary for Prostate Cancer Cell Proliferation.

Androgen receptor (AR) signaling is important for prostate cancer (PCa) cell proliferation. Here, we showed that proliferation of hormone-sensitive prostate cancer cells such as LNCaP was significantly enhanced by testosterone stimulation whereas hormone-insensitive prostate cancer cells such as PC3 and VCaP did not respond to testosterone stimulation. Blocking of AR using bicalutamide abolished testosterone-induced proliferation of LNCaP cells. In addition, knockdown of AR blocked testosterone-induced proliferation of LNCaP cells. Basal expression of low-density lipoprotein receptor-related protein 6 (LRP6) was elevated in VCaP cells whereas stimulation of testosterone did not affect the expression of LRP6. However, expression of LRP6 in LNCaP cells was increased by testosterone stimulation. In addition, knockdown of LRP6 abrogated testosterone-induced proliferation of LNCaP cells. Given these results, we suggest that androgen-dependent expression of LRP6 plays a crucial role in hormone-sensitive prostate cancer cell proliferation.

Nomogram for prediction of prostate cancer with serum prostate specific antigen less than 10 ng/mL.

Although prostate-specific antigen (PSA) is a very useful screening tool, prostate biopsy is still necessary to confirm prostate cancer (PCA). However, it is reported that PSA is associated with a high false-positive rate and prostate biopsy also has various procedure-related complications. Therefore, the authors have devised a nomogram, which can be used to estimate the risk of PCA, using available clinical data for men with a serum PSA less than 10 ng/mL. Prostate biopsies were obtained from 2,139 patients from January 1998 to March 2011. Of them, 1,171 patients with a serum PSA less than 10 ng/mL were only included in this study. Patient age, PSA, free PSA, prostate volume, PSA density and percent free PSA ratio were analyzed. Among 1,171 patients, 255 patients (21.8%) were diagnosed as PCA. Multivariate analyses showed that patient age, prostate volume, PSA and percent free PSA had statistically significant relationships with PCA (P < 0.05) and were used as nomogram predictor variables. The area under the (ROC) curve for all factors in a model predicting PCA was 0.759 (95% CI, 0.716-0.803).

Intravesical prostatic protrusion as a predictor of early urinary continence recovery after laparoscopic radical prostatectomy.

OBJECTIVES: To evaluate the significance of intravesical prostatic protrusion as a predictor of early urinary continence recovery after laparoscopic radical prostatectomy. METHODS: A total of 242 patients who underwent laparoscopic radical prostatectomy were included in the study. Data on incontinence status and the number of pads required per day for urinary incontinence were collected. Urinary continence was defined as no pad use or occasional security pad use. Intravesical prostatic protrusion was measured by the vertical distance from the tip of the protruding prostate to the base of the urinary bladder in the sagittal plane of preoperative magnetic resonance imaging. Continence at 1, 3, 6 and 12 months postoperatively was assessed by dividing the patients into two groups based on the degree of intravesical prostatic protrusion. The correlation between preoperative factors and urinary continence after laparoscopic radical prostatectomy was examined. RESULTS: The urinary continence rates at postoperative month 1, 3, 6 and 12 were 19%, 50%, 79.8% and 92.1%, respectively. In the multivariate logistic analysis, intravesical prostatic protrusion was a significant independent predictive factor of early urinary continence at 1, 3, 6, 9 and 12 months. Markedly improved urinary continence was observed in the non-significant intravesical prostatic protrusion group (intravesical prostatic protrusion <5 mm) at all periods compared with the significant intravesical prostatic protrusion group (intravesical prostatic protrusion ≥5 mm; P < 0.05). CONCLUSIONS: These findings suggest that the likelihood of postoperative urinary incontinence in patients undergoing laparoscopic radical prostatectomy is markedly higher in those with larger intravesical prostatic protrusion, and that intravesical prostatic protrusion is correlated with the duration of postoperative urinary incontinence.

Phospholipase C-ß3 is dispensable for vascular constriction but indispensable for vascular hyperplasia.

Angiotensin II (AngII) induces the contraction and proliferation of vascular smooth muscle cells (VSMCs). AngII activates phospholipase C-ß (PLC-ß), thereby inducing Ca2+ mobilization as well as the production of reactive oxygen species (ROS). Since contraction is a unique property of contractile VSMCs, signaling cascades related to the proliferation of VSMCs may differ. However, the specific molecular mechanism that controls the contraction or proliferation of VSMCs remains unclear. AngII-induced ROS production, migration, and proliferation were suppressed by inhibiting PLC-ß3, inositol trisphosphate (IP3) receptor, and NOX or by silencing PLC-ß3 or NOX1 but not by NOX4. However, pharmacological inhibition or silencing of PLC-ß3 or NOX did not affect AngII-induced VSMC contraction. Furthermore, the AngII-dependent constriction of mesenteric arteries isolated from PLC-ß3∆SMC, NOX1-/-, NOX4-/- and normal control mice was similar. AngII-induced VSMC contraction and mesenteric artery constriction were blocked by inhibiting the L-type calcium channel Rho-associated kinase 2 (ROCK2) or myosin light chain kinase (MLCK). The activation of ROCK2 and MLCK was significantly induced in PLC-ß3∆SMC mice, whereas the depletion of Ca2+ in the extracellular medium suppressed the AngII-induced activation of ROCK2, MLCK, and vasoconstriction. AngII-induced hypertension was significantly induced in NOX1-/- and PLC-ß3∆SMC mice, whereas LCCA ligation-induced neointima formation was significantly suppressed in NOX1-/- and PLC-ß3∆SMC mice. These results suggest that PLC-ß3 is essential for vascular hyperplasia through NOX1-mediated ROS production but is nonessential for vascular constriction or blood pressure regulation.

Comparison of Short-Term Outcomes and Safety Profiles between Androgen Deprivation Therapy+Abiraterone/Prednisone and Androgen Deprivation Therapy+Docetaxel in Patients with De Novo Metastatic Hormone-Sensitive Prostate Cancer.

PURPOSE: This study aimed to compare the short-term outcomes and safety profiles of androgen-deprivation therapy (ADT)+abiraterone/prednisone with those of ADT+docetaxel in patients with de novo metastatic hormone-sensitive prostate cancer (mHSPC). MATERIALS AND METHODS: A web-based database system was established to collect prospective cohort data for patients with mHSPC in Korea. From May 2019 to November 2022, 928 patients with mHSPC from 15 institutions were enrolled. Among these patients, data from 122 patients who received ADT+abiraterone/prednisone or ADT+docetaxel as the primary systemic treatment for mHSPC were collected. The patients were divided into two groups: ADT+abiraterone/prednisone group (n=102) and ADT+docetaxel group (n=20). We compared the demographic characteristics, medical histories, baseline cancer status, initial laboratory tests, metastatic burden, oncological outcomes for mHSPC, progression after mHSPC treatment, adverse effects, follow-up, and survival data between the two groups. RESULTS: No significant differences in the demographic characteristics, medical histories, metastatic burden, and baseline cancer status were observed between the two groups. The ADT+abiraterone/prednisone group had a lower prostate-specific antigen (PSA) progression rate (7.8% vs. 30.0%; p=0.011) and lower systemic treatment discontinuation rate (22.5% vs. 45.0%; p=0.037). No significant differences in adverse effects, oncological outcomes, and total follow-up period were observed between the two groups. CONCLUSIONS: ADT+abiraterone/prednisone had lower PSA progression and systemic treatment discontinuation rates than ADT+docetaxel. In conclusion, further studies involving larger, double-blinded randomized trials with extended follow-up periods are necessary.