Choung Soo Kim

Enzalutamide in Men with Chemotherapy-naïve Metastatic Castration-resistant Prostate Cancer : Extended Analysis of the Phase 3 PREVAIL Study

Enzalutamide significantly improved radiographic progression-free survival (rPFS) and overall survival (OS) among men with chemotherapy-naïve metastatic castration-resistant prostate cancer at the prespecified interim analysis of PREVAIL, a phase 3, double-blind, randomized study. We evaluated the longer-term efficacy and safety of enzalutamide up to the prespecified number of deaths in the final analysis, which included an additional 20 mo of follow-up for investigator-assessed rPFS, 9 mo of follow-up for OS, and 4 mo of follow-up for safety. Enzalutamide reduced the risk of radiographic progression or death by 68% (hazard ratio [HR] 0.32, 95% confidence interval [CI] 0.28-0.37; p<0.0001) and the risk of death by 23% (HR 0.77, 95% CI 0.67-0.88; p=0.0002). Median investigator-assessed rPFS was 20.0 mo (95% CI 18.9-22.1) in the enzalutamide arm and 5.4 mo (95% CI 4.1-5.6) in the placebo arm. Median OS was 35.3 mo (95% CI 32.2-not yet reached) in the enzalutamide arm and 31.3 mo (95% CI 28.8-34.2) in the placebo arm. At the time of the OS analysis, 167 patients in the placebo arm had crossed over to receive enzalutamide. The most common adverse events in the enzalutamide arm were fatigue, back pain, constipation, and arthralgia. This final analysis of PREVAIL provides more complete assessment of the clinical benefit of enzalutamide. PREVAIL is registered on ClinicalTrials.gov as NCT01212991.nnnPATIENT SUMMARYnAccording to data from longer follow-up, enzalutamide continued to provide benefit over placebo in patients with metastatic castration-resistant prostate cancer.

Three-Dimensional Printing: Basic Principles and Applications in Medicine and Radiology

The advent of three-dimensional printing (3DP) technology has enabled the creation of a tangible and complex 3D object that goes beyond a simple 3D-shaded visualization on a flat monitor. Since the early 2000s, 3DP machines have been used only in hard tissue applications. Recently developed multi-materials for 3DP have been used extensively for a variety of medical applications, such as personalized surgical planning and guidance, customized implants, biomedical research, and preclinical education. In this review article, we discuss the 3D reconstruction process, touching on medical imaging, and various 3DP systems applicable to medicine. In addition, the 3DP medical applications using multi-materials are introduced, as well as our recent results.

Multilocular cystic renal cell carcinoma: clinicopathological features and preoperative prediction using multiphase computed tomography

Study Type – Diagnostic (exploratory cohort)

Phase III Study Comparing a Reduced Dose of Cabazitaxel (20 mg/m2) and the Currently Approved Dose (25 mg/m2) in Postdocetaxel Patients With Metastatic Castration-Resistant Prostate Cancer—PROSELICA

Purpose Cabazitaxel 25 mg/m2 (C25) significantly improved overall survival (OS) versus mitoxantrone ( P < .001) in postdocetaxel patients with metastatic castration-resistant prostate cancer (mCRPC) in the phase III TROPIC study. The phase III PROSELICA study ( ClinicalTrials.gov identifier: NCT01308580) assessed the noninferiority of cabazitaxel 20 mg/m2 (C20) versus C25 in postdocetaxel patients with mCRPC. Methods Patients were stratified by Eastern Cooperative Oncology Group performance status, measurability of disease per Response Evaluation Criteria in Solid Tumors (RECIST), and region, and randomly assigned to receive C20 or C25. To claim noninferiority of C20 (maintenance of ≥ 50% of the OS benefit of C25 v mitoxantrone in TROPIC) with 95% confidence level, the upper boundary of the CI of the hazard ratio (HR) for C20 versus C25 could not exceed 1.214 under a one-sided 98.89% CI after interim analyses. Secondary end points included progression-free survival, prostate-specific antigen (PSA), tumor and pain responses and progression, health-related quality of life, and safety. Results Overall, 1,200 patients were randomly assigned (C20, n = 598; C25, n = 602). Baseline characteristics were similar in both arms. Median OS was 13.4 months for C20 and 14.5 months for C25 (HR, 1.024). The upper boundary of the HR CI was 1.184 (less than the 1.214 noninferiority margin). Significant differences were observed in favor of C25 for PSA response (C20, 29.5%; C25, 42.9%; nominal P < .001) and time to PSA progression (median: C20, 5.7 months; C25, 6.8 months; HR for C20 v C25, 1.195; 95% CI, 1.025 to 1.393). Health-related quality of life did not differ between cohorts. Rates of grade 3 or 4 treatment-emergent adverse events were 39.7% for C20 and 54.5% for C25. Conclusion The efficacy of cabazitaxel in postdocetaxel patients with mCRPC was confirmed. The noninferiority end point was met; C20 maintained ≥ 50% of the OS benefit of C25 versus mitoxantrone in TROPIC. Secondary efficacy end points favored C25. Fewer adverse events were observed with C20.

Proinflammatory Cytokine-Induced NF-κB Activation in Human Mesangial Cells Is Mediated through Intracellular Calcium but Not ROS: Effects of Silymarin

Background: It is not fully understood whether intracellular calcium and/or reactive oxygen species (ROS) are involved in nuclear factor-ĸB (NF-ĸB) activation by proinflammatory cytokines. Silymarin exhibits anti-inflammatory and antioxidant effects but the effect of silymarin in human mesangial cells is largely unknown. Method: NF-ĸB binding activity was measured by electrophoretic mobility shift assay. Intracellular calcium was monitored by confocal microscopy using Fluo-3 and intracellular ROS production was determined by flow cytometry. Monocyte chemoattractant protein-1 (MCP-1) expression was measured by Northern blot analysis and ELISA. Results: NF-ĸB was activated within 30 min by tumor necrosis factor-α (TNF-α) or interleukin-1β (IL-1β). Intracellular ROS was not produced until 30 min and also antioxidants such as N-acetylcysteine and tiron had no effect on the TNF-α- or IL-1β-induced NF-ĸB activation. Intracellular calcium was increased by TNF-α and IL-1β. Furthermore, a calcium chelator, BAPTA-AM, attenuated the NF-ĸB activation. Silymarin dose-dependently inhibited the TNF-α- or IL-1β-induced NF-ĸB activation and MCP-1 expression. Silymarin also inhibited TNF-α-induced intracellular calcium. Conclusions: Induction of NF-ĸB within 30 min by TNF-α- and IL-1β was mediated through intracellular calcium but not ROS. Silymarin inhibited TNF-α-induced calcium-dependent NF-ĸB activation irrespective of its antioxidant effect.

Differential alternative splicing of human transglutaminase 4 in benign prostate hyperplasia and prostate cancer

Transglutaminase 4 is a member of enzyme family that catalyzes calcium-dependent posttranslational modification of proteins. Although transglutaminase 4 has been shown to have prostate-restricted expression pattern, little is known about the biological function of transglutaminase 4 in human. To gain insight into its role in prostate, we analyzed the expression status of human transglutaminase 4 in benign prostate hyperplasia (BPH) and prostate cancer (PCa). Unexpectedly, RT-PCR and nucleotide sequence analysis showed four alternative splicing variants of transglutaminase 4: transglutaminase 4-L, -M (-M1 and -M2) and -S. The difference between transglutaminase 4-M1 and -M2 is attributed to splicing sites, but not nucleotide size. The deduced amino acid sequences showed that transglutaminase 4-L, -M1 and -M2 have correct open reading frames, whereas transglutaminase 4-S has a truncated reading frame. RT-PCR analysis of clinical samples revealed that transglutaminase 4-M and -S were detected in all tested prostate tissue (80 BPH and 48 PCa). Interestingly, transglutaminase 4-L was found in 56% of BPH (45 out of 80) and only in 15% of PCa (7 out of 48). However, transglutaminase 4-L expression did not correlate with serum prostate-specific antigen (PSA) level, prostate volumes or PSA densities. These results will provide a clue to future investigation aiming at delineating physiological and pathological roles of human transglutaminase 4.

C-Reactive Protein Induces NF-κB Activation through Intracellular Calcium and ROS in Human Mesangial Cells

Background: C-reactive protein (CRP) is known to have a direct proinflammatory effect in endothelial cells. However, little is known about the effect of CRP in intrinsic renal cells. We investigated the effects of CRP on the nuclear factor-ĸB (NF-ĸB) activation and monocyte chemoattractant protein-1 (MCP-1) gene expression in human mesangial cells and also examined whether intracellular calcium and reactive oxygen species (ROS) were involved in the CRP- induced NF-ĸB activation. Methods: NF-ĸB binding activity and MCP-1 mRNA expression were measured by electrophoretic mobility shift assay and Northern blot analysis, respectively.Intracellular calcium was monitored by confocal microscopy using calcium sensitive dye, Fluo-3 and intracellular ROS production was determined, using 2′,7′-dichlorofluorescin diacetate. Results: CRP increased NF-ĸB binding activity in a dose-dependent manner (12.5–100 µg/ml), which was induced within 1 h after incubation and peaked around 3 h. CRP also increased the MCP-1 mRNA expression via activation of NF-ĸB. Both intracellular calcium and ROS was induced by CRP. Calcium chelator, BAPTA-AM and anti-oxidants such as N-acetylcysteine and tiron suppressed CRP-induced NF-ĸB activation. Conclusion: CRP exerted a proinflammatory effect in human mesangial cells by inducing MCP-1 gene expression via NF-ĸB activation, which was mediated, at least in part, through intracellular calcium and ROS.

Desmopressin Add-On Therapy for Refractory Nocturia in Men Receiving α-Blockers for Lower Urinary Tract Symptoms

PURPOSEnAlpha-blockers improve lower urinary tract symptoms associated with benign prostatic obstruction. Nocturia, a storage symptom, is a common complaint in men. However, it does not fully respond to α-blocker therapy, likely due to its multifactorial pathophysiology. We evaluated the efficacy and safety of desmopressin as add-on therapy for refractory nocturia in men previously treated with an α-blocker for lower urinary tract symptoms.nnnMATERIALS AND METHODSnEligible patients were men 50 years old or older with lower urinary tract symptoms and persistent nocturia despite α-blocker treatment for a minimum of 4 weeks. The optimum dose of oral desmopressin was determined during a 4-week dose titration period and this dose was maintained for 24 weeks. Flow volume charts, International Prostate Symptom Score total and subscores, uroflowmetry and post-void residual urine volume were assessed.nnnRESULTSnA total of 216 patients were enrolled in the study. Of these patients there were 158 (76%) with nocturnal polyuria, 15 (7.2%) with decreased nocturnal bladder capacity and 35 (16.8%) with nocturia due to both causes. The number of nocturnal voids significantly decreased from a baseline mean of 7.0 to 5.7 episodes for 3 days at the 24-week visit. The average International Prostate Symptom Score total and subscore significantly decreased by 4 weeks and were maintained at 24 weeks. In patients younger than 65 years, International Prostate Symptom Score voiding subscores were significantly improved at 24 weeks compared to those age 65 years or older.nnnCONCLUSIONSnDesmopressin add-on therapy for refractory nocturia in men previously treated with an α-blocker for lower urinary tract symptoms improved voiding symptoms as well as nocturia, storage symptoms.

Extranodal extension in node-positive bladder cancer: the continuing controversy.

Study Type – Therapy (case series) u2028Level of Evidenceu20034

Tumor volume, surgical margin, and the risk of biochemical recurrence in men with organ-confined prostate cancer

OBJECTIVESnWe proposed to investigate predictors of biochemical recurrence (BCR) in pT2 prostate cancer by identifying the interrelationship between the tumor volume and surgical margin status, and their impact on recurrence.nnnMATERIALS AND METHODSnClinical, pathologic, and follow-up data of 404 consecutive patients who were treated with radical prostatectomy alone and were diagnosed as pT2 prostate cancer in our institution were reviewed. Percent tumor volume (PTV) was estimated from the cancer distribution map, and the surgical margin status was reviewed by a single pathologist (JYR). Clinicopathologic variables were analyzed with respect to the risk of BCR.nnnRESULTS AND LIMITATIONSnRecurrence was observed in 39 (9.7%) patients at a mean of 28.9 (5-47) months. Preoperative PSA, biopsy Gleason score, surgical Gleason score, PTV, and surgical margin status were significantly related to BCR in univariate analysis; in multivariate analysis, PTV (P < 0.001) and surgical Gleason score (P = 0.021) were independent predictors of BCR. PTV was also an independent determinant of positive surgical margin (P = 0.035, HR 1.026, 95% CI 1.002-1.050). By combining the 2 predictors 5-year recurrence-free survivals for PTV ≤ 14.5% and surgical Gleason score ≤ 7, PTV >14.5% or surgical Gleason score > 7, and PTV > 14.5% and surgical Gleason score > 7 were 97.5%, 88.7%, and 44.5%, respectively (log-rank test, P < 0.01). Retrospective study nature, use of PTV instead of actual volume, and intermediate follow-up length are the main limitations of the study.nnnCONCLUSIONSnIn men with pT2 prostate cancer, percent tumor volume and the surgical Gleason score were independently prognostic of BCR and by combining the 2 factors, risk of BCR could be significantly stratified. Tumor volume further determined surgical margin status undermining its prognostic value as an independent variable.