Chunwoo Lee

Comparative Study of Autologous Stromal Vascular Fraction and Adipose-Derived Stem Cells for Erectile Function Recovery in a Rat Model of Cavernous Nerve Injury

The abilities of intracavernous injection of autologous stromal vascular fraction (SVF) and adipose‐derived stem cells (ADSCs) to facilitate recovery of erectile function in a rat model of cavernous nerve (CN) injury were compared. Forty male Sprague‐Dawley rats were randomly divided into four groups: sham and control groups (intracavernous injection of phosphate‐buffered saline), SVF group (intracavernous injection of SVF), and ADSC group (intracavernous injection of ADSCs). Rats in the latter three groups underwent bilateral CN injury prior to injection. The evaluation of erectile function and histomorphometric studies were performed 4 weeks after injection. The ratio of maximal intracavernous pressure to mean arterial pressure was significantly lower in the control group than in the sham group (0.18 vs. 0.56, p < .001). Intracavernous injection of SVF (0.36, p = .035) significantly improved erectile function compared with that in the control group, whereas the ADSC group (0.35, p = .052) showed marginally significant improvement. The smooth muscle/collagen ratio, smooth muscle content, number of neuronal nitric‐oxide synthase‐positive nerve fibers, and expression of von Willebrand factor were significantly higher in the SVF and ADSC groups than in the control group. Expression of endothelial nitric‐oxide synthase was significantly increased in the SVF group. The increases in the smooth muscle/collagen ratio and von Willebrand factor expression were larger in the SVF group than in the ADSC group. Intracavernous injection of SVF or ADSCs was equally effective in recovering penile erection in a rat model of CN injury.

Smoking and survival after radical cystectomy for bladder cancer.

OBJECTIVE To present our long-term follow-up data to investigate whether cigarette smoking is associated with the prognosis of bladder cancer after radical cystectomy. Despite the close link between cigarette smoking and the development of bladder cancer, little is known about the influence of cigarette smoking on the bladder cancer prognosis after radical cystectomy. MATERIALS AND METHODS The cigarette smoking status of 602 patients who had undergone radical cystectomy for bladder cancer was determined using questionnaires completed before surgery. The effect of cigarette smoking on recurrence-free survival, cancer-specific survival, and overall survival was determined. RESULTS Of the 340 patients with a smoking history, 159 were current smokers. The smokers were younger (P = .001) and more likely to be male (P = .001) than were the nonsmokers. The 5-year recurrence-free survival rate of the smokers and nonsmokers was 62.1% and 56.8% (P = .182), the 5-year cancer-specific survival rate was 67.3%, 63.9% (P = .436), and the 5-year overall survival rate was 63.0% and 58.8% (P = .309), respectively. Multivariate analysis revealed that smoking was not an independent predictor of recurrence-free survival or cancer-specific survival. After adjusting for other prognostic variables, cigarette smoking status (non-, ex-, or current smoker), cumulative exposure, and years from smoking cessation were not associated with cancer-specific survival (P = .378, P = .827, and P = .876, respectively). CONCLUSION The results of the present study found no association between cigarette smoking and the prognosis of bladder cancer after radical cystectomy.

Validation of the 2009 TNM Classification for Renal Cell Carcinoma: Comparison with the 2002 TNM Classification by Concordance Index

Purpose To assess the validity of the 2009 TNM classification for renal cell carcinoma (RCC) and compare its ability to predict survival relative to the 2002 classification. Materials and Methods We identified 1,691 patients who underwent radical nephrectomy or partial nephrectomy for unilateral, sporadic RCC between 1989 and 2007. Cancer-specific survival was estimated by the Kaplan-Meier method and was compared among groups by the log-rank test. Associations of the 2002 and 2009 TNM classifications with death from RCC were evaluated by Cox proportional hazards regression models. The predictive abilities of the two classifications were compared by using Harrells concordance (c) index. Results There were 234 deaths from RCC a mean of 38 months after nephrectomy. According to the 2002 primary tumor classification, 5-year cancer-specific survival was 97.6% in T1a, 92.0% in T1b, 83.3% in T2, 61.9% in T3a, 51.1% in T3b, 40.0% in T3c, and 33.6% in T4 (p for trend<0.001). According to the 2009 classification, 5-year cancer-specific survival was 83.2% in T2a, 83.8% in T2b, 62.6% in T3a, 41.1% in T3b, 50.0% in T3c, and 26.1% in T4 (p for trend<0.001). The c index for the 2002 primary tumor classification was 0.810 in the univariate analysis and increased to 0.906 in the multivariate analysis. The c index for the 2009 primary tumor classification was 0.808 in the univariate analysis and increased to 0.904 in the multivariate analysis. Conclusions Our data suggest that the predictive ability the 2009 TNM classification is not superior to that of the 2002 classification.

Bone marrow–derived mesenchymal stromal cell therapy in a rat model of cavernous nerve injury: Preclinical study for approval

BACKGROUND AIMS Although clinical studies using stem cells to treat erectile dysfunction have been performed or are ongoing, there is little consensus on the optimal protocol. We aimed to develop a protocol optimizing human bone marrow-derived mesenchymal stromal cell (hBMSC) therapy in a rat model of cavernous nerve injury. METHODS We performed, in order, a dose-finding study, a toxicokinetic study of hBMSCs, and a study to determine the timing and number of cell injections. RESULTS From the dose-finding study, 1 × 10(6) cells were selected as the dose per hBMSC injection. From the toxicokinetic study, 14 days was selected as the interval between repeat treatments. In the final study, the ratio of maximal intracavernous pressure to mean arterial pressure was significantly lower in the control group than in the sham group (23.4% vs. 55.1%, P <0.001). An immediate single injection of hBMSCs significantly improved erectile function compared with the control group (39.8%, P = 0.035), whereas a delayed single injection showed improvement with a marginal trend (38.1%, P = 0.079). All histomorphometric changes were significantly more improved in the immediate or delayed single injection groups than in the control group. Repeat treatments did not provide any benefit for the recovery of erectile function and histomorphometric changes. CONCLUSIONS Intracavernous injection of 1 × 10(6) hBMSCs results in a recovery of penile erection and histomorphometric changes in a rat model of cavernous nerve injury, even when treatment was delayed until 4 weeks after cavernous nerve injury.

KML001 Induces Apoptosis and Autophagic Cell Death in Prostate Cancer Cells via Oxidative Stress Pathway

We investigated the effects of KML001 (NaAsO2, sodium metaarsenite, Kominox), an orally bioavailable arsenic compound, on the growth and death of human prostate cancer cells and its mechanism of action. Growth inhibition was assessed by cytotoxicity assays in the presence or absence of inhibitor of apoptosis, inhibitor of autophagy or antioxidant N-Acetyl-L-cysteine to study mechanism of cell death induced by KML001 in PC3, DU145 and LNCaP prostate cancer cell lines. Electron microscopy, flow cytometry and Western blotting were used to study apoptotic and autophagic mechanisms. The DU145 xenograft model was used to determine the efficacy of KML001 in vivo. KML001 decreased the viability of cells and increased the percentage of annexin V-positive cells dose-dependently in prostate cancer cells, and LNCaP cells were more sensitive to KML001 than PC3 or DU145 cells. Electron microscopy revealed typical apoptotic characters and autophagic vacuoles in cells treated with KML001. Exposure to KML001 in prostate cancer cells induced apoptosis and autophagy in a time- and dose-dependent manner. KML001 induced dose-dependent accumulation of reactive oxygen species, and scavenging the reactive oxygen species with N-Acetyl-L-cysteine reduced LC3 and cleaved poly (ADP-ribose) polymerase. KML001 significantly inhibited tumor growth in the DU145 xenograft model. In addition, significant decrease of proliferation and significant increases of apoptosis and autophagy were observed in KML001-treated tumors than in vehicle-treated tumors. Exposure of human prostate cancer cells to KML001 induced both apoptosis and autophagic cell death via oxidative stress pathway. And KML001 had an antiproliferative effect on DU145 cells in xenograft mice.

Effects of statin use on the response duration to androgen deprivation therapy in metastatic prostate cancer

Purpose To determine whether statin use delays the development of castration-resistant prostate cancer (CRPC) in patients with metastatic prostate cancer treated with androgen deprivation therapy (ADT). Materials and Methods A total of 171 patients with metastatic prostate cancer at the time of diagnosis who were treated with ADT between January 1997 and December 2013 were retrospectively analyzed. The patients were classified into two groups: the nonstatin use group (A group) and the statin use group (B group). Multivariate analysis was performed on statin use and other factors considered likely to have an effect on the time to progression to CRPC. Results The mean patient age was 67.1±9.1 years, and the mean follow-up period was 52 months. The mean initial prostate-specific antigen (PSA) level was 537 ng/mL. Of the 171 patients, 125 (73%) were in group A and 46 (27%) were in group B. The time to progression to CRPC was 22.7 months in group A and 30.5 months in group B, and this difference was significant (p=0.032). Blood cholesterol and initial PSA levels did not differ significantly according to the time to progression to CRPC (p=0.288, p=0.198). Multivariate analysis using the Cox regression method showed that not having diabetes (p=0.037) and using a statin (p=0.045) significantly increased the odds ratio of a longer progression to CRPC. Conclusions Statin use in metastatic prostate cancer patients appears to delay the progression to CRPC. Large-scale, long-term follow-up studies are needed to validate this finding.

Feasibility and Safety of Laparoscopic Ablative Renal Surgery in Infants: Comparative Study with Children

PURPOSE We evaluated the feasibility and safety of laparoscopic ablative renal surgery in infants and small children 10 kg or less compared to children weighing more than 10 kg. MATERIALS AND METHODS A total of 86 cases were performed by a single surgeon who had mastered the learning curve. Subjects consisted of 25 patients 12 months or younger or weighing 10 kg or less at surgery (group A) and 61 patients older than 12 months and weighing more than 10 kg at surgery (group B). Operative and convalescence parameters, and intraoperative and postoperative complications were compared between the groups. Binary logistic regression analysis was used to estimate the association of baseline characteristics with complications. RESULTS All procedures were completed laparoscopically. There was no significant difference in operative and convalescence parameters, or overall intraoperative and postoperative complications between the 2 groups. Most intraoperative complications (10 of 13) were peritoneal tear during the retroperitoneal approach. Atelectasis was the most common postoperative complication (14 of 23 cases). Operative approach (retroperitoneal vs transperitoneal) was a significant determinant of intraoperative complications (OR 7.6, p = 0.005). Type of surgery (heminephrectomy or isthmectomy vs nephrectomy) was a significant determinant of postoperative complications (OR 5.2, p = 0.014). CONCLUSIONS Laparoscopic ablative renal surgery is safe and feasible even in infants and small children. Intraoperative and postoperative complications are associated with approach and type of surgery, respectively.

Prostate-specific antigen response rate of sequential chemotherapy in castration-resistant prostate cancer: the results of real life practice

Purpose: Prostate-specific antigen (PSA) response rate (>50% PSA decline in pretreatment PSA following chemotherapy) carries a significant survival advantage in castration-resistant prostate cancer (CRPC). We compared PSA response rates in first-, second- and third-line chemotherapy after failure of previous chemotherapy according to chemotherapeutic agents. Methods: We retrospectively evaluated the oncological outcomes and PSA response rates of 384 patients with CRPC, who were treated with chemotherapy and had histologically proven adenocarcinoma of the prostate with failure after androgen ablation therapy between 1991 and 2012, at Asan Medical Center. Results: In 384 eligible patients, the median age was 67.5 years. The median pretreatment PSA and initial Gleason scores at baseline were 92.4 ng/mL (range, 2.0 to 6,370 ng/mL) and 9 (range, 6 to 10), respectively. The time from first diagnosis of prostate cancer to CRPC was 23 months (range, 1 to 164 months). As first-line chemotherapy, 245 patients (63.8%) received estramustine, 91 (23.7%) received docetaxel, and 39 (10.2%) received mitoxantrone. The PSA response rates were 39.6%, 51.6%, and 46.2%, respectively. Of 169 patients with second-line chemotherapy, estramustine was 15 (8.9%), docetaxel was 84 (49.7%), and mitoxantrone was 52 (30.8%). PSA response rates were 57.1%, 52%, and 28.0%, respectively. Of 81 patients with third-line chemotherapy, estramustine was 18 (22.2%), docetaxel was 16 (19.8%), and mitoxantrone was 28 (34.6%). The PSA response rates were 41.2%, 53.8%, and 11.1%, respectively. Declines in serum PSA levels of at least 50% occurred more frequently after treatment with docetaxel than with other chemo-agents regardless of second-and third-line chemotherapy. Even in third-line chemothrapy, docetaxel maintained the PSA response rate, whereas the PSA response rate of other agents, including mitoxantrone, decreased in patients in whom prior therapy failed. Conclusions: Docetacel was the most effective chemotherapeutic agent in second- and third-line trials of chemotherapy in Korean CRPC patients. Although docetaxel is not used as first-line chemotherapy, and new agents are not available for therapy in CRPC patients, we can consider docetaxel a second- or third-line chemotherapy in CRPC.

Antibiotic prophylaxis with intravenous ceftriaxone and fluoroquinolone reduces infectious complications after transrectal ultrasound-guided prostatic biopsy.

Purpose To assess the rates of infectious complications before and after the change of prophylactic antibiotic regimens in prostate needle biopsy. Materials and Methods The records of 5,577 patients who underwent prostate needle biopsy at Asan Medical Center between August 2005 and July 2012 were retrospectively reviewed. Group 1 (n=1,743) included patients treated between 2005 and 2009 with fluoroquinolone for 3 days, group 2 (n=2,723) included those treated between 2009 and 2012 with ceftriaxone once before the biopsy and fluoroquinolone before biopsy and continue therapy for 3 days, and group 3 (n=1,111) received the same treatment for more than 7 days after the biopsy. Univariable and multivariable logistic regression models addressed risk factors associated with infectious complication after prostate needle biopsy. Results Infectious complication after prostate needle biopsy developed in 18 (group 1), seven (group 2), and two patients (group 3) (p=0.001). In group 1, seven patients with infectious complication had positive blood cultures and harbored fluoroquinolone-resistant Escherichia coli, four had ceftriaxone susceptible isolates, and three had extended spectrum beta-lactamase-positive E. coli. Two patients in group 1 required intensive care because of septic shock. In multivariable analysis, the patients with combination of fluoroquinolone and ceftriaxone had significantly lower infectious complication rate than the fluoroquinolon alone (p=0.003). Conclusions Antibiotic prophylaxis with ceftriaxone and fluoroquinolone before prostate needle biopsy decreased the risk of potentially serious infectious complications.

Obesity as a Risk Factor for Unfavorable Disease in Men with Low Risk Prostate Cancer and its Relationship with Anatomical Location of Tumor

Purpose: We investigated the influence of obesity on unfavorable disease in men with low risk prostate cancer eligible for active surveillance and verified the underlying relationship with tumor location. Materials and Methods: We analyzed the records of 890 patients with biopsy Gleason score 6 who underwent radical prostatectomy for prostate cancer via multicore (12 or more) biopsy at our institution. Unfavorable disease was defined as primary Gleason pattern 4 or greater, or pathological stage T3 or greater. Multivariate logistic regression analysis was performed to identify factors associated with unfavorable disease. The association of unfavorable disease with anatomical location of the index tumor was assessed. Results: Overall 216 (24.3%), 544 (61.1%) and 130 men (14.6%) had a body mass index of less than 23 (normal), 23 to 27.5 (overweight) and 27.5 kg/m2 or greater (obese), respectively, according to established cutoff points for Asian men. Multivariate analysis showed that age, prostate volume and body mass index were independent factors for predicting unfavorable disease regardless of the various active surveillance criteria used. For Johns Hopkins Hospital criteria the risk of unfavorable disease was higher in obese patients than in normal weight patients (OR 3.30, p = 0.022). Unfavorable disease was more frequent in cases of transition zone cancer than nontransition zone cancer across all criteria for active surveillance (all p <0.01). Among men fulfilling Johns Hopkins Hospital criteria the proportion of transition zone cancer was 4.2% for normal weight, 11.6% for overweight and 16.7% for obesity, respectively (p = 0.022). Conclusions: Obese men with low risk prostate cancer who are eligible for active surveillance are at higher risk for unfavorable pathological features. Obese men more frequently had transition zone cancer, which was associated with unfavorable pathology findings in those with very low risk prostate cancer.