Determining the optimal time for radical cystectomy after neoadjuvant chemotherapy.

OBJECTIVE: To determine whether the recovery window (RW) between neoadjuvant chemotherapy (NAC) and radical cystectomy (RC) affects 90-day postoperative morbidity and incidence of lymph node metastasis. PATIENTS AND METHODS: We reviewed patients treated with NAC and RC from 1995 to 2013 for ≤cT4 N0 M0 bladder cancer. The association of the RW with 90-day perioperative morbidity and lymph node metastasis was determined. Generalised linear models were used to determine predictors of each endpoint. Patients were stratified into four RWs by 21-day intervals (18-42; 43-63; 64-84; and ≥85 days) from last day of NAC to RC. RESULTS: We evaluated 306 patients with RW information during the study period. The median (range) RW was 46 (18-199) days. There was no difference in overall morbidity, re-admission, or major complication rates amongst the four RWs. In the multivariable analysis extravesical disease was an independent predictor of overall morbidity (odds ratio [OR] 1.95, 95% confidence interval [CI] 1.16-3.26; P = 0.011). Age (OR 1.05, 95% CI: 1.02-1.09; P = 0.004), and surgical duration ≥7 h (OR 2.87, 95% CI: 1.52-5.42; P = 0.001) were independent predictors of major complications. Only surgical duration ≥7 h was a predictor of re-admission (OR 2.24; 95% CI: 1.26-3.98; P = 0.006). A RW of ≥85 days had the highest incidence of node-positive disease (pN+; 40%). In a separate multivariable model that included clinical predictors for pN+, a RW of ≥85 days was an independent predictor of nodal metastasis (OR 2.92, 95% CI: 1.20-7.09; P = 0.018). CONCLUSION: Patients treated with NAC for bladder cancer can undergo RC between 18 and 84 days (2.5-12 weeks) after NAC with no difference in the risk of perioperative morbidity. Delaying surgery beyond 12 weeks was associated with a significant risk of lymph node metastasis.

Surface PD-L1, E-cadherin, CD24, and VEGFR2 as markers of epithelial cancer stem cells associated with rapid tumorigenesis.

Cancer cells require both migratory and tumorigenic property to establish metastatic tumors outside the primary microenvironment. Identifying the characteristic features of migratory cancer stem cells with tumorigenic property is important to predict patient prognosis and combat metastasis. Here we established one epithelial and two mesenchymal cell lines from ascites of a bladder cancer patient (i.e. cells already migrated outside primary tumor). Analyses of these cell lines demonstrated that the epithelial cells with surface expression of PD-L1, E-cadherin, CD24, and VEGFR2 rapidly formed tumors outside the primary tumor microenvironment in nude mice, exhibited signatures of immune evasion, increased stemness, increased calcium signaling, transformation, and novel E-cadherin-RalBP1 interaction. The mesenchymal cells on the other hand, exhibited constitutive TGF-ß signaling and were less tumorigenic. Hence, targeting epithelial cancer stem cells with rapid tumorigenesis signatures in future might help to combat metastasis.

CDODA-Me decreases specificity protein transcription factors and induces apoptosis in bladder cancer cells through induction of reactive oxygen species.

OBJECTIVE: The objective is to determine whether methyl 2-cyano-3,11-dioxo-18b-olean-1,12-dien-30-oate (CDODA-Me) has therapeutic potential in bladder cancer. We investigated the effects of CDODA-Me on the growth and survival of bladder cancer cells, and expression of specificity protein (Sp) transcription factors that regulate genes associated with cancer cell proliferation and survival. METHODS: J82, RT4P, and 253JB-V bladder cancer cell lines were treated with vehicle alone or with CDODA-Me with or without the antioxidant l-glutathione. Cell viability and DNA fragmentation were measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and propidium iodide-fluorescence-activated cell sorting (FACS) analysis, respectively. Intracellular reactive oxygen species (ROS) were measured by 2',7'-dichlorofluorescin diacetate-FACS analysis. We assessed CDODA's effects on the levels of Sp and Sp-regulated proteins and induction of apoptosis in bladder cancer cells by Western blotting. We also assessed the anticancer effects of CDODA-Me in nude mice bearing RT4v6 bladder cancer. RESULTS: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and FACS analysis revealed that CDODA-Me inhibited the proliferation and survival of the 3 bladder cancer cell lines in a dose-dependent manner. FACS analysis also indicated that CDODA-Me-induced intracellular ROS, and Western blot analysis indicated that CDODA-Me decreased levels of Sp and Sp-regulated proteins and induced apoptosis in a dose-dependent and time-dependent manner. l-Glutathione attenuated CDODA-Me's down-regulation of Sp and Sp-regulated proteins. Compared with the control treatment, CDODA-Me substantially inhibited tumor growth in vivo. CONCLUSIONS: CDODA-Me has antineoplastic activity in bladder cancer cells by inducing ROS, which down-regulate Sp and Sp-regulated proteins. Thus, CDODA-Me has therapeutic potential in bladder cancer, and additional studies of the agent's efficacy and mode of action are warranted.

Papillary Recurrence of Bladder Cancer at First Evaluation after Induction Bacillus Calmette-Guérin Therapy: Implication for Clinical Trial Design.

BACKGROUND: Recurrence with papillary tumor(s) by 3-mo after induction bacillus Calmette-Guérin (BCG) is historically believed to be a poor prognostic indicator in patients with high-risk non-muscle invasive bladder cancer. However, the impact of a clinical Ta (cTa) papillary recurrence at 3 mo after BCG is often debated. OBJECTIVE: To evaluate the prognostic implications of cTa papillary recurrence found 3 mo after induction BCG therapy and to evaluate its significance in clinical trial design. DESIGN, SETTING, AND PARTICIPANTS: We reviewed our database of 917 patients who underwent transurethral resection and induction of BCG from 1995 to 2012. Clinical characteristics were compared between 3-mo recurrence stages. INTERVENTION: Transurethral resection of bladder tumor and intravesical therapy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Chi-square analysis and Student t test were used to compare clinical characteristics between 3-mo recurrence stages. Kaplan-Meier method was used to determine bladder-preservation time, progression-free survival, and disease-specific survival. RESULTS AND LIMITATIONS: We identified 84 patients who met the study criteria (66 patients with cTa and 18 patients with clinical T1 [cT1]). The median follow-up for the entire cohort was 74 mo. Of the patients with cTa recurrence, 60 continued with bladder-sparing therapy. Patients with a high-grade cTa recurrence who continued bladder-sparing therapy had a 17% incidence of disease progression and a 62% incidence of recurrence within 1 yr. No patients with low-grade cTa recurrence (n=13) developed disease progression or underwent radical cystectomy. Patients with an initial cTa at diagnosis had a higher 5-yr bladder preservation rate than those with an initial cT1 diagnosis (84% vs 61%; p=0.041). Patients with high-grade cTa recurrence and those with cT1 recurrence had similar outcomes with respect to death rates over the entire follow-up period (11% and 15%, respectively), as well as 5-yr progression-free survival (77% vs 83%). Limitations include using a single institution and a retrospective review. CONCLUSIONS: Patients with low-grade cTa papillary recurrence 3 mo after induction of BCG can safely continue with bladder-sparing therapy. Patients with high-grade cTa papillary recurrence at that time have risks of recurrence and progression similar to those of patients with cT1 recurrence. These are important factors to consider during clinical trial design. PATIENT SUMMARY: Low-grade clinical Ta papillary recurrence following induction of bacillus Calmette-Guérin therapy can be safely managed conservatively, although a high-grade clinical Ta recurrence should be treated similar to a clinical T1 recurrence due to its comparable progression rates.

Sequential gemcitabine and tamoxifen treatment enhances apoptosis and blocks transformation in bladder cancer cells.

Bladder cancer is a common malignancy for which regional or metastatic disease is identified at diagnosis. The aim of this study was to determine whether tamoxifen (Tam), an estrogen receptor (ER) antagonist, can sensitize bladder cancer cell lines to gemcitabine (Gem) chemotherapy. ERα and ERß protein levels were determined in each cell line using western blot analysis. The TCC-Sup, 5637, and RT4 bladder cancer cells were exposed to various concentrations and regimens of Tam or Gem alone or in combination. Cell viability and apoptosis were assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and propidium iodide followed by flow cytometry. Apoptosis was then evaluated by western blot analysis. Treated TCC-Sup cells were subjected to soft agar colony formation assay to determine the cellular transformation. Western blot analysis results revealed ER expression in the three cell lines. TCC-Sup and 5637 cells treated with a combination of Tam and Gem had lower cell viabilities than those treated with Tam or Gem alone for 72 h in TCC-Sup and 5637. Compared with the other treatments, sequential Gem followed by Tam (Gem→Tam) treatment caused the largest increase in DNA fragmentation at 72 h in TCC-Sup cells. Western blot analysis results revealed that this sequential Gem→Tam treatment increased poly(ADP-ribose) polymerase cleavage in TCC-Sup cells. Sequential Gem→Tam inhibited the cell transformation in TCC-Sup cells. In conclusion, sequential Gem→Tam enhanced the cytotoxicity of Gem in vitro. This regimen be useful to enhance the efficacy of Gem in bladder cancer. However, future in vivo studies are required to verify the results.

Patient-reported sexual outcomes after holmium laser enucleation of the prostate: a 3-year follow-up study.

OBJECTIVE: To evaluate the long-term patient reported sexual function outcomes of holmium laser enucleation of the prostate (HoLEP) for the treatment of lower urinary tract symptoms secondary to prostate enlargement. METHODS: Three hundred ninety-three patients underwent a HoLEP between August 2007 and July 2013 and were reviewed in this retrospective analysis. Sexual function outcomes were assessed before HoLEP, and again at 3, 6, 12, 24, and 36 months after surgery using the International Index of Erectile Function 5 survey. International Prostate Symptom Scores (IPSS) were included for comparison and contextual functional outcome analysis. RESULTS: At the time of surgery, the mean age was 70.9 years (52.0-89.0 years), mean body mass index was 27.7 kg/m(2) (18.0-48.0 kg/m(2)), and mean prostate volume was 96.7 g (20.1-375.0 g). Mean International Index of Erectile Function 5 scores at 3 (13.3 ± 8.37), 6 (12.1 ± 8.76), 12 (12.1 ± 8.83), 24 (12.6 ± 8.80), and 36 months (12.5 ± 8.45) showed no significant change from baseline. There was, however, a significant improvement from baseline seen in IPSS over the same time period (P = .0001). CONCLUSION: These data confirm HoLEP has a significant impact on IPSS and no adverse impact on long-term patient reported sexual function. We believe this series represents the largest cohort with the longest follow-up to date. It represents an important tool for preoperative patient counseling for those patients considering surgical therapy for benign prostatic hyperplasia.

Safety and feasibility of concomitant surgery during holmium laser enucleation of the prostate (HoLEP).

PURPOSE: To determine the feasibility and outcomes associated with performing simultaneous surgical procedures during holmium laser enucleation of the prostate (HoLEP) in patients with benign prostatic hyperplasia and concomitant urologic conditions. METHODS: A retrospective review of patients that underwent a HoLEP was performed. Patients undergoing a concomitant procedure at the time of HoLEP were selected and stratified based on complexity of the secondary procedure (simple, intermediate, and complex) and matched based on age and prostate volume to patients undergoing only a HoLEP. Baseline characteristics, preoperative, operative, and postoperative outcomes were collected. RESULTS: A total of 372 HoLEPs were performed. Thirty-eight (10.2 %) patients underwent concomitant procedures at the time of HoLEP. Compared to the simple and intermediate secondary surgical procedures, the matched control group that underwent a HoLEP alone did not demonstrate statistically significant differences in the preoperative, operative, or postoperative outcomes. Patients with a complex secondary surgical procedure at the time of HoLEP had statistically significant differences in operative time (221 vs. 65 min, p = 0.007), estimated blood loss (92 vs. 33 mL, p = 0.012), catheter time (8.5 vs. 1 day, p = 0.041), and length of hospitalization (2 vs. 1 day, p = 0.032) compared to the control group. CONCLUSIONS: Obstructive voiding symptoms secondary to BPH are common in older patients and may coincide with other concomitant lower urinary tract pathology that may require surgical intervention. Rather than staging surgical interventions, it appears that definitive treatment for BPH with HoLEP is safe and efficacious in those patients that also require secondary procedures.

Does prostate morphology affect outcomes after holmium laser enucleation?

OBJECTIVE: To determine whether prostate morphology or technique used has any effect on postoperative outcomes after holmium laser enucleation of the prostate. MATERIALS AND METHODS: A retrospective review of prospectively collected data was completed for all patients undergoing a holmium laser enucleation of the prostate at our institution. Prostate morphology was classified as either "bilobar" or "trilobar" according to the cystoscopic appearance. The baseline characteristics, complications, and postoperative outcomes were collected. RESULTS: A total of 304 patients with either "bilobar" (n = 142) or "trilobar" (n = 162) prostate morphology were included. The trilobar group was more likely to have longer operative times (112 vs 100 minutes, P = .04), although this difference was not significant on multivariate analysis. The postoperative outcomes were similar between the 2 groups for American Urological Association symptom score, change in American Urological Association symptom score, bother score, maximal flow rate, change in maximal flow rate, postvoid residual urine volume, and complication rate. However, the trilobar group had a significantly greater decrease in their PVR urine volume (296 vs 176 mL, P = .01), a difference that persisted on multivariate analysis. A subset analysis of the trilobar prostates revealed that performing a 2-lobe technique achieved shorter operative and enucleation times, although the difference was not significant. CONCLUSION: Those patients with trilobar prostate morphology are more likely to achieve a greater decrease in the PVR urine volume after holmium laser enucleation of the prostate. All other outcomes appeared to be similar between the 2 groups. In addition, a 2-lobe technique can be safely used for trilobar prostates when deemed feasible by the surgeon.

Age-stratified outcomes of holmium laser enucleation of the prostate.

OBJECTIVE: To present the first age-stratified assessment of outcomes after holmium laser enucleation of the prostate (HoLEP) for the treatment of lower urinary tract symptoms resulting from prostate enlargement. PATIENTS AND METHODS: We retrospectively analysed and compared the morbidity, and the peri-operative and functional outcomes of patients aged 50-59, 60-69, 70-79 and ≥80 years. Complications at 30 days were stratified using the Clavien system. Functional outcomes were assessed using the International Prostate Symptom Score (IPSS), maximum urinary flow rate (Qmax ), post-void residual urine volume (PVR) and urinary continence. RESULTS: A total of 311 patients underwent HoLEP for obstructive voiding symptoms from August 2007 to June 2011, of whom 22 patients were aged 50-59 years, 91 were aged 60-69 years, 153 were aged 70-79 years, and 45 were aged ≥80 years. The overall morbidity rates were similar among the age groups (20, 24.4, 21.6 and 22.1% for groups 1, 2, 3 and 4, respectively), as were the incidence of significant complications (Clavien grade ≥ III), change in serum haemoglobin level, and length of hospital stay. Patients ≥80 years did have a longer catheterization time (3.4 days) than patients aged 50-59 years (1.68 days). By 1 year there were no significant differences in urinary continence, IPSS, Qmax , or PVR among the age groups. CONCLUSIONS: Overall morbidity, hospital stay, and 1-year functional outcomes of HoLEP were similar among all age groups. This study shows that HoLEP is a safe and effective treatment for benign prostatic hyperplasia regardless of age.

Oncologic outcomes for lymph node-positive urothelial carcinoma patients treated with robot assisted radical cystectomy: with mean follow-up of 3.5 years.

PURPOSE: Previous studies have shown robot assisted radical cystectomy (RARC) to have comparable perioperative outcomes to open radical cystectomy. There are few reports that have examined the oncologic results of RARC, specifically with respect to lymph node-positive patients. We report the outcomes of pathologic node-positive patients who have undergone RARC with medium-term follow-up. MATERIALS AND METHODS: A total of 275 patients underwent RARC at 2 institutions for invasive bladder cancer between April 2005 and June 2009. We examined the 50 patients with lymph node-positive disease. Oncologic outcomes, overall, and recurrence-free survival were analyzed and compared with the open literature. RESULTS: Mean (median) clinical follow-up in this cohort was 42 (39.5) months (range 16-75 months). The mean (median) number of lymph nodes (LN) removed was 18 (17.5) (range 5-35), and mean (median) number of positive LN was 3 (2) (range 1-12). Mean lymph node density was 18%. Seventeen (34%) patients had ≤ pT2 disease and 33 (66%) pT3/T4 disease. At this follow-up, 29 patients have recurred, and 22 patients have died of disease. Mean (median) time to recurrence was 10 (9) months. The estimated overall survival at 36 and 60 months was 55%, and 45%, respectively. The recurrence-free survival at 36 and 60 months was 43%, and 39%, respectively. Thirty-three (66%) patients had an LN density <20%. The estimated overall survival at 36 months of patients with a lymph node density of <20% was higher than those with a lymph node density >20%, though the difference was not statistically significant. A total of 58% of patients received chemotherapy in this cohort. The use of chemotherapy was associated with a statistically significant (P = 0.033) improvement in overall survival, with an overall survival of 68% at 36 months compared with 36% for the patients who did not receive any chemotherapy. CONCLUSIONS: The oncologic outcomes of patients with lymph node-positive bladder cancer treated with robot assisted radical cystectomy (RARC) compare favorably to previous published studies of open radical cystectomy at medium-term (mean follow-up of 42 months). As our follow-up increases, we expect to continue to accurately define the long-term clinical suitability and oncologic success of this procedure in this high-risk population.

Cost analysis of open radical cystectomy versus robot-assisted radical cystectomy.

Bladder cancer is the fourth and ninth most common malignancy in males and females, respectively, in the U.S. and one of the most costly cancers to manage. With the current economic condition, physicians will need to become more aware of cost-effective therapies for the treatment of various malignancies. Robot-assisted radical cystectomy (RARC) is the latest minimally invasive surgical option for muscle-invasive bladder cancer. Current reports have shown less blood loss, a shorter hospital stay, and a lower morbidity with RARC, as compared with the traditional open radical cystectomy (ORC), although long-term oncologic results of RARC are still maturing. There are few studies that have assessed the cost outcomes of RARC as compared with ORC. Currently, ORC appears to offer a direct cost advantage due to the high purchase and maintenance cost of the robotic platform, although when the indirect costs of complications and extended hospital stay with ORC are considered, RARC may be less expensive than the traditional open procedure. In order to accurately evaluate the cost effectiveness of RARC versus ORC, prospective randomized trials between the two surgical techniques with long-term oncologic efficacy are needed.

Multicenter experience with robot-assisted radical prostatectomy in renal transplant recipients.

OBJECTIVE: To evaluate our multi-institutional outcome with robot-assisted radical prostatectomy (RARP) in renal transplant recipients and describe technical modifications of the procedure. MATERIALS AND METHODS: We retrospectively reviewed 1677 patients, 1422 from Mayo Clinic Arizona and 255 from Loyola University Medical Center, undergoing RARP from March 2004 to October 2010, of which 7 were renal transplant recipients. Baseline demographic features, perioperative data, and oncologic outcomes were reviewed. RESULTS: At diagnosis, mean patient age was 63.3 years and serum prostate specific antigen was 6.17 ng/mL. The mean total operative time was 186 minutes (range, 80-210 minutes). No intraoperative complications were noted. The mean hospital length of stay was 1.8 days (range, 1-3 days). Clavien grade II postoperative complications occurred in 3 of the 7 patients (42.9%), consisting of urosepsis, atrial fibrillation, and gross hematuria, all resolving with appropriate medical management. No significant changes were observed in graft function. Two patients (28.6%) had positive surgical margins. During a mean follow-up of 16 months, 1 patient with pathologic T3a, Gleason 9 cancer experienced a biochemical recurrence, which was treated with salvage external-beam radiation and androgen-deprivation therapy. CONCLUSION: Our series suggests that RARP is a safe and feasible form of therapy for localized prostate cancer in a select group of renal transplant recipients.

Impact of margin status at 37 months after robot assisted radical prostatectomy.

INTRODUCTION: We evaluate the impact of margin length, location, and pathologic stage on biochemical recurrence (BCR) after robot assisted radical prostatectomy (RARP) at 37 months of follow up. MATERIALS AND METHODS: A total of 1420 patients underwent a robot assisted radical prostatectomy between March 2004 and May 2010. Patients who received adjuvant therapy, those who never achieved an undetectable prostate-specific antigen (PSA), and those who had less than 18 months of follow up were excluded. Patients were then divided and evaluated based on margin status. RESULTS: In total, 419 patients were included in the analysis. Eighty-three had a positive surgical margin (PSM) (19.8%), 336 had a negative surgical margin (NSM) (80.2%). The overall mean follow up was 37 months. On multivariate analysis the Gleason sum and PSM were independent predictors of BCR. Margin length and location had no significant difference on the rate of BCR. Patients with a PSM and pT2 disease had an increased rate of BCR compared to pT2 and NSM. The relative risk of BCR was 2.03 and 3.21 for patients who have a PSM versus a NSM, overall and in those with pT2 disease respectively. No different BCR is seen in pT2 PSM versus ≥ pT3 NSM; or ≥ pT3 PSM versus NSM. CONCLUSION: With 37 months follow up; positive surgical margin and postoperative Gleason sum impact the rate of BCR. Location and length of the PSM do not appear to have an impact on BCR. There was an increased risk of BCR with PSM, especially in pT2 disease.