Destroyed bladders: Characterization of progressive inflammatory cystitis.

PURPOSE: We identified a subset of patients with noninfectious cystitis who develop refractory symptoms marked by diffuse inflammatory changes, reduced bladder capacity, and vesicoureteral reflux (VUR), termed here as "progressive inflammatory cystitis" (PIC). Our objective was to describe the phenotype, disease outcomes, and pathologic findings of PIC. MATERIAL AND METHODS: A single institution retrospective cohort study of patients with PIC. Patients with a history of pelvic radiation, urologic malignancy, or neurogenic bladder were excluded. We describe cohort characteristics and use bivariate analyses to compare subgroups. Kaplan-Meier methods estimate time to urinary diversion. RESULTS: From 2008 to 2020, 46 patients with PIC were identified. The median age of symptom onset was 63 years old (interquartile range [IQR]: 56, 70) and the most common presenting symptoms were urinary urgency/frequency (54%) and incontinence (48%). Urodynamics showed a median maximum bladder capacity of 80 mL (IQR: 34, 152), commonly with VUR (68%) and hydronephrosis (59%). Ultimately 36 patients (78%) underwent urinary diversion at a median of 4.5 years (IQR: 2, 6.5) after symptom onset. Significant pathologic findings include presence of ulceration (52%), acute and chronic inflammation (68%), including eosinophils (80%), lymphoid follicles (56%), and mast cells in both lamina and muscularis propria (76%). CONCLUSIONS: PIC is a newly defined entity characterized by significantly diminished bladder capacity, upper tract changes, and relatively quick progression to urinary diversion. Larger prospective cohort studies are required to further characterize this severe phenotype of chronic noninfectious cystitis, aid earlier diagnosis, and guide management decisions.

The Utility of Radiologic and Symptomatic Surveillance After Minimally-invasive Adult Pyeloplasty.

OBJECTIVE: To evaluate different types of failure after minimally-invasive pyeloplasty (MIP) when stratified by initial radiologic study and symptoms after ureteral stent removal. METHODS: We retrospectively reviewed adults who underwent MIP (1996-2019) at a single academic center. Patients with at least 11 months of follow-up and patients who had a Mag3 scan as their initial postoperative imaging were included. Postprocedure, patients were categorized as having normal, equivocal, or obstructed imaging based on their initial radiologic test. Patients who were obstructed were excluded. Primary outcome was procedural failure, defined as the need for a procedure to treat recurrent obstruction. Secondary outcomes were radiologic failure and symptomatic failure. Groups were compared to assess for statistical significance (P <.05). RESULTS: Overall, 122 patients met inclusion criteria. On initial postoperative imaging, 108 (89%) patients had no obstruction and 14 (11%) had equivocal findings. The procedural failure rate was 6.5% in the unobstructed group and 28.6% in the equivocal group (P = .023). Seven unobstructed patients (6.5%) and 2 equivocal patients (14.3%) eventually experienced radiologic failure (P = .275). Among patients who had no obstruction on initial imaging and remained asymptomatic, only one (0.9%) required a salvage procedure. CONCLUSION: Recurrent obstruction after pyeloplasty varied based on the outcome of the initial radiologic study. These rates can be used to counsel patients and guide physicians' choice of surveillance schedules. The risk of future failure is very low in asymptomatic patients with normal initial imaging. The utility of routine radiologic surveillance in these patients may be limited.

Surveillance After Ureteroneocystostomy: Is it Necessary?

OBJECTIVE: To determine the utility of post-operative imaging after ureteroneocystostomy and whether long-term symptom or radiographic surveillance aided in the detection of recurrent obstruction. MATERIALS AND METHODS: Adult patients were identified who underwent a ureteroneocystostomy with or without psoas hitch or Boari flap between January 2012 and June 2021. Patients who underwent a bilateral procedure, had active malignancy or immediate failure, or did not have 6 months of follow-up with 2 imaging studies were excluded. Using the initial imaging study after stent removal, patients were categorized into normal and equivocal groups according to predefined radiologic criteria. Patients were followed longitudinally to determine whether they subsequently developed radiographic evidence of obstruction. Follow up visits were reviewed for patient symptoms suggestive of post-operative obstruction, defined as flank pain, hematuria, or pyelonephritis. RESULTS: One hundred and twelve patients met criteria. Normal and equivocal initial imaging was seen in 99 and 13 patients, respectively. At a mean radiologic follow-up of 32 months, stricture recurrence was identified in 3 patients with normal initial imaging. No patients with initial equivocal imaging demonstrated recurrent obstruction at mean radiologic follow-up of 29 months. All patients with recurrent stricture presented with symptoms of obstruction. Of patients who developed symptoms after ureteroneocystostomy, 13.6% had recurrent stricture. CONCLUSION: Asymptomatic patients after ureteroneocystostomy who had either normal or equivocal post-operative imaging did not benefit from additional radiologic testing in this cohort. All patients that demonstrated failure presented with symptomatic obstruction that warranted imaging. Surgeons may consider restricting surveillance imaging to symptomatic patients after the initial post-operative period.

Risk factors for orgasmic and concomitant erectile dysfunction in men with type 1 diabetes: a cross-sectional study.

In this study, we sought to determine the burden and characteristics of orgasmic dysfunction (OD) and concomitant erectile dysfunction (ED) in men with type 1 diabetes (T1D) enrolled in the Epidemiology of Diabetes Interventions and Complications (EDIC) study. In 2010, we assessed orgasmic and erectile function using the International Index of Erectile Function (IIEF). Sociodemographic, clinical, and diabetes characteristics were compared by OD status (OD only, OD and ED, no ED or OD). Age-adjusted associations between risk factors and OD status were examined. OD and ED information was available from 563 men. Eighty-three men (14.7%) reported OD of whom 21 reported OD only and 62 reported OD and ED. Age-adjusted odds ratios demonstrated that men who reported OD only had higher odds of depression, low sexual desire, and decreased alcohol use compared with men reporting no dysfunction. Men with OD concomitant with ED had greater odds of elevated hemoglobin A1C, peripheral and autonomic neuropathy, and nephropathy. Men reporting both dysfunctions were also more likely to report smoking, lower urinary tract symptoms, and had greater odds of androgen deficiency than men with no sexual dysfunction. Men with longstanding T1D suffer from an increased burden of OD. Psychogenic factors predominate in men reporting OD only while men who present with concomitant ED report increased burden of diabetes severity, characteristics previously observed with incident ED. ED may be the central impediment to sexual function in men with OD and ED. Longitudinal studies to characterize OD and ED experience over time are warranted.

Treatment of urethral stricture disease in women: A multi-institutional collaborative project from the SUFU research network.

AIM: Female urethral stricture disease is rare and has several surgical approaches including endoscopic dilations (ENDO), urethroplasty with local vaginal tissue flap (ULT) or urethroplasty with free graft (UFG). This study aims to describe the contemporary management of female urethral stricture disease and to evaluate the outcomes of these three surgical approaches. METHODS: This is a multi-institutional, retrospective cohort study evaluating operative treatment for female urethral stricture. Surgeries were grouped into three categories: ENDO, ULT, and UFG. Time from surgery to stricture recurrence by surgery type was analyzed using a Kaplan-Meier time to event analysis. To adjust for confounders, a Cox proportional hazard model was fit for time to stricture recurrence. RESULTS: Two-hundred and ten patients met the inclusion criteria across 23 sites. Overall, 64% (n = 115/180) of women remained recurrence free at median follow-up of 14.6 months (IQR, 3-37). In unadjusted analysis, recurrence-free rates differed between surgery categories with 68% ENDO, 77% UFG and 83% ULT patients being recurrence free at 12 months. In the Cox model, recurrence rates also differed between surgery categories; women undergoing ULT and UFG having had 66% and 49% less risk of recurrence, respectively, compared to those undergoing ENDO. When comparing ULT to UFG directly, there was no significant difference of recurrence. CONCLUSION: This retrospective multi-institutional study of female urethral stricture demonstrates that patients undergoing endoscopic management have a higher risk of recurrence compared to those undergoing either urethroplasty with local flap or free graft.

Patient-reported outcomes from a single-centre prospective post-marketing study on Collagenase Clostridium Histolyticum injections for Peyronie's disease.

The aim of this study was to evaluate patient-reported outcomes of Collagenase Clostridium Histolyticum (CCHi) for Peyronie's Disease. Patients treated with 2-4 cycles of CCHi between 01/2016 and 08/2018 were asked to fill out the "bother domain" of the Peyronie's Disease Questionnaire (PDQ) at scheduled appointments for injections. CCHi cycles involved two injections (0.58 mg) separated by 48-72 hr. During the study, 34 patients were treated, seven patients were excluded due to incomplete baseline values. Mean (standard deviation) PDQ bother domain baseline score was 11.1 (2.6). ANOVA demonstrated statistically significant effects of injections (p < .001) with a decrease in PDQ bother domain scores 6 weeks after the 1st cycle (9.9 [3.3], p = .013), 6 weeks after the 2nd cycle (8.2 [4.0], p = .009) and 6 weeks after the 3rd cycle (6.5 [3.6], p < .001). After 2-4 cycles of CCHi treatment, patients reported changes in penile curvature as "Worse" (0), "No Change" (2), "Little decrease" (10), Decrease (10) and "Significant decrease" (4). After completion of CCHi treatment, 82% of patients still reported that vaginal intercourse was difficult or impossible. Patients with Peyronie's Disease undergoing CCHi treatment reported statistically significant decreases in PDQ bother domain scores. However, most patients still report difficulty with intercourse after treatment.

Robotic Versus Open Ureteroneocystostomy: Is There a Robotic Benefit?

Aim: We sought to compare the outcomes of patients who underwent an open vs robotic ureteroneocystostomy for ureteral obstruction. Methods: Retrospective review was performed on adult patients who underwent primary ureteroneocystostomy for obstruction from January 2012 to April 2018. Intraoperative outcomes of estimated blood loss (EBL) and operative time, as well as postoperative outcomes of catheter and stent duration, length of hospital stay, inpatient nurse-controlled opioid use, patient-controlled analgesia (PCA), and outpatient opioid prescription, complications, readmission, radiologic and clinical stricture recurrence, and follow-up, were compared. Among the open cohort, indications for an open approach were evaluated, identifying patients with prior complex open abdominal surgery that would make an open approach preferable. Results: Open ureteroneocystostomy was performed in 27 patients compared with 18 who underwent a robotic approach. The open and robotic cohorts were not significantly different in age, gender, Charlson comorbidity index, stricture location or side, abdominal surgery (laparoscopic or open), pelvic radiation, or preoperative urinary tract infection. The robotic group had a significantly lower rate of prior open abdominal surgery. The robotic cohort had significantly lower EBL, length of stay (LOS), catheter duration, prescribed morphine milliequivalents (MME) at discharge, and rate of PCA usage. Among the open cohort, 13 (48%) patients demonstrated indications making an open approach preferable. Comparing the robotic group with the remaining 14 open patients revealed a significantly lower rate of inpatient PCA use, prescribed MME at discharge, LOS, and catheter duration. Mean operative time was higher in the robotic group. EBL was not significantly different in this subanalysis. Conclusions: Robotic ureteroneocystostomy provides similar outcomes when compared with an open approach in well-selected patients when assessing for recurrent ureteral obstruction or adverse events. Robotic surgery is associated with lower postoperative narcotic pain prescriptions at discharge, lower PCA usage, and shorter LOS, which are important benefits when compared with open surgery.

Does Early Ureteroneocystostomy After Iatrogenic Ureteral Injury Jeopardize Outcome?

OBJECTIVE: To compare the outcomes of patients who underwent early repair (≤7 days) of iatrogenic ureteral injury with ureteroneocystostomy and compare them to those repaired in a delayed fashion (>7 days). METHODS: A retrospective review of billing data between 2012 and 2018 identified patients who underwent ureteroneocystostomy for a benign ureteral disease. Inclusion criteria included all ureteral injuries related to a laparoscopic, robotic, or open surgical injury. Patients with ureteral injury related to radiation, stones, or reconstructive surgery were excluded. Patients undergoing reconstruction during the initial injury or within ≤7 days were designated as having undergone early repair, while the remaining were considered delayed repair. Demographics, as well as inpatient and postdischarge data were acquired, and statistical analysis was performed comparing the 2 groups. RESULTS: Sixty-seven patients met inclusion criteria. Early repair was performed on 12 patients, while 55 underwent delayed repair. No significant difference in age, gender, Charlson Comorbidity Score, laterality, stricture location, or history of pelvic/abdominal radiation was noted. Inpatient complications were significantly higher in the immediate group (58 vs 18%, P =.004). Thirty- and 90-day complications were similar. Two patients in the delayed group and none in the immediate group demonstrated stricture recurrence (P =.710). A higher rate of Boari flap ureteral reconstruction was performed in the delayed cohort (P =.001). CONCLUSION: In this cohort, there was no detectable difference in outcomes when comparing early and delayed ureteroneocystostomy for iatrogenic ureteral injuries.

Extended Case Duration and Hypotension Are Associated With Higher-grade Postoperative Complications After Urinary Diversion for Non-oncological Disease.

OBJECTIVE: To report survival for patients who undergo urinary diversion for benign indications and to identify risk factors for morbidity at 90 days. METHODS: This is a retrospective review of consecutive urinary diversions with or without cystectomy for non-oncological indications at a single institution. The indication for diversion was intractable incontinence, upper tract deterioration, urinary fistula, and unmanageable bladder pain. Patients were categorized according to their most severe complication within 90 days of surgery, using the Clavien-Dindo system. Multivariable analysis was performed to identify factors associated with high-grade complications. Survival analysis was performed. RESULTS: Between 2007 and 2014, 141 patients underwent urinary diversion for non-oncological indications. The postoperative rate of high-grade adverse events (class III or greater) was 28%. Risk factors for class III or greater complications at 90 days included prolonged intraoperative mean arterial pressure below 75% of baseline, operative duration greater than 343 minutes, and postoperative vasopressor requirement. Kaplan-Meier survival analysis demonstrated a 1- and 5-year survival of 88.4% and 77.2%, respectively. The long-term survival of patients who experienced higher-grade complications was not statistically different from the survival of the rest of the group. The study was limited by a retrospective design and sample size in identifying additional variables associated with increased risk of long-term mortality. CONCLUSION: Urinary diversion for non-oncological conditions has a good 5-year survival in this cohort. Extended case duration and hemodynamic instability during or immediately after urinary diversion are associated with a high-grade complication within 90 days of the procedure.

The Value of Urodynamics in an Academic Specialty Referral Practice.

OBJECTIVE: To describe and evaluate the use of urodynamics (UDS) studies for all indications in an academic specialty referral urology practice. MATERIALS AND METHODS: This is a prospective questionnaire-based study wherein clinicians completed a pre- and post-UDS questionnaire on each UDS that they ordered for all clinical indications between May 2013 and August 2014. Questions pertained to patient demographics and history, the clinical indication for the UDS, the clinician's pre- and post-UDS clinical impressions, and changes in post-UDS management plans. Pre- and post-UDS diagnoses were compared using the McNemar test. RESULTS: Clinicians evaluated a total of 285 UDS studies during the study period. The average age of study participants was 56.0 (±16.4) years, 59.5% were female, and 29.3% had a neurologic diagnosis. The most common indication for performing UDS was to discern the predominant type of urinary incontinence (stress vs urgency) in patients with mixed incontinence symptoms (38.5%) and to assess the safety of the bladder during filling (38.2%). UDS statistically significantly changed the ordering clinician's clinical impression of the patient's lower urinary tract diagnosis for stress urinary incontinence and for urgency and urgency urinary incontinence (both had P values of <.05). Fluoroscopy was found to be helpful in 29.5% of urodynamic studies, and clinicians reported that UDS changed their treatment plans in 42.5% of the studies, most commonly pertaining to changes related to surgery (35.0%). CONCLUSION: Overall, UDS was a clinically useful tool that altered the clinical impression and treatment plan in a large percentage of carefully selected patients.

The S-CAHPS Survey in Urology.

INTRODUCTION: The S-CAHPS survey assesses patient experience and satisfaction with 1 episode of surgical care. We describe the initial implementation, results and experience using S-CAHPS in urology. METHODS: This was a prospective, institutional review board approved, observational study at a tertiary care academic medical center. Adult patients who underwent elective outpatient or 23-hour observation surgery during a 33-month period were mailed the survey. Survey content was separated into composites 1 to 6 and percent top box scoring (percent of most positive responses) was performed. Summary scores for each composite were correlated with the mean of a global surgeon rating question. RESULTS: A total of 430 surveys were returned for a 33.8% response rate. Respondents were statistically older than nonrespondents and more likely to reside in Michigan (p <0.05). Mean ± SD global surgeon rating was 9.50 ± 1.04 on a scale of 0-worst to 10-best surgeon possible. Global surgeon rating correlated most highly with the question composites for "How well surgeon communicates with patients after surgery" (composite 5, τ = 0.459), followed by "Information to help you recover from surgery" (composite 4, τ = 0.400). Conversely, there was lower correlation with composites pertaining to "Information to help you prepare for surgery" (composite 1, τ = 0.251). CONCLUSIONS: Survey results suggest that patient satisfaction with the surgeon is more influenced by postoperative communication and information than by preoperative counseling and decision making processes. This underscores the importance of attention to continued postoperative care and interactions. The role of S-CAHPS in urology requires further exploration in this era of quality improvement.

Should blunt segmental vascular renal injuries be considered an American Association for the Surgery of Trauma Grade 4 renal injury?

BACKGROUND: Renal segmental vascular injury (SVI) following blunt abdominal trauma is not part of the original American Association for the Surgery of Trauma (AAST) renal injury grading system. Recent recommendations support classifying SVI as an AAST Grade 4 (G4) injury. Our primary aim was to compare outcomes following blunt renal SVI and blunt renal collecting system lacerations (CSLs). We hypothesize that renal SVI fare well with conservative management alone and should be relegated a less severe renal AAST grade. METHODS: We retrospectively identified patients with SVI and G4 CSL admitted to a Level 1 trauma center between 2003 and 2010. Penetrating trauma was excluded. Need for surgical intervention, length of stay, kidney salvage (>25% renal preservation on renography 6-12 weeks after injury), and delayed complication rates were compared between the SVI and CSL injuries. Statistical analysis used χ, Fisher's exact, and t tests. RESULTS: A total of 56 patients with SVI and 88 patients with G4 CSL sustained blunt trauma. Age, Injury Severity Score (ISS), and length of stay were similar for the two groups. Five patients in each group died of concomitant, nonrenal injuries. In the G4 CSL group, 15 patients underwent major interventions, and 32 patients underwent minor interventions. Only one patient in the SVI group underwent a major intervention. The renal salvage rate was 85.7% following SVI versus 62.5% following CSL (p = 0.107). CONCLUSION: Overall, surgical interventions are significantly lower among the SVI cohort than the G4 CSL cohort. Further analysis using a larger cohort of patients is recommended before revising the current renal grading system. Adding SVI as a G4 injury could potentially increase the heterogeneity of G4 injuries and decrease the ability of the AAST renal injury grading system to predict outcomes, such as nephrectomy rate. LEVEL OF EVIDENCE: Epidemiologic study, level IV.

External validation of a substratification of the American Association for the Surgery of Trauma renal injury scale for grade 4 injuries.

BACKGROUND: The traditional American Association for the Surgery of Trauma (AAST) grading of renal injury does not adequately identify the subset of patients who are most likely to require intervention for bleeding. Recently, several high-risk criteria (HRC) for bleeding after renal injury were identified, and we sought to externally validate these criteria among patients with grade 4 renal injury. STUDY DESIGN: All patients presenting to a level I trauma center with blunt grade 4 renal injuries from 2003 to 2010 were reviewed, and stage was determined by the 1989 AAST staging criteria. Dependent variables included the presence of a hilar injury or any of the HRC (perirenal hematoma size, intravascular contrast extravasation, and medial or complex laceration). The primary outcome was the need for intervention (renorrhaphy, nephrectomy, or angiography) for hemodynamic instability. RESULTS: A total of 84 patients with grade 4 renal lacerations were identified. Two or more HRC were present in 18 patients (21%), and intervention for hemodynamic instability was performed in 14 patients (17%). Compared with patients with 0 or 1 HRC, those with ≥ 2 HRC were approximately 25 times more likely to require intervention for hemodynamic instability (odds ratio [OR]24.9, 95% CI 5.5 to 112.9, p < 0.001). Patients with no HRC were unlikely to require intervention for hemodynamic instability. CONCLUSIONS: Among patients with blunt grade 4 renal injury, the presence of ≥ 2 HRC effectively predicts the need for intervention for hemodynamic instability and can be used to identify patients who require intensive monitoring. The AAST grading system for renal injury should be modified to better reflect injury severity.

Impact of graft position on failure of single-stage bulbar urethroplasties with buccal mucosa graft.

OBJECTIVE: To determine whether patency rates after bulbar urethroplasty with buccal mucosa graft onlay differ on the basis of whether the graft is placed ventrally or dorsally. METHODS: This was a retrospective single-center study of all single-stage bulbar urethroplasties performed from 2001 to 2011 by 2 surgeons in which buccal mucosa was used as an onlay graft. Failure was defined as the need for endoscopic or open revision of the reconstruction or the placement of a suprapubic catheter for urinary retention. RESULTS: A total of 103 patients were reviewed; 41 underwent dorsal onlay, and 62 underwent ventral onlay. Mean age was 40.8 years. Most patients (84%) underwent a previous procedure, which consisted of direct vision internal urethrotomy in 69%, dilation in 53%, and urethroplasty in 14%. Mean stricture length was 3.9 cm. At a mean follow-up of 36 months, failure occurred in 19 patients (12 ventral and 7 dorsal). The vast majority of these patients (79%) were successfully treated with a single dilation or direct vision internal urethrotomy. There was no difference in failure rate or time to failure according to whether graft position was ventral or dorsal. In multivariate analysis, diabetes was predictive of failure (odds ratio 8.7; 95% confidence interval 1.6-46.5; P = .01). CONCLUSION: Single-stage bulbar urethroplasty with buccal mucosa graft is an effective procedure for patients with a bulbar urethral stricture that is not amenable to primary anastomosis. From our experience, we cannot conclude that dorsal or ventral graft position is inherently superior. Patients with diabetes may be more likely to require additional procedures after bulbar urethroplasty with buccal grafting.

National trends in surgical therapy for benign prostatic hyperplasia in the United States (2000-2008).

OBJECTIVE: To report an update of the change in usage trends for different surgical treatments of benign prostatic hyperplasia (BPH) among the United States Medicare population data from 2000-2008. The rate of usage of thermotherapy and laser therapy in the surgical treatment of BPH has been changing over the past decade in conjunction with a steady decrease of transurethral resection of the prostate (TURP). METHODS: Using the 100% Medicare carrier file for the years 2000-2008, we calculated counts and population-adjusted rates of BPH surgery. Rates of TURP, thermotherapy, and laser-using modalities were calculated and compared in relation to age, race, clinical setting, and reimbursement. RESULTS: After years of a steady rise, the total rate of all BPH procedures peaked in 2005 at 1078/100,000 and then declined by 15.4% to 912/100,000 in 2008. TURP rates continued to decline from 670 in 2000 to 351/100,000 in 2008. Rates of microwave thermoablation peaked in 2006 at 266/100,000 and then declined 26% in 2008. Laser vaporization almost completely replaced laser coagulation and in 2008 was the most commonly performed procedure second to TURP, with the majority performed as outpatient procedures (70%) and an increasing percentage in the office (12%). Men between ages 70 and 75 had the highest rate of procedures. Reimbursement rates correlate using some but not all procedures. Racial disparities reported previously appear to have resolved. CONCLUSION: Surgical treatment of BPH continues to change rapidly. TURP continues to decline and laser vaporization is the fastest growing modality. There is a big shift toward outpatient/office procedures. Reimbursement rates do not appear to have a consistent effect on usage.

Long-term urinary adverse effects of pelvic radiotherapy.

OBJECTIVE: Radiation for tumors arising in the pelvis has been utilized for over a 100 years. Adverse effects (AEs) of radiotherapy (RT) continue to accumulate with time and are reported to show decades after treatment. The benefit of RT for pelvic tumors is well described as is their acute AEs. Late AEs are less well described. The burden of treatment for the late AEs is large given the high utilization of RT. REVIEW: For prostate cancer, 37% of patients will receive radiation during the first 6 months after diagnosis. Low-and high-grade AEs are reported to occur in 20-43 and 5-13%, respectively, with a median follow-up of ~60 months. For bladder cancer, the grade 2 and grade 3 late AEs occur in 18-27 and 6-17% with a median follow-up of 29-76 months. For cervical cancer, the risk of low-grade AEs following radiation can be as high as 28%. High-grade AEs occur in about 8% at 3 years and 14.4% at 20 years or ~0.34% per year. Radiation AEs appear to be less common or at least less well studied after radiation for rectal and endometrial cancers. CONCLUSION: Properly delineating the rate of long-term AEs after pelvic RT is instrumental to counseling patients about their options for cancer treatment. Further studies are needed that are powered to specifically evaluate long-term AEs.

Osteoblasts can stimulate prostate cancer growth and transcriptionally down-regulate PSA expression in cell line models.

INTRODUCTION: To investigate the effect of bone environment on cellular proliferation, mature prostate-specific antigen (PSA) production and secretion, and PSA transcriptional regulation of prostate cancer cells. MATERIALS AND METHODS: Androgen-independent C4-2 prostate cancer cells were co-cultured with various osteoblastic cells in a transwell system. Proliferation was measured via cell counting and MTT assay. Lactate and PSA were determined in the conditioned media (CM). Transcriptional activity of the full-length PSA promoter (6.1 kilobases) and of 3 deletion constructs was determined via luciferase reporter assay upon exposure to CM from various osteoblastic cell lines. RESULTS: Osteoblastic bone cells and CM, but not control cells (fibroblast) or CM, reproducibly stimulated the proliferation of C4-2 cells. The co-culture system, PSA production by C4-2 cells transiently decreased when in co-culture with osteoblastic, but not with control cells. After abundant prostate cell proliferation, the secreted PSA levels rose exponentially. Addition of CM from osteoblastic cells, but not control cells, consistently decreased (about 3-fold) the transcriptional activity of the PSA promoter in C4-2 cells. Deletion construct analysis of the PSA promoter revealed that the transcriptional down-regulation is dually controlled by elements close to the TATA and upstream androgen responsive (ARE(III)) components. CONCLUSIONS: The osteoblastic environment stimulates prostate cancer cell proliferation but reduces PSA production initially. The mechanism of PSA down-regulation is transcriptional, most likely in response to soluble factors present in the osteoblastic bone stromal cell CM. Transcriptional down-regulation appears to be mediated by elements near both the TATA box and the ARE(III) component.

Telomerase enzyme inhibition (TEI) and cytolytic therapy in the management of androgen independent osseous metastatic prostate cancer.

BACKGROUND: Recurrent prostate cancer can be osseous, androgen independent and lethal. The purpose is to discern the efficacy of synthetic small molecule telomerase enzyme inhibitors (TEI) alone or in combination with other cytotoxic therapies in controlling metastatic osseous prostate cancer. METHODS: C4-2B was pre-treated with a match or mismatch TEI for 6 weeks and then inoculated into nude mice subcutaneously or intraosseously. In a separate experiment, untreated C4-2B was injected into femur of nude mice. The mice were divided into seven systemic "combination" treatment groups of control, Ad-BSP-E1a virus, docetaxel, mismatch and match TEI. Serum PSA was followed longitudinally. Histology analyses and histomorphometry were performed. Repeated measure analysis was applied for statistical analysis and Bonferroni method was used in multiple comparisons. RESULTS: In the pre-treated study, the PSA of match treated cells in subcutaneous or intraosseous model was significantly lower than mismatch TEI or PBS treated group (P < 0.05). Histology revealed increased fibrosis, apoptosis and decreased PSA staining in the match TEI treated subcutaneous xenografts. In the combination treatment study, the PSA was significantly lower in single/double treatment and triple treatment than control (P < 0.05). Histology revealed that triple therapy mice had normal femur architecture. Histomorphometrics revealed that the area of femur tumor and woven bone was significantly positively correlated (P = 0.007). CONCLUSIONS: Multiple lines of data point toward the efficacy of systemically administered telomerase inhibitors. Combining cytotoxic regimens with telomerase inhibitors could be beneficial in controlling prostate cancer. Clinical trials are warranted to explore the efficacy of TEI in prostate cancer.

Prostate cancer disease-free survival after radical retropubic prostatectomy in patients older than 70 years compared to younger cohorts.

OBJECTIVES: To evaluate the feasibility of radical retropubic prostatectomy (RRP) as an option for treating men older than 70 years with organ confined prostate cancer and to compare biochemical progression-free survival with younger cohorts. MATERIALS AND METHODS: A total of 689 consecutive patients who were treated with RRP from 1994 to 2002 for clinically localized prostate cancer were categorized into 3 different age groups: younger than 50 years (n = 49), 50-70 years (n = 601), and older than 70 years (n = 39). Patients older than 70 years were healthy individuals for their age. Preoperative and postoperative cancer-specific characteristics were compared among these 3 groups. RESULTS: There was no statistical significant difference among the 3 age strata in terms of clinical parameters (prostate-specific antigen, Gleason score, clinical stage, percent and number of positive biopsy cores) and pathologic findings (surgical margin, lymph node status, extracapsular extension, lymphovascular invasion, and pathologic Gleason score). The rate of seminal vesicle invasion and prostate volume increased with advancing age (P = 0.034 and P < 0.001). In multivariate logistic regression analysis, age was not associated with seminal vesicle invasion. The 5-year prostate-specific antigen progression-free estimates for patients younger than 50, 50-70, and older than 70 years were 82% (95% confidence interval [CI] 69% to 96%), 82% (95% CI 78% to 86%), and 65% (95% CI 43% to 86%), respectively (P = 0.349). The overall and cause-specific mortalities were not different. CONCLUSIONS: RRP could be considered a standard treatment option in men older than 70 years with localized prostate cancer. Further studies are necessary to assess the survival benefit and health-related quality of life after radical prostatectomy versus watchful waiting in patients older than 70 years.

Conditionally replicating adenovirus-mediated gene therapy in bladder cancer: an orthotopic in vivo model.

INTRODUCTION: The effects of a conditionally replicating adenovirus on various bladder cancer lines were explored, a truncated bone sialoprotein (BSP) promoter controlling the E1a/b lytic-regulating sequence was used, since BSP protein is found in many osteotropic neoplasms, including bladder cancer. METHODS: Reverse transcriptase polymerase chain reaction analysis was used to determine expression patterns of BSP and Coxsackie adenovirus receptor, a receptor known to interact with adenovirus, on multiple lines of bladder cancer (253J, 253J B-V, RT4, transitional cell carcinoma, T24, UMUC3, and WH). Ad-BSP-E1a was tested in vitro for lytic activity on 4 of these cell lines. The 253J B-V cell line was used and inoculated into female nude mice either subcutaneously in the flank or orthotopically into the bladder, and treated with control or Ad-BSP-E1a virus. RESULTS: BSP is expressed in RT4, transitional cell carcinoma, and WH. Meanwhile, Coxsackie adenovirus receptor was expressed in all lines except T24. Ad-BSP-E1a had the most impact on 253J and 253J B-V cells; cell density declined significantly when compared to phosphate-buffered saline and Ad-BSP-TK "dummy" virus-treatment groups. The 253J B-V tumors treated with Ad-BSP-E1a revealed a decreased percent change of size in the subcutaneous model when compared to controls at week 3. The orthotopic murine model showed decreased end tumor mass in the Ad-BSP-E1a treated group over controls. Histologic examination of in vivo tumors showed evidence of fibrosis and apoptosis in the Ad-BSP-E1a treated groups using hematoxylin-eosin, trichrome, and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling (TUNEL) staining. Control groups only had viable tumor in in vivo models. CONCLUSION: Adenovirus therapy of orthotopic murine bladder tumors is feasible. Ad-BSP-E1a is effective in treating very aggressive yet sensitive bladder tumor cells. Further study of this conditionally replicating adenovirus treatment (Ad-BSP-E1a) with chemotherapeutic combination is warranted, and future translation of such combination therapy into human beings is a possibility.