Utility of the RENAL nephrometry scoring system in the real world: predicting surgeon operative preference and complication risk.

OBJECTIVE: • To evaluate the utility of the RENAL scoring system in predicting operative approach and risk of complications. The RENAL nephrometry scoring system is designed to allow comparison of renal masses based on the radiological features of (R)adius, (E)xophytic/endophytic, (N)earness to collecting system, (A)nterior/posterior and (L)ocation relative to polar lines. METHODS: • A retrospective review of all patients at a single institution undergoing radical nephrectomy (RN) or partial nephrectomy (PN) for a renal mass between July 2007 and May 2010 was carried out. • Preoperative RENAL score was calculated for each patient. Surgical approach and operative outcomes were then compared with the RENAL score. RESULTS: • In all, 249 patients underwent either RN (158) or PN (91) with average RENAL scores of 8.9 and 6.3, respectively (P < 0.001). • Patients who underwent RN were more likely to have hilar tumours (64% vs 10%, P < 0.001) than patients who underwent PN, but were no more likely to have posteriorly located tumours (50% each). • There were more complications among patients with RN (58%) vs patients with PN (42%, P= 0.02). • RENAL scores were higher in patients with PN who developed complications than in patients with PN who did not develop complications (6.9 vs 6.0, P= 0.02), with no difference noted among patients with RN developing complications (8.9 vs 8.9, P= 0.99). CONCLUSION: • The RENAL system accurately predicted surgeon operative preference and risk of complications for patients undergoing PN.

Role of routine transurethral biopsy and isolated upper tract cytology after intravesical treatment of high-grade non-muscle invasive bladder cancer.

OBJECTIVES: To investigate whether random bladder, and prostatic urethral biopsies and individual upper tract cytologies (restaging) provide useful clinical information in addition to cystoscopy and bladder cytology in assessing initial intravesical therapy response for high-grade non-muscle invasive bladder cancer. METHODS: We retrospectively reviewed records of all patients who underwent restaging at our institution after treatment for high-grade non-muscle invasive bladder cancer (Ta, T1 and Tis) between January 2000 and October 2009. A total of 78 patients undergoing 116 consecutive restagings were included. The presence of intravesical cancer at restaging was assessed by cystoscopy, bladder wash cytology and random bladder biopsies, whereas ureteral and prostatic urethral disease was determined using upper tract barbotage cytology and prostatic urethral biopsies. RESULTS: Indication for intravesical treatment was carcinoma in situ in 86, high-grade T1 in 16 and high-grade Ta in 14 cases. A total of 48 patients had primary disease and 68 had recurrence. Overall, 59 of 116 (50.9%) restagings showed positive bladder or prostatic biopsy and/or a positive cytology localized to the upper tract. Of the total number of recurrences, 12.9% (15 of 116) showed a negative cystoscopy and negative bladder cytology, and would have been missed on routine surveillance. A total of 23 of 116 (19.8%) restagings showed evidence of prostatic urethral and or ureteral disease. CONCLUSION: Roughly 25% of high-grade non-muscle invasive bladder cancer early recurrences after induction intravesical therapy would go unnoticed without the addition of random and directed prostate biopsies, and isolated upper tract cytologies to standard cystoscopy and bladder cytology.

Usefulness of the Spanish Urological Club for Oncological Treatment scoring model to predict nonmuscle invasive bladder cancer recurrence in patients treated with intravesical bacillus Calmette-Guérin plus interferon-α.

PURPOSE: The Spanish Urological Club for Oncological Treatment recently developed a scoring model to stratify the recurrence risk in patients treated with intravesical bacillus Calmette-Guérin using gender, age, grade, tumor status, T category, multiplicity and associated carcinoma in situ. We investigated the ability of this model to stratify the recurrence risk in patients with nonmuscle invasive bladder cancer undergoing combination bacillus Calmette-Guérin plus interferon α-2B therapy. MATERIALS AND METHODS: We retrospectively reviewed data from a national multicenter phase II trial of bacillus Calmette-Guérin plus interferon α-2B in patients with nonmuscle invasive bladder cancer to identify 718 with the data required to use the model. Recurrence was defined as visible tumor on cystoscopy unless histologically confirmed as benign, definitive positive cytology or biopsy proven disease even with negative cystoscopy. Time to recurrence was indexed to the first intravesical treatment date. Patients were assigned points based on the model and then divided into 4 groups based on total score, including 0 to 4, 5 or 6, 7 to 9 and 10 or greater. RESULTS: The model successfully stratified the recurrence risk into 4 statistically different groups based on score with a 3-year recurrence-free rate of 58%, 52%, 42% and 26% for scores of 0 to 4, 5 or 6, 7 to 9 and 10 or greater, respectively (p < 0.001). CONCLUSIONS: The Spanish Urological Club for Oncological Treatment scoring model is a useful prognostic tool to stratify recurrence risk in patients with nonmuscle invasive bladder cancer who are treated with combined intravesical bacillus Calmette-Guérin plus interferon α-2B. Larger, prospective trials are required for full model validation.

Current and future need for academic urologists in the United States.

PURPOSE: We assessed the need for academic urologists in 2010 and for the following 5 years. MATERIALS AND METHODS: An 8-question survey was emailed to the 115 accredited academic urology residency programs recognized by the American Urological Association. Questions were related to the anticipated number of hires during the next 5 years, ideal minimum level of training, areas of expertise needed, current top need and allotted research time. RESULTS: Of 115 chairs or division heads 91 (79%) responded to the survey. Of all chairs 71% (65 of 91) expect to hire 2 to 4 physicians in the next 5 years. In total 91 chairs will be attempting to fill 292 openings. When carried out to 115 chairs, there will be 369 openings in the next 5 years (or 74 per year). The ideal minimum level of training was cited as clinical/research fellowship (37.1%), clinical fellowship (33.6%) and residency (10.5%). Areas of expertise needed most from each respective program include female urology/neurourology (51.7%), oncology (44.8%), and pediatrics and general urology (36.8%). The current top needs for respective programs include pediatrics 23.3%, female urology/neurourology 21.1% and oncology 18.9%. Of the chairs and division heads currently attempting to fill positions 53.5% have been searching for 2 or more years. CONCLUSIONS: There will be a tremendous need for academic urologists in the next 5 years. This need is thought to be due to an increased number of physicians retiring and decreased level of compensation compared to private practice.

Factors affecting response to bacillus Calmette-Guérin plus interferon for urothelial carcinoma in situ.

PURPOSE: The unpredictable behavior of carcinoma in situ and its high potential for recurrence and progression make identifying patient characteristics predicting a poor prognosis a priority. We assessed which factors affect the response to bacillus Calmette-Guérin plus interferon-α therapy in patients with urothelial carcinoma in situ. MATERIALS AND METHODS: We analyzed data on a subset of 231 patients with carcinoma in situ enrolled in a multicenter, phase II trial of bacillus Calmette-Guérin plus interferon-α therapy for nonmuscle invasive bladder cancer. Analysis included patients who were bacillus Calmette-Guérin naïve and those with previous exposure to failed bacillus Calmette-Guérin therapy. We evaluated factors potentially affecting the bacillus Calmette-Guérin plus interferon-α response, including patient age, gender, tumor stage, multifocality, prior tumor stage, the previous bacillus Calmette-Guérin failure pattern, courses and maintenance, and prior chemotherapy. RESULTS: The complete response rate at 3 and 6 months in naïve vs previously failed bacillus Calmette-Guérin cases was 76% and 70% vs 76% and 66%, respectively. The 24-month disease-free rate was decreased in the 53 patients with a history of 2 or more failed bacillus Calmette-Guérin courses vs that in the 71 with a history of 1 failed course and bacillus Calmette-Guérin naïve patients (23% vs 57% and 60%, respectively). The 22 patients with refractory carcinoma in situ had the worst outcome of a 23% disease-free rate at 24 months while the 59 with relapse within 1 year had an intermediate outcome of 42% vs 59% in the 33 with relapse after 1 year. Patients with a history of papillary disease did better than those without such a history (p=0.019). CONCLUSIONS: Factors associated with a poor response to bacillus Calmette-Guérin plus interferon-α therapy in patients with carcinoma in situ are prior tumor stage, 2 or more prior bacillus Calmette-Guérin failures and a bacillus Calmette-Guérin failure pattern.

Recognition and treatment of BCG failure in bladder cancer.

Patients with high-grade Ta, T1, or carcinoma in situ non-muscle-invasive bladder cancer (NMIBC) are at high risk for recurrence and, more importantly, progression. Thus, both the American Urological Association and European Association of Urology recommend initial intravesical treatment with bacillus Calmette-Guerin(BCG) followed by maintenance therapy for a minimum of 1 year. The complete response rate to BCG therapy in patients with high-risk NMIBC can be as high as ~80%; however, most patients with high-risk disease suffer from recurrence. BCG failure can be further characterized into BCG refractory, BCG resistant, BCG relapsing, and BCG intolerant. Current recommendations include one further course of BCG or cystectomy. In patients who continue to fail conservative treatment and who refuse surgical therapy or are not surgical candidates, treatment options become even more complicated. In this setting, treatment options are limited and include repeat BCG treatment, an alternate immunotherapy regimen, chemotherapy, or device-assisted therapy. To date, however, further research is necessary for all secondary treatment options in order to determine which might be the most efficacious. All conservative treatments should be considered investigational. Currently, cystectomy remains the standard of care for high-risk patients who have failed BCG therapy.

Rubin H. Flocks and colloidal gold treatments for prostate cancer.

In the early 1950s, Rubin H. Flocks of the University of Iowa began to treat prostate cancer patients with colloidal gold (Au(198)) therapy, evolving his technique over nearly 25 years in 1515 patients. We reviewed the long-term outcomes of Flocks' prostate cancer patients as compared to those patients treated by other methods at the University of Iowa before Flocks' chairmanship. We reviewed archived patient records, Flocks' published data, and long-term survival data from the Iowa Tumor Registry to determine short- and long-term outcomes of Flocks' work with colloidal gold. We also reviewed the literature of Flocks' time to compare his outcomes against those of his contemporaries. The use of colloidal gold, either as primary or adjunctive therapy, provided short- and long-term survival benefit for the majority of Flocks' patients as compared to historical treatment options (p < 0.001). Flocks' use of colloidal gold for the treatment of locally advanced prostate cancer offered short- and long-term survival benefits compared to other contemporary treatments.

The role of neutrophils and TNF-related apoptosis-inducing ligand (TRAIL) in bacillus Calmette-Guérin (BCG) immunotherapy for urothelial carcinoma of the bladder.

Intravesical Mycobacterium bovis bacillus Calmette-Guérin (BCG) immunotherapy is a highly effective treatment for carcinoma in situ of the bladder, as well as high-risk nonmuscle invasive urothelial carcinoma of the bladder. Despite over 30 years of clinical experience with BCG, the therapy's mechanism has remained enigmatic. Observations regarding the role of neutrophils in BCG immunotherapy have led to exciting discoveries regarding the potential role of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in creating the therapeutic benefit of BCG immunotherapy. In this paper, we will review the scope of the disease, highlight our understanding of the role for BCG in urothelial carcinoma of the bladder, explain the recent discoveries regarding the role of neutrophils and TRAIL in therapy, and theorize on potential future areas of research.

Safety and efficacy of intravesical bacillus Calmette-Guérin plus interferon α-2b therapy for nonmuscle invasive bladder cancer in patients with prosthetic devices.

PURPOSE: Patients with bladder cancer who have prosthetic devices, such as a cardiac pacemaker, artificial heart valve or orthopedic hardware, and who undergo intravesical bacillus Calmette-Guérin therapy are theoretically at higher risk for complications, including bacterial seeding of pacemaker wires or orthopedic hardware, and at further risk for infective endocarditis. We assessed the safety and efficacy of bacillus Calmette-Guérin plus interferon α-2b therapy in patients with nonmuscle invasive bladder cancer and a pacemaker, artificial heart valve or orthopedic hardware. MATERIALS AND METHODS: We evaluated 1,045 patients with nonmuscle invasive bladder cancer enrolled in a multicenter American phase II trial of bacillus Calmette-Guérin plus interferon α-2b therapy, including 143 with a prosthetic device (pacemaker in 87, artificial heart valve in 13 and orthopedic hardware in 43). Weekly physician toxicity assessments and standard adverse effect reporting were done. RESULTS: No patient had infective endocarditis or hardware infection. One patient with a pacemaker, 2 with orthopedic hardware and none with an artificial heart valve required treatment cessation for fever greater than 102.5F. All defervesced within 24 hours and had no long-term sequelae. Due to intolerable, nonlife threatening side effects 12 patients with a pacemaker, 2 with orthopedic hardware and 1 with an artificial heart valve stopped treatment. Of the remaining patients with a prosthesis 99 and 24 stopped treatment due to intolerable, nonlife threatening and serious side effects, respectively. CONCLUSIONS: Patients with a pacemaker, artificial heart valve or orthopedic hardware were no more likely than the general population to have infection or fever, or discontinue treatment due to side effects. These patients should not be excluded from intravesical bacillus Calmette-Guérin plus interferon α-2b therapy for nonmuscle invasive bladder cancer.

Bacillus Calmette-Guérin with or without interferon α-2b and megadose versus recommended daily allowance vitamins during induction and maintenance intravesical treatment of nonmuscle invasive bladder cancer.

PURPOSE: In a multicenter, prospectively randomized study we evaluated bacillus Calmette-Guérin alone vs bacillus Calmette-Guérin plus interferon α-2b and megadose vitamins vs recommended daily allowance vitamins during induction and maintenance intravesical therapy in the treatment of nonmuscle invasive bladder cancer. MATERIALS AND METHODS: Patients who were bacillus Calmette-Guérin naïve with carcinoma in situ, Ta or T1 urothelial cancer were randomized to receive intravesical bacillus Calmette-Guérin or bacillus Calmette-Guérin plus interferon α-2b. Patients were further randomized to receive a recommended daily allowance or megadose vitamin preparation. Induction bacillus Calmette-Guérin treatment was given weekly for 6 weeks, and patients who were recurrence-free received maintenance treatment at 4, 7, 13, 19, 25 and 37 months. Patients were followed with quarterly cystoscopy for 2 years, then semiannually through year 4 and then annually. The primary end point was biopsy confirmed tumor recurrence or positive cytology. RESULTS: A total of 670 patients were accrued and randomized. At 24-month median followup recurrence-free survival was similar in all groups with 63% in the bacillus Calmette-Guérin with recommended daily allowance vitamins group, 59% in bacillus Calmette-Guérin with megadose vitamins, 55% in bacillus Calmette-Guérin/interferon α-2b with recommended daily allowance vitamins and 61% in bacillus Calmette-Guérin/interferon α-2b with megadose vitamins (p >0.05). The addition of interferon α-2b was associated with a more frequent incidence of fever (11% vs 5%) and constitutional symptoms (18% vs 11%) vs bacillus Calmette-Guérin alone (p <0.05). CONCLUSIONS: Interferon α-2b added to bacillus Calmette-Guérin induction and maintenance intravesical therapy did not decrease tumor recurrence in bacillus Calmette-Guérin naïve cases, but was associated with increased fever and constitutional symptoms. No difference in time to recurrence was present in patients receiving recommended daily allowance vs high dose vitamins.

Inflatable penile prostheses: an update.

PURPOSE OF REVIEW: Since the advent of oral medication for the treatment of erectile dysfunction the disease has garnered increasing attention by both scientists and the general public alike. Coinciding with this, more patients are seeking treatment of their disease. When medical management is not successful, surgical implantation of a penile prosthesis may be considered. RECENT FINDINGS: Because inflatable penile prostheses are vastly preferred by patients over noninflatable prostheses, this review will focus on their current use, reported durability and safety, and patient satisfaction. SUMMARY: Inflatable penile prostheses are associated with decreasing risks of infection and device malfunction and extremely high patient and partner satisfaction rates. Because of this, inflatable penile prostheses remain a viable tertiary treatment option for erectile dysfunction.

Identification of novel alpha7 nAChR positive allosteric modulators with the use of pharmacophore in silico screening methods.

The pharmacophore model of in house potent and selective alpha7 nAChR positive allosteric modulators is reported. The model was used to fish out commercially-available compounds from corporate 3D databases. As a result, novel alpha7 positive modulator chemotypes were identified. A rat full PK profile of a representative compound is also described.

1,2,4-triazol-3-yl-thiopropyl-tetrahydrobenzazepines: a series of potent and selective dopamine D(3) receptor antagonists.

The discovery of new highly potent and selective dopamine D3 receptor antagonists has recently permitted characterization of the role of the dopamine D3 receptor in a wide range of preclinical animal models. A novel series of 1,2,4-triazol-3-yl-thiopropyl-tetrahydrobenzazepines demonstrating a high level of D3 affinity and selectivity with an excellent pharmacokinetic profile is reported here. In particular, the pyrazolyl derivative 35 showed good oral bioavailability and brain penetration associated with high potency and selectivity in vitro. In vivo characterization of 35 confirmed that this compound blocks the expression of nicotine- and cocaine-conditioned place preference in the rat, prevents nicotine-triggered reinstatement of nicotine-seeking behavior in the rat, reduces oral operant alcohol self-administration in the mouse, increases extracellular levels of acetylcholine in the rat medial prefrontal cortex, and potentiates the amplitude of the relative cerebral blood volume response to d-amphetamine in a regionally specific manner in the rat brain.

Synthetic entries to substituted bicyclic pyridones.

The synthesis of 6,6- and 5,6-bicyclic pyridone scaffolds has been completed using (i) an intramolecular Mitsunobu reaction and/or (ii) hydrolysis of a bicyclic pyridinium salt intermediate. Regioselective functionalization of the pyridone ring has been achieved via either direct lithiation or use of the "halogen dance" reaction. Suzuki coupling then allows introduction of aryl units at C(7)/C(9) or C(8) onto the bicyclic pyridone scaffold at either an early or late stage in the synthetic sequence. Suzuki couplings involving iodopyridinium intermediates are particularly effective.

A novel, efficient, diastereo- and enantioselective Mukaiyama aldol-based synthesis of a vinyl cyclopentanone core derivative of viridenomycin.

A strategy has been developed for a rapid seven-step construction of a chiral, nonracemic vinyl cyclopentanone building block as part of a synthetic approach to viridenomycin, using a diastereo- and enantioselective Mukaiyama aldol and intramolecular Knoevenagel condensation as key steps.

Low levels of serum testosterone in middle-aged men impact pathological features of prostate cancer.

BACKGROUND: Serum testosterone deficiency increases with aging. Age is also a major risk factor for prostate cancer (PrCa) and PCa tumors are more frequently diagnosed among men >65 years old. We evaluated the relationship between preoperative serum testosterone and clinical/ pathological features of PrCa in middle-aged and elderly patients. METHODS: A total of 605 PrCa patients who underwent robotic-assisted radical prostatectomy between September 2010 and January 2013 at the University of Pennsylvania, and who had serum testosterone levels measured using Elecsys Testosterone II Immunoassay were included in this IRB-approved protocol. Androgen deficiency was determined as serum free testosterone (FT) <47 pg/ml and total testosterone (TT) <193 ng/dl. Demographic, clinical and tumor characteristics of men with low vs. normal TT or FT were compared using t-test or chi-square tests. Logistic regression was used to determine associations of clinical and pathological variables with FT or TT levels. RESULTS: Among middle-aged men (45-64 years; n = 367), those with low FT and low TT had, on average, a higher BMI (29.7 vs. 27.4, P < 0.01; and 32.2 vs. 27.6; P < 0.01, respectively) and higher proportion of Gleason 8-10 PrCa (13.3% vs. 4.8%, P = 0.011; and 19.2% vs. 5.1%, P = 0.012) compared to men with normal FT and normal TT values. Patients with low FT had also higher number of positive cores on biopsy (3.9 vs. 3.1 P = 0.019) and greater tumor volume (7.9 ml vs. 6.1 ml, P = 0.045) compared to those with normal FT. Among men ≥65 years (n = 135) there was no difference in prostatectomy specimens of PrCa between patients with low or normal FT or TT. CONCLUSION: Among men aged 45-64 years low serum pretreatment FT and TT predicted more aggressive features of PrCa in prostatectomy specimens. In middle-aged patients low testosterone levels measured pre-operatively may indicate more aggressive disease parameters.

ACL tears in collegiate wrestlers: report of six cases in one season.

Six NCAA Division I wrestlers at The University of Iowa tore an anterior cruciate ligament (ACL) during the 2002-03 season. In comparison, between the years of 1993 and 2002, only five wrestlers sustained the same injury. Retrospective review and video data analysis were performed. All six were injured while their knee was near terminal extension and in a vulnerable position. Eighty-three percent of all injuries occurred during takedowns. Five of the six wrestlers' mechanism of injury involved rotation and stress on the weight-bearing knee. Eighty-three percent sustained their injuries while their foot was firmly planted on the ground. Five of the injuries occurred in competition. Of the six wrestlers injured, four underwent immediate rehabilitation in hope of wrestling that same season. Three ultimately needed surgery and one continued to wrestle in the same season without having surgery. Of the five wrestlers who underwent surgical reconstruction of their ACL, each had bone-patellar-bone grafts.

Can robot-assisted radical prostatectomy be taught to chief residents and fellows without affecting operative outcomes?

PURPOSE: To determine whether robot-assisted radical prostatectomy (RARP) may be taught to chief residents and fellows without influencing operative outcomes. METHODS: Between August 2011 and June 2012, 388 patients underwent RARP by a single primary surgeon (DIL) at our institution. Our teaching algorithm divides RARP into five stages, and each trainee progresses through the stages in a sequential manner. Statistical analysis was conducted after grouping the cohort according to the surgeons operating the robotic console: attending only (n = 91), attending and fellow (n = 152), and attending and chief resident (n = 145). Approximately normal variables were compared utilizing one-way analysis of variance, and categorical variables were compared utilizing two-tailed χ(2) test; P < 0.05 was considered statistically significant. RESULTS: There was no difference in mean age (P = 0.590), body mass index (P = 0.339), preoperative SHIM (Sexual Health Inventory for Men) score (P = 0.084), preoperative AUASS (American Urologic Association Symptom Score) (P = 0.086), preoperative prostate-specific antigen (P = 0.258), clinical and pathological stage (P = 0.766 and P = 0.699, respectively), and preoperative and postoperative Gleason score (P = 0.775 and P = 0.870, respectively). Operative outcomes such as mean estimated blood loss (P = 0.807) and length of stay (P = 0.494) were similar. There was a difference in mean operative time (P < 0.001; attending only = 89.3 min, attending and fellow 125.4 min, and attending and chief resident 126.9 min). Functional outcomes at 3 months and 1 year postoperatively such as urinary continence rate (P = 0.977 and P = 0.720, respectively), and SHIM score (P = 0.661 and P = 0.890, respectively) were similar. The rate of positive surgical margins (P = 0.058) was similar. CONCLUSIONS: Training chief residents and fellows to perform RARP may be associated with increased operative times, but does not compromise short-term functional and oncological outcomes.

Positive Surgical Margin Trends in Patients with Pathologic T3 Prostate Cancer Treated with Robot-Assisted Radical Prostatectomy.

INTRODUCTION: We analyzed the trends of positive surgical margin (PSM) location in patients who had pT3 disease at robot-assisted radical prostatectomy (RARP). We aimed to describe our changing incidence of PSMs in the largest series to date of patients with pT3 disease who were treated by RARP. METHODS: A single-institution, single-surgeon review was performed of all patients who underwent RARP from 2005 to 2011. Perioperative data were collected for all patients with pT3 prostate cancer from a prospectively maintained RARP database. The PSM incidence and rates were stratified by location. The PSM rates per location were trended over time. RESULTS: In total, 2478 consecutive patients underwent RARP between July 2005 and December 2011. Of these patients, 555 were found to have pT3 disease. The PSM rate for patients with pT3 disease was 47%. The PSM rate for patients with pT3a and pT3B disease was 42.8% and 60.6%, respectively. Over the duration of this study, the PSM rate in patients with pT3 disease decreased significantly from 70.6% in 2005 to 32.3% in 2011 (p=0.002). The apical PSM rate showed the greatest decrease during this period going from 52.9% in 2005 to 5.2% in 2011 (p=0.018). CONCLUSION: We present the largest series to date involving the treatment of locally advanced prostate cancer initially managed with RARP. Our findings suggest that patients with locally advanced prostate cancer can be treated with RARP with acceptable positive margin rates. Overall PSM rates improved nearly 40% over the 6.5-year period of this study.