Nikolai A. Sopko

Understanding and targeting the Rho kinase pathway in erectile dysfunction

Erectile dysfunction (ED) is a common disorder that affects a quarter of US men, and has many causes, including endothelial impairment, low testosterone levels, prior surgical manipulation, and/or psychogenic components. Penile erection is a complex process requiring neurally mediated relaxation of arteriolar smooth muscle and engorgement of cavernosal tissues, mediated by nitric oxide (NO). Current medical therapies for ED largely seek to maximize endogenous NO signalling. Certain aetiologies, including diabetes, are difficult to treat with current modalities, emphasizing the need for new molecular targets. Research has demonstrated the importance of RhoA–Rho-associated protein kinase (ROCK) signalling in maintaining a flaccid penile state, and inhibition of RhoA–ROCK signalling potentiates smooth-muscle relaxation in an NO-independent manner. The mechanisms and effects of RhoA–ROCK signalling and inhibition suggest that the RhoA–ROCK pathway could prove to be a new therapeutic target for the treatment of ED.

Frailty as a marker of adverse outcomes in patients with bladder cancer undergoing radical cystectomy

OBJECTIVE To investigate the modified frailty index (mFI) as a preoperative predictor of postoperative complications following radical cystectomy (RC) in patients with bladder cancer. MATERIALS AND METHODS Patients undergoing RC were identified from the National Surgical Quality Improvement Program participant use files (2011-2013). The mFI was defined in prior studies with 11 variables based on mapping the Canadian Study of Health and Aging Frailty Index to the National Surgical Quality Improvement Program comorbidities and activities of daily livings. The mFI groups were determined by the number of risk factors per patient (0, 1, 2, and≥3). Univariable and multivariable regression were performed to determine predictors of Clavien 4 and 5 complications, and a sensitivity analysis was performed to determine the mFI value that would be a significant predictor of Clavien 4 and 5 complications. RESULTS Of the 2,679 cystectomy patients identified, 843 (31%) of patients had an mFI of 0, 1176 (44%) had an mFI of 1, 555 (21%) had an mFI of 2, and 105 (4%) had an mFI≥3. Overall, 1585 (59%) of patients experienced a Clavien complication. When stratified at a cutoff of mFI≥2, the overall complication rate was not different (61.7% vs. 58.3%, P = 0.1), but the mFI2 or greater group had a significantly higher rate of Clavien grade 4 or 5 complications (14.6% vs. 8.3%, P<0.001) and overall mortality rate (3.5% vs. 1.8%, P = 0.01) in the 30-day postoperative period. The multivariate logistic regression model showed independent predictors of Clavien grade 4 or 5 complications were age>80 years (odds ratio [OR] = 1.58 [1.11-2.27]), mFI2 (OR = 1.84 [1.28-2.64]), and mFI3 (OR = 2.58 [1.47-4.55]). CONCLUSIONS Among patients undergoing RC, the mFI can identify those patients at greatest risk for severe complications and mortality. Given that bladder cancer is increasing in prevalence particularly among the elderly, preoperative risk stratification is crucial to inform decision-making about surgical candidacy.

Caspase-3 dependent nitrergic neuronal apoptosis following cavernous nerve injury is mediated via RhoA and ROCK activation in major pelvic ganglion

Axonal injury due to prostatectomy leads to Wallerian degeneration of the cavernous nerve (CN) and erectile dysfunction (ED). Return of potency is dependent on axonal regeneration and reinnervation of the penis. Following CN injury (CNI), RhoA and Rho-associated protein kinase (ROCK) increase in penile endothelial and smooth muscle cells. Previous studies indicate that nerve regeneration is hampered by activation of RhoA/ROCK pathway. We evaluated the role of RhoA/ROCK pathway in CN regulation following CNI using a validated rat model. CNI upregulated gene and protein expression of RhoA/ROCK and caspase-3 mediated apoptosis in the major pelvic ganglion (MPG). ROCK inhibitor (ROCK-I) prevented upregulation of RhoA/ROCK pathway as well as activation of caspase-3 in the MPG. Following CNI, there was decrease in the dimer to monomer ratio of neuronal nitric oxide synthase (nNOS) protein and lowered NOS activity in the MPG, which were prevented by ROCK-I. CNI lowered intracavernous pressure and impaired non-adrenergic non-cholinergic-mediated relaxation in the penis, consistent with ED. ROCK-I maintained the intracavernous pressure and non-adrenergic non-cholinergic-mediated relaxation in the penis following CNI. These results suggest that activation of RhoA/ROCK pathway mediates caspase-3 dependent apoptosis of nitrergic neurons in the MPG following CNI and that ROCK-I can prevent post-prostatectomy ED.

The Effect of Repair Costs on the Profitability of a Ureteroscopy Program

BACKGROUND AND PURPOSE Ureteroscopy (URS) is a common treatment for patients with stone disease. One of the disadvantages of this approach is the great capital expense associated with the purchase and repair of endoscopic equipment. In some cases, these costs can outpace revenues and lead to an unprofitable and unsustainable enterprise. We sought to characterize the profitability of our URS program when accounting for endoscope maintenance and repair costs. MATERIALS AND METHODS We identified all URS cases performed at a single hospital during fiscal year 2013 (FY2013). Charges, collection rates, and fixed and variable costs including annual equipment repair costs were obtained. The net margin and break-even point of URS were derived on a per-case basis. RESULTS For 190 cases performed in FY2013, total endoscope repair costs totaled

Erection rehabilitation following prostatectomy--current strategies and future directions.

115,000, resulting in an average repair cost of

Ex Vivo Model of Human Penile Transplantation and Rejection: Implications for Erectile Tissue Physiology

605 per case. The vast majority of cases (94.2%) were conducted in the outpatient setting, which generated a net margin of

Inguinal Hernia Repair During Extraperitoneal Robot-Assisted Laparoscopic Radical Prostatectomy.

659 per case, while inpatient cases yielded a net loss of

Pathologic response in patients receiving neoadjuvant chemotherapy for muscle-invasive bladder cancer: Is therapeutic effect owing to chemotherapy or TURBT?

455. URS was ultimately associated with a net positive margin approaching

Intravesical BCG Induces CD4+ T-cell expansion in an immune competent model of bladder cancer

600 per case. On break-even analysis, URS remained profitable until repair costs reached

Immune checkpoint inhibitors: a new frontier in bladder cancer

1200 per case. CONCLUSIONS Based on these findings, an established URS program can sustain profitability even with large equipment repair costs. Nonetheless, our findings serve to emphasize the importance of controlling costs, particularly in the current setting of decreasing reimbursement. A multifaceted approach, based on improving endoscope durability and exploring digital and disposable platforms, will be critical in maintaining the sustainability of URS.