Study Type – Therapy (case series) Level of Evidence 4 What's known on the subject? and What does the study add? Upper urinary tract urothelial carcinomas (UTUC) have historically been treated with radical, extirpative surgery, primarily nephroureterectomy with bladder‐cuff excision. In general, there has been growing interest in renal preservation, as evidenced by the broadening application of nephron‐sparing surgery for renal parenchymal tumours. Beyond imperative reasons such as tumour in a solitary kidney, bilateral disease, or comorbidities preventing radical surgery, there is a growing role for endoscopic management of upper tract tumours. The aim has been to obtain similar oncological results to those of extirpative surgery, while preserving long‐term renal function. Properly selecting patients for these therapies, designing specific treatments based on a complex presentation, and general information with regard to outcomes and risks for patient counselling have been based historically on results from relatively small series without long‐term follow‐up. This study reflects all patients with UTUC treated by a single tertiary referral surgeon, accrued prospectively over 15 years using the same surgical techniques and treatment algorithms throughout the entire study period, with 10‐year survival data. The consecutively accrued nature and size of the study groups, uniformity in treatments, statistical review and long‐term follow‐up provide baseline oncological data that could help frame future study. OBJECTIVE To present long‐term oncological outcomes of all patients treated surgically for upper urinary tract urothelial carcinoma (UTUC) over a 15‐year period. PATIENTS AND METHODS All patients (N= 160) treated from January 1996 to August 2011 were prospectively studied and placed into three distinct groups after initial diagnostic ureteroscopy (URS): Group 1: low grade lesions treated with URS (n= 66); Group 2: high grade lesions palliatively treated with URS (n= 16); and Group 3: extirpative surgery (nephroureterectomy [NU]; n= 80). Statistical analysis was performed using Kaplan–Meier methodology to calculate overall (OS), cancer‐specific (CSS) and metastasis‐free survival (MFS). RESULTS The median patient age at presentation was 73 years, and the mean (range) follow‐up time was 38.2 (1–185) months. At initial diagnostic URS, 71 (44.4%) patients presented with high grade and 89 (55.6%) patients presented with low grade disease. The 2‐, 5‐ and 10‐year CSS rates were 98, 87 and 81% for patients with low grade disease, and 97, 87 and 78% for patients treated with URS (Group 1), not significantly different from those patients with low grade disease treated with NU (Group 3), (P= 0.54). Of the patients treated with URS for low grade disease, 10 (15.2%) progressed to high grade disease at a mean time of 38.5 months. Patients with high grade disease treated with NU had a 2‐, 5‐, and 10‐year CSS of 70, 53 and 38%, with a MFS of 55, 45 and 35%. Median survival of patients with high grade disease treated with pall...

Ureteroscopic lithotripsy has evolved since the first reported cases employing rigid rod-lens endoscopes and stiff ultrasonic lithotrites. Fiber optics facilitated rigid endoscope miniaturization and the development of a steerable, deflectable flexible ureteroscopes. Over 30 years of technical innovations culminating in digital imagers and powerful, precise laser lithotrites, complimented by progressive endoscopic techniques have produced efficient endoscopic therapies with minimal morbidity and commonly performed in an outpatient setting.

Although interferon (IFN) has been often used as immunotherapy for bladder cancer, its efficacy is rather unsatisfactory, demanding further improvement. Combination therapy is one of viable options, and grape seed proanthocyanidin (GSP) could be such an agent to be used with IFN because it has been shown to have anticancer activity. We thus investigated whether combination of IFN and GSP might enhance the overall antiproliferative effect on bladder cancer cells in vitro. Human bladder cancer T24 cells were employed and treated with the varying concentrations of recombinant IFN-α2b (0-100,000 IU/ml), GSP (0-100 μg/ml), or their combinations. IFN-α2b alone led to a ~50% growth reduction at 20,000 (20K) IU/ml, which further declined to ~67% at ≥50K IU/ml. Similarly, GSP alone induced a ~35% and ~100% growth reduction at 25 and ≥50 μg/ml, respectively. When IFN-α2b and GSP were then combined, combination of 50K IU/ml IFN-α2b and 25 μg/ml GSP resulted in a drastic >95% growth reduction. Cell cycle analysis indicated that such an enhanced growth inhibition was accompanied by a G1 cell cycle arrest. This was further confirmed by Western blot analysis revealing that expressions of G1-specific cell cycle regulators (CDK2, CDK4, cyclin E and p27/Kip1) were distinctly modulated with such IFN-α2b/GSP treatment. Therefore, these findings support the notion that combination of IFN-α2b and GSP is capable of additively enhancing antiproliferative effect on T24 cells with a G1 cell cycle arrest, implying an adjuvant therapeutic modality for superficial bladder cancer.

The present study demonstrates that the combination of PDF and VC can become highly cytotoxic, inducing severe cell death in ACHN cells. This cytotoxic mechanism appears to be primarily attributed to oxidative stress, accompanied by a G1 cell cycle arrest. Such cell death induced by PDF + VC could be more likely linked to apoptosis, as indicated by the modulation of apoptosis regulators (Bcl2, Bax, and PARP). Therefore, as PDF and VC may work synergistically to induce apoptotic cell death, they may have clinical implications in an alternative, improved therapeutic modality for advanced RCC.

The combination of VK3 and DF can lead to a profound reduction in ACHN cell viability, through a p21(WAF1)-mediated G1 cell cycle arrest, and ultimately induces apoptosis. Therefore, the combination of VK3/DF may have clinical implications as an alternative, improved therapeutic modality for advanced RCC.