INTRODUCTION AND OBJECTIVES: We investigated the prognostic significance of the various manifestations of extrarenal extension which comprise pathologic stage T3a renal cell carcinoma (RCC) among patients treated with extirpative therapy for nonmetastatic disease.METHODS: A retrospective review of 595 patients who underwent nephrectomy for pathologically-confirmed T3aN0/NxM0 clear cell RCC between 1970 and 2011 was performed. All pathologic slides were re-reviewed by a single urologic pathologist. Associations of the type of extrarenal extension (perinephric fat, renal sinus fat, and renal vein in isolation or in any combination) with disease progression, death from RCC, and death from any cause were evaluated using Cox models adjusting for demographic and pathologic features.RESULTS: Overall, perinephric fat invasion, renal sinus fat invasion, renal vein tumor thrombus, and multiple sources of extrarenal extension were present in 160 (27%), 59 (10%), 167 (28%), and 209 (35%) patients, respectively. Median follow-up after surgery was 9.1 years (IQR 6.7, 13.2), during which time 343 patients developed disease progression at a median of 1.5 years (IQR 0.5-4.3), 271 patients died from RCC at a median of 3.5 years (IQR 1.6-7.3), and 463 patients died from any cause at a median of 4.9 years (IQR 2.0-10.0) following surgery. No significant differences in the rates of disease progression, death from RCC, or death from any cause were observed in the presence of isolated perinephric fat invasion, renal sinus fat invasion, or renal vein tumor thrombus. However, on multivariable analyses, patients with multiple sources of extrarenal extension were at a significantly increased risk of disease progression (HR 1.31, 95%CI¼1.05-1.64, P¼0.017), death from RCC (HR 1.64, 95%CI¼1.28-2.11, P<0.001), and death from any cause (HR 1.31, 95%CI¼1.08-1.60, P¼0.007) compared to patients with an isolated source of extrarenal extension.CONCLUSIONS: Isolated involvement of the perinephric fat, renal sinus fat, or renal vein carry similar prognostic weight, justifying grouped classification as T3a in the contemporary AJCC primary tumor classification. However, presence of multiple sources of extrarenal extension is associated with higher risk for disease progression, cancerrelated death, and death from any cause after nephrectomy. If validated, these findings may help refine risk-stratification of non-metastatic T3a RCC.

INTRODUCTION AND OBJECTIVES: The Moses Technology developed to enhance the High power Holmium lasers (HPH) lithotripsy is challenged by the novel Super-pulse Thulium fibre laser. The goal of our study was to evaluate in-vitro which laser has a better stone ablation effect.METHODS: An in-vitro observational study was performed using a Super-Pulse Thulium fiber (SPT) laser prototype with 200 µm fibre and a High-Power Holmium (HPH) laser Moses Technology (Lumenis Pulse 120H) with 230 µm fibre. A mechanical device for precisely holding the laser fibre was created (Fig. 1). Fine metal sheets calibrated at different widths were used to fix the laser fibre at the required distance from the tissue. The laser was activated for ten seconds using different laser settings and at different distances from the target (0 mm, 1 mm, 2 mm), in saline.Calcium oxalate monohydrate (COM) -like artificial stones were created in a standardised manner. The ablation volumes were precisely measured using a 3D high precision computer controlled optical microscanner. The obtained images were processed using two Autodesk softwares.RESULTS: On the stone phantoms, the laser ablation volume increased with the laser power and decreased with the distance to target.Moses technology in distance mode provided bigger ablation volumes than close mode, especially at 1 mm distance from the stone, at the same laser settings The difference was not statistically significant. SPT ablation volume was similar to HPH Moses distance mode when same power and energy were used. SPT ablation volume was similar to HPH Moses close mode when same power but very low energy and very high frequency were used.Ablation volume for each machine's best capabilities for dusting settings (HPH 0.2J/80Hz, SPT 0.05J/900 Hz) was almost three times better for SPT. (Table 1) CONCLUSIONS: At same power, HPH Moses and SPT have similar effect on stones.The big difference is when maximal dusting setting are used, SPT being more efficient than HPH Moses.

METHODS: A 3D model was constructed based on data of multispiral computed tomography (MSCT) of patients with kidney stones. The simulator consists of two parts: a non-biological 3D printed soft model of the kidney with reproduced intrarenal vascular and collecting systems and a printed 3D model of a human body. With the use of fluoroscopy and ultrasound, PCNL was performed in the interventional radiology operating room. (Pic. 1)To determine the utility of this model, five residents of the 3D Model group (group A) passed a questionnaire (psychometric Likert scale, from 0 to 10) in which it was proposed to evaluate their skills in understanding of collecting system's anatomy, definition of stone localization, shape and position, selection of correct calyx for punction and the ability to puncture the kidney. Another five residents passed the same questionnaire after the training on PERC-Mentor (group B).RESULTS: The designed 3D printed model completely reproduced individual features of intrarenal structures of a particular patient. During the training, all main stages of PCNL were performed successfully: puncture, dilation of the nephrostomy tract, endoscopic examination and intrarenal lithotripsy. Mean score of the group A was 41/ 50, group B -35,4/50. The biggest difference was achieved in the abilities to punctate the kidney (7/10 in group A, 5/10 in group B) and to define stone shape and orientation (8/10 in group A, 6/10 in group B).CONCLUSIONS: Our 3D printed simulator is promising development which is intended to reduce the frequency of endourological complications associated with urolithiasis. Initial data supports the value of 3D printed kidney models although further educational validation is required.

INTRODUCTION AND OBJECTIVES: Expression of androgen receptor splice variants (AR-Vs) is associated with resistance to current androgen deprivation therapies and antiandrogens. Constitutively active AR-Vs lack the ligand binding domain of androgen receptor (AR-LBD) which is the direct or indirect target of anti-androgens such as enzalutamide (ENZ) and abiraterone which blocks steroidogenesis. Recently the PLATO trial showed that the addition of abiraterone to ongoing ENZ did not improve progression-free survival in patients with castration resistant prostate cancer (CRPC). These data imply a limitation of combining AR-LBD targeting therapies. Therefore, novel therapeutic approaches are needed to improve the outcomes of CRPC patients. Both AR and truncated AR-Vs require a functional N-terminal domain (NTD) for activity and hence first-in-class antagonists of the AR NTD have been developed such as EPI-002 (ralaniten). Herein a next-generation EPI compound (EPI-7170) was evaluated as a monotherapy or in combination of ENZ in ENZ resistant prostate cancer cells that express AR-Vs.METHODS: We developed ENZ resistant VCaP cells (VCaP-MDVR) by chronic exposure to ENZ. These cells and C4-2B-MDVR cells were used as ENZ resistant prostate cancer cells to test monotherapies versus combination therapy with ENZ and EPI-7170. BrdU incorporation, clonogenic assays and flow cytometry were used to analyze effects on proliferation and cell cycle. Inhibition of expression of AR and AR-V7 target genes by ENZ, EPI-7170 or a combination was analyzed by qPCR.RESULTS: EPI-7170 had 10 times better potency than EPI-002 as measured using proliferation and PSA-reporter gene assays. VCaP-MDVR cells expressed significantly higher levels of AR-V7 protein and mRNA compared to the parental cell line. Knockdown of AR-V7 restored sensitivity of VCaP-MDVR cells to ENZ. A combination of EPI-7170 and ENZ caused synergistic inhibition of proliferation of ENZ resistant cells. Consistent results were also obtained with the clonogenic assay. While ENZ did not inhibited AR-V7 target genes, EPI-7170 inhibited both AR and AR-V7 target genes. A combination of EPI-7170 with ENZ led to a complete inhibition of DNA synthesis in S phase.CONCLUSIONS: The role of AR-Vs in the mechanism of ENZ resistance was provided by knockdown experiments and response to EPI-7170. Synergic inhibition was achieved with a combination of EPI-7170 with ENZ. These results suggest that targeting AR-NTD in addition to AR-LBD to block both FL-AR and AR-Vs could be a potential treatment option for CRPC.

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