Ex vivo organotypic cultures for synergistic therapy prioritization identify patient-specific responses to combined MEK and Src inhibition in colorectal cancer.

Translating preclinical studies to effective treatment protocols and identifying specific therapeutic responses in individuals with cancer is challenging. This may arise due to the complex genetic makeup of tumor cells and the impact of their multifaceted tumor microenvironment on drug response. To find new clinically relevant drug combinations for colorectal cancer (CRC), we prioritized the top five synergistic combinations from a large in vitro screen for ex vivo testing on 29 freshly resected human CRC tumors and found that only the combination of mitogen-activated protein kinase kinase (MEK) and proto-oncogene tyrosine-protein kinase Src (Src) inhibition was effective when tested ex vivo. Pretreatment phosphorylated Src (pSrc) was identified as a predictive biomarker for MEK and Src inhibition only in the absence of KRASG12 mutations. Overall, we demonstrate the potential of using ex vivo platforms to identify drug combinations and discover MEK and Src dual inhibition as an effective drug combination in a predefined subset of individuals with CRC.

Dynamic 68Ga-PSMA-11 PET/CT for the Primary Evaluation of Localized Renal Mass: A Prospective Study.

The potential role of prostate-specific membrane antigen (PSMA) PET/CT in non-prostate cancer tumors has shown promising results. We examined the performance of dynamic 68Ga-PSMA-11 PET/CT (DPSMA) for the evaluation of localized renal mass. Methods: A prospective case series of patients with a newly diagnosed renal mass who were referred for surgery was examined. DPSMA was performed in a standardized manner before surgery. The final surgical histology served as the standard of reference. PSMA expression in the tumor vasculature was assessed and staining intensity was scored. Tracer uptake and PSMA expression were compared between benign and malignant tissue. Results: Of 29 enhancing renal masses evaluated in 27 patients, 24 (83%) were malignant lesions. The median SUVmean of benign and malignant lesions was 2.3 (interquartile range [IQR], 2.2-2.7) and 6.8 (IQR, 4.2-10.1), respectively (P = 0.009). Median SUVmax of benign and malignant lesions was 3.8 (IQR, 3.3-4.5) and 9.4 (IQR, 5.4-15.8), respectively (P = 0.015). The median washout coefficient (K2) was significantly lower in malignant lesions than in benign lesions (0.17 vs. 0.70, P = 0.02). Positive PSMA staining was found in 20 of 24 malignant lesions and in 2 of 5 benign lesions (P = 0.04). Conclusion: This pilot study demonstrated DPSMA uptake and kinetics in localized renal masses. Increased 68Ga-PSMA-11 tracer uptake and intratumoral retention correlate with PSMA expression in malignant renal tumors compared with benign renal masses, supporting further assessment of DPSMA as a potential tool for evaluating localized renal masses.

Patient Compliance With Maintenance Intravesical Therapy for Nonmuscle Invasive Bladder Cancer.

OBJECTIVE: To assess patient adherence to intravesical instillation therapy for nonmuscle invasive urothelial carcinoma outside of clinical trials. MATERIALS AND METHODS: We reviewed the records of patients from 2000 to 2013 who received intravesical therapy for nonmuscle invasive urothelial carcinoma. Patients with evidence of tumor recurrence or progression were excluded. We performed univariable and multivariable regression analyses to predict adherence to intravesical therapy. RESULTS: A total of 729 patients started 861 induction cycles, 63% with bacillus Calmette-Guèrin (BCG) and 37% with mitomycin C (MMC). The rate of completion of 6 weeks induction therapy with BCG and MMC was similar (86% and 87%, respectively). Within the BCG cohort, 161 (35%) patients commenced the Southwest Oncology Group (SWOG) maintenance protocol after induction and 16 (10%) completed all 21 treatments. A monthly protocol for BCG was started by 87 patients (19%) and 48 (55%) completed all 9 treatments. MMC therapy was started in 270 patients, 97 of whom (36%) commenced monthly maintenance treatment, and 46 (47%) completed treatments. Median number of instillations was 7 for patients undergoing monthly maintenance therapy (MMC or BCG) and 9 for patients allocated to 3 years BCG. On multivariable analysis, recurrence after prior treatment of urothelial carcinoma was predictive of patients' adherence to treatment. CONCLUSION: Compliance with intravesical therapy is low in clinical practice, notably for longer treatment schedules.

Diagnostic Needle Biopsies in Renal Masses: Patient and Physician Perspectives.

BACKGROUND: The utility of renal mass biopsies (RMB) in the diagnosis of kidney tumors remains debatable. OBJECTIVE: To assess patient and urologist preferences regarding the utilization of RMB. DESIGN, SETTING, AND PARTICIPANTS: Seventy-three patients diagnosed with renal tumors and 59 board-certified urologists were asked to participate in an interview-based study. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Using the standard gamble method we determined the minimal accepted accuracy at which RMB would be favored as part of the diagnostic process. Clinical and demographic data with potential to affect participants' preferences were analyzed. RESULTS AND LIMITATIONS: At the time of the study interview, 56 patients (77%) were referred for kidney surgery and 17 (23%) opted for surveillance. Overall, 59% of the patients accepted some level of inaccuracy (1-20%), whereas 27% refuted a biopsy. Anxiety associated with the possibility of missing cancer was the primary determinant (82%) for declining RMB among patients referred for surgery, while fear of complications was the primary reason (58%) among those undergoing surveillance. Having an academic degree was associated with a lower accuracy threshold (p=0.03). Of the 59 participating urologists, 39% were reluctant to recommend RMB, primarily because of its inexorable nondiagnostic rate. CONCLUSIONS: Most patients and urologists would favor RMB to facilitate their definitive treatment decision. Diagnostic accuracy of 95% was acceptable by the majority of study participants. The utility of RMB as part of the diagnostic algorithm for renal tumors should be discussed with patients, emphasizing its potential benefits and limitations. PATIENT SUMMARY: Although needle biopsy seems to be an effective tool to differentiate benign from malignant kidney lesions, it is not commonly used. Our study shows that most patients would opt for a biopsy before definitive treatment decision despite its imperfect accuracy. Hence, the option of undergoing renal biopsy should be discussed with all patients diagnosed with small renal tumors.

Nitric oxide charged catheters as a potential strategy for prevention of hospital acquired infections.

BACKGROUND: Catheter-Associated Hospital-Acquired Infections (HAI's) are caused by biofilm-forming bacteria. Using a novel approach, we generated anti-infective barrier on catheters by charging them with Nitric Oxide (NO), a naturally-produced gas molecule. NO is slowly released from the catheter upon contact with physiological fluids, and prevents bacterial colonization and biofilm formation onto catheter surfaces. AIMS AND METHODS: The aim of the study was to assess the anti-infective properties of NO-charged catheters exposed to low concentration (up to 103 CFU/ml) of microbial cells in-vitro. We assessed NO-charged tracheal tubes using Pseudomonas aeruginosa, dialysis and biliary catheters using Escherichia coli, and urinary catheters using E. coli, Candida albicans or Enterococcus faecalis. Safety and tolerability of NO-charged urinary catheters were evaluated in a phase 1 clinical study in 12 patients. Six patients were catheterized with NO-charged catheters (NO-group), followed by 6 patients catheterized with regular control catheters (CT-group). Comparison of safety parameters between the study groups was performed. RESULTS: NO-charged tracheal, dialysis biliary and urinary catheters prevented P. aeruginosa, E. coli and C. albicans attachment and colonization onto their surfaces and eradicated corresponding planktonic microbial cells in the surrounding media after 24-48 hours, while E. faecalis colonization onto urinary catheters was reduced by 1 log compared to controls. All patients catheterized with an NO-charged urinary catheter successfully completed the study without experiencing NO-related AE's or serious AE's (SAE's). CONCLUSION: These data highlight the potential of NO-based technology as potential platform for preventing catheter-associated HAI's.

The role of diagnostic ureteroscopy in the era of computed tomography urography.

BACKGROUND: To examine the contemporary role of ureteroscopy in the diagnosis of upper urinary tract urothelial carcinoma. METHODS: We retrospectively evaluated 116 diagnostic ureteroscopies, performed in our institution to rule out primary UTUC. Demographics, cytological findings and interpretation of preoperative imaging were obtained. Ureteroscopic diagnosis and histological results were recorded and the predictive values of diagnostic studies were determined. Follow-up data was reviewed to evaluate the oncological outcomes in patients treated endoscopically. RESULTS: The pre-ureteroscopic evaluation included CTU in 91 (78%) patients. Positive and Negative predictive values of CTU were 76 and 80%, respectively. Typical filling defect on CTU was demonstrated in 38 of 89 patients. UTUC has been ruled out in 9 patients (24%) with suspicious filling defect on CTU. Endoscopic approach was implemented in 7 patients (18%). During a median follow up period of 17 months (IQR, 9-25) none of the followed patients experienced disease progression. CONCLUSIONS: Nephroureterectomy was spared from 42% of patients who underwent diagnostic ureteroscopy for suspected UTUC, demonstrated on CTU. In about half of those patients tumor has been ruled out and the others were managed endoscopically. Therefore, diagnostic ureteroscopy is advised as a crucial step in confirming UTUC and treatment planning.

Simplifying laparoscopic nephrectomy: the inferior approach with en bloc stapling of the renal hilum.

INTRODUCTION: Laparoscopic nephrectomy (LN) is likely the most common laparoscopic procedure performed by general urologists without formal laparoscopic training. The traditional technique is cumbersome because it entails making an early approach to the hilum with the risk of bleeding and need for conversion. We perform a different technique that we believe is simpler to learn and to teach. It consists of a complete dissection of the inferior and posterior aspects of the kidney, followed by en bloc stapling of the renal hilum. The present report is a detailed description of our technique including outcomes and complications. MATERIALS AND METHODS: Perioperative data of 129 consecutive patients who underwent LN between November 2003 and September 2007 were prospectively collected and retrospectively reviewed. Complications were reported using the Clavien classification system, and follow-up was performed according to our institution's protocol and included physical examination, blood count, blood chemistry, and renal function tests at every visit, in addition to abdominal computed tomography scan six months after surgery. Additional imaging was scheduled according to disease stage and grade. RESULTS: Mean patient age, tumor size, and operative time were 63±15.6 years, 6.3±2.4 cm, and 128±41.4 minutes, respectively. Median estimated blood loss was 0 mL (0.200). Conversion to open surgery occurred in 3.1% of patients, and 8% of the patients had a blood transfusion. Complications were recorded in 26% of the patients; 91% of them had Clavien grade scores of 1 or 2. CONCLUSION: We present a standardized technique for LN. Its main advantage is that postpones any manipulation of the hilum to a later step during the procedure when it is easy to identify and control. This decreases early bleeding and main vascular complications.

Laparoscopic partial nephrectomy (LPN) for totally intrarenal tumours.

OBJECTIVE: To evaluate the feasibility and outcomes of laparoscopic partial nephrectomy (LPN) for totally intrarenal tumours (TIT). PATIENTS AND METHODS: TIT were defined as completely intraparenchymatic masses, without any exophytic element. Identification of such a tumour necessitates guidance of intraoperative laparoscopic ultrasonography. Data of patients with TIT who underwent LPN was collected from our Ethical Committee-approved database. Their data was compared with that of patients who underwent LPN for tumours with any degree of exophytic element. The two groups were compared for preoperative data (age, gender, tumour size and location), intraoperative variables (warm ischemia time [WIT], open conversions rate, radical nephrectomy [RN] rate, blood loss and other complications), and postoperative data (renal function, reoperation rates, pathological results, and incidence of positive surgical margins). RESULTS: Among 458 patients who underwent LPN, 41 had TIT. The mean (sd) tumour size was 2.6 (0.8) cm, mean WIT was 22.6 (13.8) min and blood loss was 279 (210) mL. The RN rate was significantly higher in the TIT group compared with the remaining cohort of LPNs (9.7% vs 5.3%). The intra- and postoperative complications, open conversion and positive margin rates were similar between the two groups. Malignant tumours were found in 84.2% and 78.2%, respectively. CONCLUSIONS: LPN for a TIT is technically feasible. TIT carry a significantly higher RN rate due to tumour involvement of vital kidney structures. This aspect should be discussed with the patient preoperatively but TIT should not be considered a definitive indication for RN.

Multidisciplinary team approach to management of severe endometriosis affecting the ureter: long-term outcome data and treatment algorithm.

STUDY OBJECTIVE: To examine the efficiency of laparoscopic ureterolysis for ureteral endometriosis and to describe appropriate treatment. DESIGN: Prospective trial (Canadian Task Force classification II-2). SETTING: University hospital. PATIENTS: Forty-five patients who underwent surgery to treat ureteral endometriosis between 2005 and 2009. INTERVENTION: Laparoscopic ureteral ureterolysis. MEASUREMENTS AND MAIN RESULTS: Long-term follow up of symptoms, urinary tract anatomy and function, and the need for further intervention were performed. Ureteral endometriosis was observed in 14.2% of 315 patients with endometriosis. Of the 45 study patients, 95.5% had dysmenorrhea, 60% had dyspareunia, and 45% were infertile. Half of the patients had previously undergone laparoscopic procedures. Urinary tract symptoms were present in 15.9% of patients. Preoperative hydronephrosis or hydroureter was observed in 10 patients (22.2%), and impaired urinary function in 2 patients (4.4%). Laparoscopy demonstrated left ureteral involvement in 82.2% of patients, and deep infiltrative endometriosis in 80%. Laparoscopic ureterolysis was feasible in 91.1% of patients. In 4 patients, ureterolysis was not feasible, and primary reimplantation of the ureter was performed. Forty-one patients (91.1%) had no symptoms or had marked improvement postoperatively and required no further treatment. Two patients (4.8%) underwent repeat surgery. In 80% of patients with hydroureteronephrosis, the postoperative sonogram was normal. CONCLUSIONS: Ureteral endometriosis can be treated effectively using laparoscopic ureterolysis in almost all patients. Different treatment approaches should be based on the results of preoperative evaluation and operative findings by a multidisciplinary team. Urinary assessment is crucial because most patients demonstrate no urinary tract symptoms and initial renal investigation can prevent irreversible damage.

Single-incision transureteral laparoscopic nephrectomy: a proof of concept.

PURPOSE: Single-umbilical incision laparoscopic nephrectomy has been recently advocated as an alternative to pure natural orifice transluminal endoscopic surgery. We present a novel, hybrid technique for laparoscopic nephrectomy that combines single-incision laparoscopy with natural orifice transluminal endoscopic surgery principles consisting of using the ureteral stump as a natural orifice. MATERIALS AND METHODS: Six renal units were operated in a nonsurvival pig study by combining a single umbilical incision with a novel natural orifice, the divided ureter. A transurethral 16F Amplatz sleeve inserted in the ureter under cystoscopic guidance became a natural orifice port after transection of the ureter. Regular laparoscopic instruments and scopes were used through two adjacent single-incision umbilical ports. The camera was placed in one of the umbilical ports and two operating instruments were introduced through the additional umbilical port and the "natural orifice port," respectively. RESULTS: Right and left laparoscopic nephrectomy were successfully performed. No complications occurred except one case of a periureteral hematoma due to the dilation of the ureter. The hylar blood vessels were thoroughly dissected and controlled by either clips or vascular staplers. The operative time decreased from 140 minutes in the first procedure to 70 minutes in the last (median time: 85 minutes). The learning curve was short because the basic principles of laparoscopy such as correct instrument angulation and geometry could be achieved through the inferior, natural orifice port. CONCLUSIONS: Laparoscopic nephrectomy combining a single umbilical incision with a natural orifice provided by the ipsilateral ureter is technically feasible in a large animal model. Further studies in human patients together with assessment of advantages over classic laparoscopic nephrectomy are needed.

Is postoperative arteriovenous fistula still a concern after en bloc stapling of the renal hilum during laparoscopic nephrectomy?

PURPOSE: To report our experience with en bloc stapling of the renal hilum during laparoscopic nephrectomy (LN) and nephroureterectomy and to compare it with separate stapling performed during the same period at the same institution. PATIENTS AND METHODS: We conducted a retrospective review of 125 laparoscopic nephrectomies and nephroureterectomies performed between November 2003 and September 2006 for benign and malignant conditions. The main outcome was assessment of complications, with special emphasis on postoperative arteriovenous fistula. Secondary outcomes included operative blood loss and operative time. Statistical analysis was performed using two-sided parametric, nonparametric, or categorical tests as appropriate. Statistical significance was set at P < or = 0.05. RESULTS: The transperitoneal approach and 2.5 mM vascular titanium clips were used in all cases. En bloc stapling (group 1) was performed in 65 patients and individual stapling (group 2) in 60. There was a significantly higher proportion of right-side surgeries in group 1 than in group 2 (51 vs 25%, P = 0.05). Overall complications were 31% vs 32%, P = 0.91; mean operative time (confidence interval [CI]) 130 (95% 119, 141) vs 125 min (95% 115, 136), P = 0.3; and mean operative blood loss (CI) 100 (95% 39, 160) vs 135 mL (95% 76, 193), P = 0.33 did not differ for groups 1 and 2, respectively. After a median follow-up (interquartile range) of 25 (24.7) vs 30 (30.0) months, P = 0.14, no cases of arteriovenous fistula were detected. CONCLUSIONS: En bloc stapling of the renal hilum is as safe and effective as individual stapling. Arteriovenous fistula after LN does not seem to be a concern with the use of modern inorganic titanium staplers.

Laparoscopic surgery for renal stones: is it indicated in the modern endourology era?

PURPOSE: To report the outcomes of laparoscopic surgery combined with endourological assistance for the treatment of renal stones in patients with associated anomalies of the urinary tract. To discuss the role of laparoscopy in kidney stone disease. MATERIALS AND METHODS: Thirteen patients with renal stones and concomitant urinary anomalies underwent laparoscopic stone surgery combined with ancillary endourological assistance as needed. Their data were analyzed retrospectively including stone burden, associated malformations, perioperative complications and outcomes. RESULTS: Encountered anomalies included ureteropelvic junction obstruction, horseshoe kidney, ectopic pelvic kidney, fussed-crossed ectopic kidney, and double collecting system. Treatment included laparoscopic pyeloplasty, pyelolithotomy, and nephrolithotomy combined with flexible nephroscopy and stone retrieval. Intraoperative complications were lost stones in the abdomen diagnosed in two patients during follow up. Mean number of stones removed was 12 (range 3 to 214). Stone free status was 77% (10/13) and 100% after one ancillary treatment in the remaining patients. One patient had a postoperative urinary leak managed conservatively. Laparoscopic pyeloplasty was successful in all patients according to clinical and dynamic renal scan parameters. CONCLUSIONS: In carefully selected patients, laparoscopic and endourological techniques can be successfully combined in a one procedure solution that deals with complex stone disease and repairs underlying urinary anomalies.

Laparoscopic surgery for renal stones: is it indicated in the modern endourology era?

Purpose: To report the outcomes of laparoscopic surgery combined with endourological assistance for the treatment of renal stones in patients with associated anomalies of the urinary tract. To discuss the role of laparoscopy in kidney stone disease. Materials and Methods: Thirteen patients with renal stones and concomitant urinary anomalies underwent laparoscopic stone surgery combined with ancillary endourological assistance as needed. Their data were analyzed retrospectively including stone burden, associated malformations, perioperative complications and outcomes. Results: Encountered anomalies included ureteropelvic junction obstruction, horseshoe kidney, ectopic pelvic kidney, fussed-crossed ectopic kidney, and double collecting system. Treatment included laparoscopic pyeloplasty, pyelolithotomy, and nephrolithotomy combined with flexible nephroscopy and stone retrieval. Intraoperative complications were lost stones in the abdomen diagnosed in two patients during follow up. Mean number of stones removed was 12 (range 3 to 214). Stone free status was 77 percent (10/13) and 100 percent after one ancillary treatment in the remaining patients. One patient had a postoperative urinary leak managed conservatively. Laparoscopic pyeloplasty was successful in all patients according to clinical and dynamic renal scan parameters. Conclusions: In carefully selected patients, laparoscopic and endourological techniques can be successfully combined in a one procedure solution that deals with complex stone disease and repairs underlying urinary anomalies.

Male infertility associated with adult dominant polycystic kidney disease: a case series.

INTRODUCTION: Although described earlier, the association of male infertility with adult dominant polycystic kidney disease (ADPKD) is quite rare and unfamiliar to some of the multidisciplinary team members caring for affected men. MATERIALS AND METHODS: Infertile men diagnosed to have ADPKD were evaluated by clinical characteristics including testis volume, as well as serum hormone levels, semen analysis, and transrectal ultrasonography (TRUS) because of low volume ejaculate. RESULTS: Semen analysis revealed low-normal volume, normal pH, and azoospermia/virtual azoospermia. Serum hormones were within the normal range. Transrectal ultrasonography demonstrated cystic dilatation of the seminal vesicles in all three men. CONCLUSION: Patients should be referred for andrological evaluation of a presentation similar to obstructive azoospermia. Their potential to achieve paternity by surgical sperm retrieval combined with assisted reproductive technology is another example of cooperation between andrologists and gynecologists.

Laparoscopic partial nephrectomy for central tumors: analysis of perioperative outcomes and complications.

PURPOSE: We report our experience with laparoscopic partial nephrectomy for central tumors compared to peripheral tumors to analyze the feasibility and safety of the laparoscopic approach to these complex cases. MATERIALS AND METHODS: Between October 2002 and July 2007, 212 patients underwent laparoscopic partial nephrectomy. In 53 patients the tumor was central and in 159 it was peripheral. The preoperative, intraoperative and postoperative data, the type and incidence of complications, and the quality of excision in terms of surgical margin status were compared between the 2 groups. RESULTS: Mean estimated blood loss (320 and 360 ml, respectively, p >0.05) and mean operative time (126 and 118 minutes, respectively, p >0.05) were similar in the central and peripheral tumor groups. Mean warm ischemia time in the central tumor group was longer (37 and 28 minutes, respectively, p <0.05) but median time was similar (30 and 29 minutes, respectively, p >0.05). The open conversion rate was significantly lower in the study group (1% vs 5.6%, p <0.05). The urological complication rate was similar in the 2 groups (9.4% vs 8.4%, p >0.05). However, different types of complications developed in each group. Four patients (7.5%) with central tumors had late hematuria (arterial pseudoaneurysm) and only 1 (1.9%) had a urine leak. Central tumors were larger (3.2 vs 2.5 cm) and more frequently malignant (94% vs 82%, p >0.05). Positive surgical margins were diagnosed in 0% vs 5% of cases (p <0.05). CONCLUSIONS: Provided that there is adequate laparoscopic expertise the outcome of laparoscopic partial nephrectomy for central tumors is comparable to that of peripheral tumors. The main major complication in this group was late onset hematuria, which necessitated angiographic embolization. This facility should be available at centers where these advanced procedures are performed.

Renal angiomyolipoma: long-term results following selective arterial embolization.

BACKGROUND: The treatment for and long-term outcome of renal angiomyolipoma (AML) at high-risk for bleeding has not been determined. OBJECTIVE: To evaluate the complication rates and the long-term outcomes among patients treated by selective arterial embolization (SAE) for a large or symptomatic renal AML. DESIGN, SETTING, AND PARTICIPANTS: Forty-one patients with 48 kidneys containing AML were treated by SAE at a single tertiary academic center. INTERVENTION: All patients were treated by SAE and followed in a single center. MEASUREMENTS: SAE was performed with a mixture of 96% ethanol and polyvinyl alcohol particles. The variables used for the analysis included age, gender, presence of tuberous sclerosis (TS), and maximal tumor size prior to SAE. The study end points were recurrence of symptoms or bleeding, the need for re-embolization or surgery, and disease-specific survival. The mean follow-up period for the entire group was 4.8 yr. RESULTS AND LIMITATIONS: Mean patient age was 51 yr (range: 24-82), and the mean initial tumor size was 10.3 cm. Successful SAE was achieved in 40 patients (91%) with a minor complication rate of 11%. Avoidance of surgery was achieved in 96% of the kidneys. No retroperitoneal hemorrhage was noted during follow-up, and 98% of the kidneys were preserved during the follow-up period. No significant changes in creatinine levels were noted following SAE (P=0.27). The freedom from surgical treatment at 5 yr following SAE was 94% (95% CI, 89-99%). Disease-specific survival of the entire cohort was 100%. The study is a retrospective, and treatment was not given according to prospective protocol, and therefore sample bias may be present. CONCLUSIONS: SAE of renal AML has long-term efficacy in preventing hemorrhagic complications of renal AML, and preservation of the involved kidneys is amenable in both TS and sporadic cases.