Combined treatment with pazopanib and vinflunine in patients with advanced urothelial carcinoma refractory after first-line therapy.

The role of pazopanib in the second-line setting of refractory metastatic transitional cell carcinoma of the urothelium has not been defined clearly. The aim of this phase I/II trial was to assess the safety, tolerability, and efficacy of combining pazopanib and vinflunine in patients with metastatic transitional cell carcinoma of the urothelium after failure of first-line platinum-containing therapy. From May 2011 to December 2011, five patients were enrolled in this trial. Pazopanib was the investigated compound; four levels were planned (200, 400, 600, and 800 mg/day). Vinflunine was dosed at 280 mg/m for the first dose and 320 mg/m every 3 weeks thereafter. After the definition of a tolerated dose for the combined therapy, a subsequent phase II study was planned. At the starting level, pazopanib 200 mg/day, dose-limiting toxicities were observed in two of five patients. One patient experienced grade 4 febrile neutropenia, which led to treatment discontinuation. A second patient showed grade 3 hepatobiliary disorder with an increase in γ-glutamyltransferase. The study was interrupted at dose level 1 for safety reasons. The initially planned phase II study was therefore not carried out. This phase I study showed that combined therapy of daily pazopanib (200 mg) and vinflunine (280/320 mg/m) every 3 weeks is poorly tolerated in patients with refractory advanced urothelial cancer.

IDEAL in meshes for prolapse, urinary incontinence, and hernia repair.

PURPOSE: Mesh surgeries are counted among the most frequently applied surgical procedures. Despite global spread of mesh applying surgeries, there is no current systematic analysis of incidence and possible prevention of adverse events after mesh implantation. MATERIALS AND METHODS: Based on the recommendations of IDEAL an in vitro test system for biocompatibility of surgical meshes has been generated (Innovation). Coating strategies for biocompatibility optimization have been developed (Development). The native and modified alloplastic materials have been tested in an animal model over 2 years (Exploration and Assessment and Long-term study). RESULTS: In 3 meshes, implanted in sheep and explanted at 4 different time points (a, 3 months; b, 6 months; c, 12 months; and d, 24 months) over 24 months, thickness of inflammatory tissue (TVT a, 35 µm; b, 32 µm; c, 33 µm; d, 28 µm; UltraPro, a, 25 µm; b, 24 µm; c, 21 µm; d, 22 µm; PVDF a, 20 µm; b, 21 µm; c, 14 µm; d, 15µm), connective tissue (TVT a, 37 µm; b, 36 µm; c, 43 µm; d, 41 µm; UltraPro a, 33 µm; b, 32 µm; c, 40 µm; d, 38 µm; PVDF a, 25 µm; b, 22 µm; c, 22 µm; d, 24 µm), and macrophage infiltration (TVT a, 36%; b, 33%; c, 23%; d, 20%; UltraPro a, 34%; b, 28%; c, 25%; d, 22%; PVDF a, 24%; b, 18%; c, 18%; d, 16%) revealed comparable ranking characteristics at every time point after explantation. The in vivo performance of these meshes in a sheep model was predictable with a previously developed in vitro test system. Coating of meshes with autologous plasma prior to implantation seems to have a positive effect on the meshes biocompatibility. CONCLUSION: We have applied IDEAL criteria on a new innovation for surgical meshes. The results permit the generation of a ranking of currently available meshes with potential to optimize future meshes.

mTOR inhibition in advanced renal cell carcinoma: which criteria should be used to evaluate therapeutic outcome?

With the implementation of mammalian target of rapamycin (mTOR) inhibitors in the systemic treatment of advanced renal cell carcinoma (RCC), considerable progress has been made regarding survival time and quality of life (QoL) compared with the treatment options used earlier. The prognostic factors used and the diagnostic measures taken to evaluate the oncological outcome and QoL of affected patients have not been adapted to this development adequately. This study analyses the recent phase III mammalian target of rapamycin inhibition trials for patients with metastatic RCC focussing on parameters for measurement of efficacy and QoL. It emphasizes the importance of adequate evaluation criteria for survival and QoL, as achieved by quality adjusted-time without symptoms and toxicity, in the palliative setting of advanced RCC.

Vinflunine as second-line treatment in platin-resistant metastatic urothelial carcinoma: a review.

The novel third-generation bifluorinated semisynthetic vinca alkaloid, vinflunine, is a microtubule inhibitor that shows superior antitumor activity and a favorable safety profile compared with other vinca alkaloids. The main antineoplastic effects of vinflunine arise from its interaction with tubulin, the major component of microtubules in mitotic spindles. Vinflunine is known to have low affinity for tubulin, high intracellular accumulation, and important effects on microtubule dynamics. It has been shown to have activity against transitional cell carcinoma of the urothelial tract. Vinflunine was investigated in a randomized phase III clinical trial comparing vinflunine and best supportive care versus best supportive care alone in patients with advanced transitional cell carcinoma of the urothelial tract, who were progressive after first-line platinum-containing therapy. At an acceptable safety profile without cumulative toxicity, second-line treatment with vinflunine has shown a survival advantage and has therefore been approved in 2009 for this indication. This review gives a brief outline on vinflunine as a second-line treatment for platin-resistant advanced urothelial carcinoma; it describes pharmacology, efficacy studies, tolerance, and side effects and briefly discusses future clinical perspectives.

Evaluation of Biocompatibility of Alloplastic Materials: Development of a Tissue Culture In Vitro Test System.

Optimized biocompatibility is a major requirement for alloplastic materials currently applied in surgical approaches for hernia, incontinence, and prolapse situations. Tissue ingrowth/adherence and formation of connective tissue seem to have important influence in mesh incorporation at the implant site. In an in vitro approach we randomly investigated 7 different mesh types currently used in surgeries with various indications with regard to their adherence performance. Using a tissue culture approach, meshes were incubated with tissue representative of fibroblasts, muscle cells, and endothelial cells originating from 10 different patients. After 6 weeks, the meshes were assessed microscopically and a ranking of their adherence performance was established. Tissue culture was successful in 100% of the probes. We did not remark on interindividual differences concerning the growth and adherence performance after incubation with the different meshes in the investigated 10 patients. The ranking was consistent in all patients. In this test system, PVDF Dynamesh® (FEG Textiltechnik, Aachen, Germany) was the mesh with the best growth-in score. The test system was feasible and reproducible. Pore size seems to be a predictor of adherence performance. The test system may be a helpful tool for further investigations, and the predictive value should be assessed in further in vitro and in vivo experiments.

Inflammatory reaction as determinant of foreign body reaction is an early and susceptible event after mesh implantation.

PURPOSE: To investigate and relate the ultrashort-term and long-term courses of determinants for foreign body reaction as biocompatibility predictors for meshes in an animal model. MATERIALS AND METHODS: Three different meshes (TVT, UltraPro, and PVDF) were implanted in sheep. Native and plasma coated meshes were placed bilaterally: (a) interaperitoneally, (b) as fascia onlay, and (c) as muscle onlay (fascia sublay). At 5 min, 20 min, 60 min, and 120 min meshes were explanted and histochemically investigated for inflammatory infiltrate, macrophage infiltration, vessel formation, myofibroblast invasion, and connective tissue accumulation. The results were related to long-term values over 24 months. RESULTS: Macrophage invasion reached highest extents with up to 60% in short-term and decreased within 24 months to about 30%. Inflammatory infiltrate increased within the first 2 hours, the reached levels and the different extents and ranking among the investigated meshes remained stable during long-term follow up. For myofibroblasts, connective tissue, and CD31+ cells, no activity was detected during the first 120 min. CONCLUSION: The local inflammatory reaction is an early and susceptible event after mesh implantation. It cannot be influenced by prior plasma coating and does not depend on the localisation of implantation.

Coating with autologous plasma improves biocompatibility of mesh grafts in vitro: development stage of a surgical innovation.

PURPOSE: To investigate mesh coating modalities with autologous blood components in a recently developed in vitro test system for biocompatibility assessment of alloplastic materials. MATERIALS AND METHODS: Seven different mesh types, currently used in various indications, were randomly investigated. Meshes were coated prior to cultivation with autologous peripheral blood mononuclear cells (PBMCs), platelets, and blood plasma. Pretreated meshes were incubated over 6 weeks in a minced tissue assay, representative for fibroblasts, muscle cells, and endothelial cells originating from 10 different patients. Adherence of those tissues on the meshes was microscopically investigated and semiquantitatively assessed using a previously described scoring system. RESULTS: Coating with peripheral blood mononuclear cells did not affect the adherence score, whereas coating with platelets and blood plasma increased the score suggesting improved biocompatibility in vitro. The previous ranking of native meshes remained consistent after coating. CONCLUSION: Plasma coating of meshes improves their biocompatibility score in a novel in vitro test system.

Early endoscopic detection and subsequent removal of sphincter penetrating anastomotic sutures may prevent irreversible urinary incontinence after radical prostatectomy.

BACKGROUND AND PURPOSE: Iatrogenic sphincter lesions are possible reasons for sphincteric incompetence and postprostatectomy urinary incontinence. The aim of this study was to identify early possible sphincter injuries as causes for urinary incontinence after radical prostatectomy by endoscopic evaluation of the anastomotic region. PATIENTS AND METHODS: Among 374 patients who had undergone radical prostatectomy from 2005 to 2009 at our institution, we investigated patients with early postoperative urinary incontinence. Nineteen incontinent patients were identified with the symptomatic triad of early incontinence, reduced urinary flow, and post-void residual (PVR) volume after catheter removal. Patients were examined endoscopically, and the clinical effect of early suture removal in patients with sphincter penetration was evaluated. RESULTS: Urethrocystoscopic evaluation revealed an isolated sphincter penetration as reason for early postoperative incontinence in 15/19 cases. The suture penetration was observed predominantly in the 3-degree (7/19) and 9-degree (8/19) positions and less frequently in the 12-degree (2/19) and 6-degree (2/19) positions. Four of (21%) 19 patients did show an additional sphincter transection. The penetrating sutures of the urethrovesical anastomosis were removed during the endoscopic procedure, and initial urinary incontinence could be corrected in all cases of isolated sphincter penetration. CONCLUSION: Early severe urinary incontinence, reduced urinary flow, and PVR volume after radical prostatectomy may indicate sphincter penetration by anastomosis sutures. In our patients, early transurethral punctual removal of the penetrating sutures could decrease the early postoperative incontinence rate.

Sphincter lesions after radical prostatectomy-evaluation and classification.

PURPOSE: The aim of this study was to analyze the sphincteric/perisphincteric lesions and modifications in incontinent patients with iatrogenic damage to the external urethral sphincter after radical prostatectomy (RP). PATIENTS AND METHODS: We evaluated 169 patients with postprostatectomy urinary incontinence who were referred from 28 German hospitals from December 2004 to March 2009. Inclusion criteria were refractory grade III stress urinary incontinence and duration of incontinence of at least 12 months. Patients underwent clinical, ultrasonographic examination, urethrocystoscopy, and if technically possible, urethrocystomanometry. Sphincteric defects were classified and evaluated with regard to type and localization. RESULTS: Mean duration of incontinence before evaluation was 44.8 (12-156) months. Distribution of the previous prostatectomy technique was 66.9% retropubic RP, 27.8% laparoscopic RP, 3.5% perineal RP, and 1.8% robot-assisted RP. A transection of the sphincter was seen in 65.1% (110/169) of cases, a sphincter penetration in 46.2% (78/169) of cases. A combination of both sphincter injuries was seen in 37% (63/169) of patients. In 87% (147/169) of the cases, the sphincter defect was localized to the lower circumference, and in 13% (22/169) of cases, to the upper circumference. A stricture of the vesicourethral anastomosis was found in 45% (76/169) of cases. CONCLUSIONS: Direct iatrogenic damages to the urethral sphincter are a potential reason for postprostatectomy urinary incontinence. They seem to follow a particular local distribution pattern, indicating that apex preparation and building of the urethrovesical anastomosis show an increased risk for these sphincter injuries. Cystoscopic evaluation of the sphincteric region in incontinent patients after surgery may be a valuable tool for examination.

Nephrocutaneous bypass in ureteral obstruction.

OBJECTIVES: To describe our experiences with nephrocutaneous bypass and to assess the role of this procedure as a mean of urinary diversion in patients with incurable ureteral obstruction who are not appropriate candidates for subcutaneous pyelovesical bypass. METHODS: Nephrocutaneous bypass was performed on 15 (12 male, 3 female) patients with incurable ureteral obstruction of malignant (n = 13; 87%) or benign (n = 2; 13%) etiology. Only patients with a significant disturbance of the bladder/sphincter-system were eligible for the procedure. RESULTS: In total, 29 stents were applied using this technique. No major complications were observed perioperatively. The operating time for bilateral nephrocutaneous bypass was 74 (46-102) minutes and for unilateral bypass (1 patient) 38 minutes. Time of indwelling percutaneous nephrostomy before application of nephrocutaneous bypass was 190 (40-870) days. The patients who survived have a mean follow-up of 27 months, whereas for those patients who died the mean follow-up was 7.8 months. Nephrocutaneous bypass resulted in an improved renal function in all patients. Quality of life improvement was reported by all patients, and the objective criteria of "useful life" were met by 13 patients (87%). CONCLUSIONS: Nephrocutaneous bypass is a safe and feasible method to provide effective pyelovesical drainage of urine in patients who have a short-term life expectancy, who are in poor general conditions, or otherwise would need a permanent nephrostomy drainage. The technique offers patients a higher mobility, increased independence resulting in higher quality of life during their final period of life, and may also be applied in nonmalignant patients after careful consideration of alternative urinary diversions.

Feasibility of sequential use of sunitinib and temsirolimus in advanced renal cell carcinoma.

Targeted agents sunitinib and temsirolimus are effective in advanced renal cell carcinoma. Treatment algorithms for single-agent use have been proposed in order to optimize timing and type of therapy. The aim of this study was to investigate the tolerability and adverse event profile of patients who received sunitinib and temsirolimus in sequence. We performed a retrospective analysis of patients with advanced renal cell carcinoma who received temsirolimus after disease progression under sunitinib therapy. Dosages of both drugs were in accordance with the recommendations given by the respective manufacturers. Temsirolimus was provided before its official approval within a compassionate use program. Adverse event assessment followed the National Cancer Institute Common Toxicity Criteria. Thirteen patients receiving temsirolimus after progression under sunitinib were identified. Overall treatment time with targeted drugs (sunitinib/temsirolimus) was 34.8 (17-78) weeks, treatment with sunitinib was 28.6 (12-72), and with temsirolimus 6.2 (2-16) weeks, respectively, whereas mean therapy interruption time between both approaches was 4.4 (2-12) weeks. Under sunitinib, we observed 52 transient adverse events, 49 (94.2%) were of grade I/II, whereas 3 (5.8%) were of grade III. Under temsirolimus 36 adverse events, only grade I/II in nature were remarked. Sequential use of temsirolimus after progression under sunitinib seems to be feasible and results in a predictable, medically manageable side effect profile. Further evaluation is necessary to define the oncological validity of this sequencing approach.

Experiences and practical conclusions concerning temsirolimus use and adverse event management in advanced renal cell carcinoma within a compassionate use program in Germany.

PURPOSE: To detail tolerance of temsirolimus in a routine practice setting within a compassionate use program for patients with renal cell carcinoma. METHODS: We treated 32 patients with advanced renal cell carcinoma with temsirolimus within the German compassionate use program on an individual patient basis free of charge according to EU guidelines at our two institutions. Twenty-five milligrams of temsirolimus was applied weekly in an inpatient clinical setting. Adverse events were classified following National Cancer Institute Common Toxicity Criteria. RESULTS: No dose modification or therapy interruptions were necessary due to adverse events. Adverse events like asthenia/fatigue were observed in 43.8%, increased creatinine in 40.6%, mucositis in 31.3%, secondary diabetes in 28.1%, hypothyreosis in 12.5% and rash in 12.5%, hypercholesterolemia and hypertriglyceridemia in 9.3% of the patients. CONCLUSION: Therapy with temsirolimus in advanced renal cell carcinoma is well tolerated. In a routine practice setting it results in a predictable adverse event profile that can be managed medically.

Successful transureteropyelostomy after heminephrectomy of a bilateral hydronephrotic horseshoe kidney: a case report.

INTRODUCTION: Horseshoe kidney is a rare congenital malformation that is found in approximately 0.25% of the general population and usually remains asymptomatic. CASE PRESENTATION: We report a successful transureteropyelostomy after heminephrectomy of the non-functional right moiety in a 25-year-old man with horseshoe kidney who had a combined 50% functional loss and hydronephrosis due to multiple distal ureteral strictures on the functionally remaining left side. Continuous ureteral stenting of the remaining part of the former horseshoe kidney was avoided during a follow-up of 2 years. CONCLUSION: Urologists are often faced with technically difficult cases that are not responsive to standard operative procedures, and this case illustrates an individual surgical approach in a clinical situation.