Thomas Kunit

Inhibition of smooth muscle force generation by focal adhesion kinase inhibitors in the hyperplastic human prostate

Smooth muscle contraction may be critical for lower urinary tract symptoms (LUTS) in patients with benign prostate hyperplasia and requires stable anchorage of the cytoskeleton to the cell membrane. These connections are regulated by focal adhesion kinase (FAK). Here, we addressed the involvement of FAK in the regulation of smooth muscle contraction in hyperplastic human prostate tissues. Prostate tissues were obtained from radical prostatectomy. Expression of FAK and focal adhesion proteins was assessed by Western blot analysis and immunohistochemical stainings. Effects of the FAK inhibitors PF-573228 and Y-11 on contraction of prostate strips were examined in the organ bath. Expression of FAK and focal adhesion proteins (integrin-5α, paxilin, and c-Src) was detected by Western blot analysis in prostate samples. By double immunofluorescence staining with calponin and pan-cytokeratin, expression of FAK was observed in stromal and epithelial cells. Immunoreactivity for FAK colocalized with integrin-5α, paxilin, talin, and c-Src. Stimulation of prostate tissues with the α1-adrenergic agonist phenylephrine increased the phosphorylation state of FAK at Tyr³⁹⁷ and Tyr⁹²⁵ with different kinetics, which was blocked by the α1-adrenoceptor antagonist tamsulosin. Norepinephrine and phenylephrine induced concentration-dependent contractions of prostate strips. Both FAK inhibitors PF-573228 and Y-11 significantly inhibited norepinephrine- and phenylephrine-induced contractions. Finally, PF-573228 and Y-11 inhibited contractions induced by electric field stimulation, which was significant at the highest frequency. In conclusion, α1-adrenergic smooth muscle contraction or its regulation involves FAK in the human prostate. Consequently, FAK may be involved in the pathophysiology of LUTS and in current or future LUTS therapies.

Inhibition of prostate smooth muscle contraction and prostate stromal cell growth by the inhibitors of Rac, NSC23766 and EHT1864.

Medical therapy of lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH) targets smooth muscle contraction in the prostate, or prostate growth. However, current therapeutic options are insufficient. Here, we investigated the role of Rac in the control of smooth muscle tone in human prostates and growth of prostate stromal cells.

The receptor antagonist picotamide inhibits adrenergic and thromboxane-induced contraction of hyperplastic human prostate smooth muscle

Inhibition of prostate smooth muscle contraction is an important strategy for medical treatment of lower urinary tract symptoms (LUTS). Besides α1-adrenoceptors, prostate smooth muscle contraction is induced by activation of thromboxane (TXA2) receptors (TXA2-R). Here, we examined the effects of the TXA2-R antagonist picotamide on contraction of human prostate tissue. Prostate tissues were obtained from radical prostatectomy. The effects of picotamide (300 μM), L-665,240 (3 μM), and seratrodast (3 μM) on U46619-, electric field stimulation- (EFS-), phenylephrine-, and norepinephrine-induced contractions were studied in organ baths. Expression of TXA2-R and TXA2 synthase (TXS) was examined by fluorescence stainings. Picotamide, seratrodast, and L-655,240 inhibited concentration-dependent contractions induced by the TXA2 analog U46619. Picotamide, but not seratrodast or L-655,240, inhibited frequency-dependent contractions induced by EFS. Picotamide inhibited concentration-dependent contractions induced by norepinephrine or by the selective α1-adrenoceptor agonist phenylephrine. In prostate strips, where only submaximal contraction by a low dose of phenylephrine was induced, application of U46619 raised tone to maximum phenylephrine-induced tension. Immunoreactivity for TXA2-R and TXS was observed in the stroma and in epithelial cells of glands. Colocalization of both immunoreactivites was observed with the smooth muscle markers calponin and α-smooth muscle actin, with the epithelial marker pan-cytokeratin, and with prostate-specific antigen in the stroma and glands. The receptor antagonist picotamide inhibits α1-adrenergic, TXA2-mediated, and EFS-induced contractions in the human prostate. To the best of our knowledge, this is the first antagonist able to inhibit two different contraction systems in the prostate.

Emerging techniques in ‘truly’ minimal-invasive treatment options of benign prostatic obstruction

Purpose of review Benign prostatic enlargement is a common age-related condition, affecting over 50% of men aged more than 60 years. Side effects of medical therapy and significant morbidity of transurethral resection of the prostate and open surgery led to the development of so-called minimally invasive procedures, with the aim to be efficient but with less morbidity and shorter or no hospitalization. For this review, a systematic literature was performed. We report recent results in different treatment options for benign prostate hypoplasia (BPH) and recommend the best minimal-invasive treatment for BPH. Recent findings Within recent years, BPH surgical interventions underwent a shift. Although standard techniques have further improved because of new products and increased business competition, there has been a request from healthcare administration to reduce costs and inpatient treatment. As important, the patients understanding of outcome, fast relief, and recovery might change the common urological outcome measurement. The two main aspects are quality of life and sexuality. Summary Some of the presented treatments are already established in EAU guidelines, others may be recognized in clinical practice as a suitable alternative treatment to transurethral resection of the prostate and medical therapy. Patients now wish to be more involved in the treatment option decision-making and seem very concerned about side effects and their return to normal life. However, variations in reimbursements allowed in different countries can affect the treatment option.

A cost analysis of stenting in uncomplicated semirigid ureteroscopic stone removal

ObjectiveTo evaluate the outcome and the costs of stenting in uncomplicated semirigid ureteroscopic stone removal.Materials and methodsA decision tree model was created to evaluate the economic impact of routine stenting versus non-stenting strategies in uncomplicated ureteroscopy (URS). Probabilities of complications were extracted from twelve randomized controlled trials. Stone removal costs, costs for complication management, and total costs were calculated using Treeage Pro (TreeAge Pro Healthcare version 2015, Software, Inc, Williamstown Massachusetts, USA).ResultsStone removal costs were higher in stented URS (€1512.25 vs. €1681.21, respectively). Complication management costs were higher in non-stented procedures. Both for complications treated conservatively (€189.43 vs. €109.67) and surgically (€49.26 vs. €24.83). When stone removal costs, costs for stent removal, and costs for complication management were considered, uncomplicated URS with stent placement yielded an overall cost per patient of €1889.15 compared to €1750.94 without stent placement. The incremental costs of stented URS were €138.25 per procedure.ConclusionSemirigid URS with stent placement leads to higher direct procedural costs. Costs for managing URS-related complications are higher in non-stented procedures. Overall, a standard strategy of deferring routine stenting uncomplicated ureteroscopic stone removal is more cost efficient.

In-bore 3.0-T Magnetic Resonance Imaging-guided Transrectal Targeted Prostate Biopsy in a Repeat Biopsy Population: Diagnostic Performance, Complications, and Learning Curve

OBJECTIVE To evaluate the diagnostic performance and complication rate of the in-bore magnetic resonance imaging-guided transrectal targeted prostate biopsy (MRGB) in a repeat biopsy population on the basis of a nearly 4-year learning curve (2014-2017). MATERIALS AND METHODS A total of 142 consecutive males with previous biopsies and persistent suspicion of prostate cancer (PCa) due to high prostate-specific antigen level initially underwent MRGB in the case of prostate imaging reporting and data system (PI-RADS) 3-5 lesions. Cancer detection rate (CDR), number and length of cores, biopsy time, operator experience, complications, and prediction of clinically significant (cs) PCa (Gleason score ≥7) were investigated. RESULTS PCa was found in 57% of patients. CDR in PI-RADS 3, 4, and 5 lesions were 46%, 52%, and 74%, respectively. csPCa was found in 9%, 25%, and 48% of patients. In univariate analysis the PI-RADS score (P = .0067) was a significant predictor of csPCa. In the multivariate logistic regression, age (P = .0007), number of previous biopsies (P = .0236), and prostate-specific antigen density (P = .0250) were significant predictors of csPCa. Location and size of the index lesion, number and length of cores obtained, and operator experience did not affect CDR. Concerning learning curve, biopsy time and number of cores obtained improved significantly after 10 procedures. Complications requiring medical intervention were seen in 6% (infections 2%). CONCLUSION In a re-biopsy setting the MRGB showed sufficient diagnostic performance in detecting csPCa in PI-RADS 3-5 lesions, with low complication rate. The skill of performing biopsy is quickly acquired, and location of index lesion did not have an impact on CDR.

Minimally Invasive Retroperitoneal Lymphadenectomy

The feasibility of laparoscopic retroperitoneal lymphadenectomy (RLA) for testicular cancer was shown >25 years ago. Initially the indication was clinical stage I (CS I) nonseminomatous germ cell tumor (NSGCT). Compared with that of open surgery, the morbidity was much decreased. However, in Europe, surgery for CS I is now replaced by chemotherapy. A relatively new indication is laparoscopic retroperitonal lymphadenectomy for small unilateral residual tumor after chemotherapy. The technique of unilateral lymphadenectomy for both indications is described in detail and with a video. The most recent development is bilateral laparoscopic RLA for residual tumors larger than 5 cm.

PD41-03 VALIDATION OF THE EUROPEAN SIMULATE URETERORENOSCOPY TRAINING CURRICULUM

INTRODUCTION AND OBJECTIVES: Surgical simulation is known to enhance technical skills and this effect is typically strongest for novices because complex procedures such as the PCNL have a steep learning curve. While the benefit of simulation is evident for cases when residents participate, it is unclear how preoperative rehearsal can impact patient safety in the hands of experienced practitioners. We present our initial experience using a high fidelity 3D printed simulation for surgical rehearsal in patients undergoing a PCNL. METHODS: A total of 15 consecutive patients underwent PCNL by a single Urologist. Before the live procedure, 7 patient specific simulations were performed for preoperative rehearsal. These models were created by converting DICOM images into stereolithography files and 3D printing components for assembly. In addition to the patient0s pelvicalyceal system and staghorn calculi, their kidney, spine, and posterior abdominal wall were also fabricated to create a complete procedural simulation. All steps of a PCNL were practiced including fluoroscopic access, nephroscopy, and lithotripsy. Procedure specific metrics such as radiation time and number of needle attempts were collected for live and simulation events. Outcomes from the first 8 patients without prior rehearsal were compared to the next 7 patients with preoperative practice. RESULTS: The mean fluoroscopy time was significantly lower in the rehearsal group (6.2 vs 12.7 mins, p 1⁄4 0.03). The average combined time of fluoroscopy for simulation and live cases was still lower than the mean time for unrehearsed group (10.2 vs 12.7 mins, p 1⁄4 0.22). Similarly, the average number of percutaneous needle access attempts was lower in the rehearsed group (1.8 vs 5 attempts, p < 0.001). The total number of complications and additional procedures was higher in the unrehearsed group (5 vs 1 and 9 vs 1, respectively). There were no differences in mean patient age, body mass index, or stone size between the two groups. CONCLUSIONS: This study demonstrated that patient specific rehearsal improved surgeon performance for a complex endourological procedure. There was a significant reduction in fluoroscopy time, percutaneous needle access attempts, additional procedures and complications, with an improved stone clearance rate. There was no significant increase in radiation dose to the surgeon despite rehearsal. Advances in 3D printing technology permit it0s routine use for simulation of complicated operations and possess the ability to directly impact patient outcomes.