Tyrosine Kinase Inhibitors in the Treatment of Metastasised Renal Cell Carcinoma-Future or the Past?

BACKGROUND: To review and discuss the literature on applying tyrosine kinase inhibitors (TKIs) in the treatment of metastasised renal cell carcinoma (mRCC). MATERIALS AND METHODS: Medline, PubMed, the Cochrane database, and Embase were screened for randomised controlled trials, clinical trials, and reviews on treating renal cell carcinoma, and the role of TKI. Each substance's results were summarised descriptively. RESULTS: While TKI monotherapy is not currently recommended as a first-line treatment for metastasized renal cell carcinoma, TKIs are regularly applied to treat treatment-naïve patients in combination with immunotherapy. TKIs depict the first-choice alternative therapy if immunotherapy is not tolerated or inapplicable. Currently, seven different TKIs are available to treat mRCC. CONCLUSIONS: The importance of TKIs in a monotherapeutic approach has declined in the past few years. The current trend toward combination therapy for mRCC, however, includes TKIs as one significant component of treatment regimens. We found that to remain applicable to ongoing studies, both when including new substances and when testing novel combinations of established drugs. TKIs are of major importance for the treatment of renal cancer now, as well as for the foreseeable future.

Ex-vivo evaluation of miniaturized probes for endoscopic optical coherence tomography in urothelial cancer diagnostics.

Background: The gold standard for detecting bladder cancer is white light cystoscopy (WLC) and resection of suspicious lesions. In this study, we evaluate two miniaturized Optical Coherence Tomography (OCT) probes for endoscopic use, regarding their applicability in diagnosing urothelial cancer. Materials and methods: In total, 33 patients who underwent a radical cystectomy were included. Preoperative oncological staging and determining the indication for the surgical intervention were done following the latest European Association of Urology (EAU) guidelines. Samples were taken from bladder tissue after bladder removal and prepared for OCT measurement. Additionally, porcine bladder samples were used as reference tissue. We took measurements using two miniaturized probes: a bimodal probe and a single modality OCT probe. A non-miniaturized standard OCT scanner was used as a reference. Results: Histopathological examination revealed urothelial cancer in all but three patients. Measurements on porcine tissue revealed a clear distinction between the urothelial layers for all probes. Furthermore, we detected improved image quality thanks to the stretching of the tissue. We took 271 measurements in human samples. While the urothelial layers were well delineated in healthy tissue, all the probes revealed a loss of these structures in cancerous regions. While the single-modality probe delivered an image quality equaling the reference images, it was possible to detect cancerous areas with the bimodal probe. Conclusion: We demonstrate that endoscopic probes for OCT imaging are technologically feasible and deliver acceptable image quality. A distinction between healthy and abnormal tissue is possible. We propose combining different endoscopic imaging modalities as a promising approach for urothelial cancer diagnostics.

Evaluation of functional parameters, patient-reported outcomes and workload related to continuous urinary bladder irrigation after transurethral surgery.

BACKGROUND: Continuous saline bladder irrigation (CBI) is a common procedure after transurethral surgery and to treat gross hematuria. We conducted this study to gather data on parameters of CBI, medical staff's work load associated with CBI monitoring, patients' feeling of safety and of patients' impairments during CBI. METHODS: We observed CBI taking place after transurethral surgery for a 2-9-hour period. Patients were asked to rank how safe they felt, general impairments and impaired mobility. Irrigation parameters and complications were documented at least every 30 minutes. The staff's workload was evaluated through the frequency of visits and presence time. RESULTS: The patients' mobility was notably reduced with an average of 10.5%±16.7% of time spent outside of bed, pain was low (mean 0.60±1.15). Patients felt very safe with CBI (8.8±1.9), hardly impaired overall (3.8±3.0), but restricted in mobility (5.9±2.8). Pain was associated with general impairment and impaired mobility. Clot retention occurred in 5 patients. Average irrigation speed was 9.46±8.69 mL/min (0 to 86.7 mL/min). Urine bags were emptied on average every 2.2±1.2 hours. Patients were visited by medical personnel 1 to 11 times. CONCLUSIONS: CBI remains an improvable procedure in terms of the irrigation process itself to prevent complications, the patients' feeling of safety and comfort during CBI and the amount of work associated with its monitoring. We have provided parameters for the implementation of more individualized CBI monitoring. TRIAL REGISTRATION: German Clinical Trial Registry; DRKS00023707; Registered retrospectively November 25 2020, https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00023707.

Cerebral oxygenation in 45-degree trendelenburg position for robot-assisted radical prostatectomy: a single-center, open, controlled pilot study.

BACKGROUND: Within the last decade, robotically-assisted laparoscopic prostatectomy (RALP) has become the standard for treating localized prostate cancer, causing a revival of the 45° Trendelenburg position. In this pilot study we investigated effects of Trendelenburg position on hemodynamics and cerebral oxygenation in patients undergoing RALP. METHODS: We enrolled 58 patients undergoing RALP and 22 patients undergoing robot-assisted partial nephrectomy (RAPN) (control group) in our study. Demographic patient data and intraoperative parameters including cerebral oxygenation and cerebral hemodynamics were recorded for all patients. Cerebral function was also assessed pre- and postoperatively via the Mini Mental Status (MMS) exam. Changes in parameters during surgery were modelled by a mixed effects model; changes in the MMS result were evaluated using the Wilcoxon signed rank test. RESULTS: Preoperative assessment of patient characteristics, standard blood values and vital parameters revealed no difference between the two groups. CONCLUSIONS: Applying a 45° Trendelenburg position causes no difference in postoperative brain function, and does not alter cerebral oxygenation during a surgical procedure lasting up to 5 h. Further studies in larger patient cohorts will have to confirm these findings. TRIAL REGISTRATION: German Clinical Trial Registry; DRKS00005094; Registered 12th December 2013-Retrospectively registered; https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00005094 .

Current Disposable Ureteroscopes: Performance and Limitations in a Standardized Kidney Model.

Objectives: Due to the increasing fragility of the instruments and rising concerns about the sterility of reprocessable scopes, several single-use devices for flexible ureteroscopy have been introduced. In this study, we compare currently available disposable digital and fiberoptic flexible ureteroscopes with a contemporary reusable fiberoptic device. Materials and Methods: LithoVue™, Pusen Uscope® (UE3011, UE3022), Flexor®Vue™, and a reusable fiber optic flexible ureteroscope (BOA vision®) were tested in kidney models. The setup included (1) visualization of all calices (correct assignment of colored pearls) and (2) the extraction of human calculi with a standard disposable extraction device (NGage®). We documented the effective visualization, stone extraction, and times to completion. In addition, the surgeons' workload and performance were determined using the National Aeronautics and Space Administration-Task Load Index. Results: In visualizing and identifying calices, the LithoVue and both generations of the Uscope performed similarly, but time to completion was significantly longer for all single-use devices in comparison with the Boa Vision. LithoVue retracted stones almost as well as the reusable scope (97% vs 95%/82%/96% stone clearance), while accessibility was impeded using Uscope UE3011, as reflected by the retrieval time per stone (73 vs 102 seconds/stone). This disadvantage has, however, been overcome with the new Uscope Generation UE3022, showing a retrieval time of only 65 seconds per stone, excelling over the reusable scope in this category. The Uscope UE3022 image quality was also rated best, but showed no significant difference. Conclusions: In comparison with disposable ureteroscopes available, LithoVue offers performance and characteristics similar to a reusable device, while the FlexorVu's performance does not yet yield satisfactory results for clinical use. The first generation of Uscope exhibits potential, but requires further technical improvements to match the performance of a reusable device. With the new-generation UE3022, Pusen has made significant improvement and offers a quality comparable with the LithoVue's.

In Vitro Effects of a Novel Coating Agent on Bacterial Biofilm Development on Ureteral Stents.

OBJECTIVES: Ureteral stenting is a widely used method for noninvasive urinary drainage in ureteral obstruction. However, biofilm development due to transient bacteriuria can cause severe complications such as incrustation with subsequent obstruction as well as recurrent urinary tract infection. Apart from local ailment such as dysuria, this increases both stent replacement frequency and incidence of complications. In this work, we investigated in vitro the bacterial adhesion to a surface-attached and cross-linked poly(N,N-dimethylacrylamide) (PDMAA) hydrogel network, which is known for its nonfouling and protein-repellent characteristics. MATERIALS AND METHODS: To mimic the conditions encountered in vivo, PDMAA-coated and uncoated cyclic olefin polymer (COP) slides as well as polyurethane (PU)-coated glass slides were incubated in sterile human urine for 48 hours. Colonization was then simulated by adding known uropathogens, cultivated from clinical urine samples (such as Escherichia coli). After further incubation for 24 and 48 hours, slides were washed, and the remaining adherent bacteria were solubilized by ultrasound. CFUs were counted after plating and incubation for 48 hours of the resulting solution. RESULTS: PDMAA reduced adherent E. coli about fivefold on coated PU glass slides as well as in PDMAA-coated COP slides. With adherent Enterococcus faecalis and Klebsiella pneumoniae there was a tendency to decreased biofilm formation, but the difference was not statistically significant. CONCLUSIONS: PDMAA reduces surface adherence of the most common uropathogen significantly. Assessment of clinical relevance and of the effect on further uropathogens needs further experimental and clinical evaluations. German Clinical Trial Register ID: DRKS00013264 (approved WHO primary register).

Combined prostatic urethral lift and remodeling of the prostate and bladder neck: a modified transurethral approach in the treatment of symptomatic lower urinary tract obstruction.

PURPOSE: The aim of the study was to evaluate the feasibility and safety of combining prostatic urethral lift (PUL) and a limited resection of the prostatic middle lobe or bladder neck incision in the treatment of lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH). METHODS: Twenty-eight patients were treated at two tertiary centers and followed prospectively. Patient evaluations included patient characteristics, relief of LUTS symptoms, erectile and ejaculatory function, continence, operative time and adverse events. Patients were followed for a mean of 10.9 months. RESULTS: Patient characteristics were as follows: age 66 years (46-85), prostate volume 39.6 cc (22-66), preoperative IPSS/AUASI 20 (6-35)/QoL 3.9 (1-6)/peak flow 10.5 mL/s (4.0-19)/post-void residual volume (PVR) 123 mL (0-500). Mean operating time was 31 min (9-55). Postoperative complications were minor except for the surgical retreatment of one patient for blood clot retention (Clavien 3b). One patient required catheterization due to urinary retention. Reduction of symptoms (IPSS - 59.6%), increase in QoL (+ 49.0%), increase in flow (+ 111.5%), and reduction of PVR (- 66.8%) were significant. Antegrade ejaculation was always maintained. CONCLUSION: Our data suggest that a combination of PUL and transurethral surgical techniques is feasible, safe, and effective. This approach may be offered to patients with moderate size prostates including those with unfavorable anatomic conditions for PUL. This procedure is still 'minimally invasive' and preserves sexual function. In addition, it may add to a higher functional efficacy compared to PUL alone. STUDY REGISTER NUMBER: DRKS00008970.

Viability and biocompatibility of an adhesive system for intrarenal embedding and endoscopic removal of small residual fragments in minimally-invasive stone treatment in an in vivo pig model.

PURPOSE: To evaluate the viability and biocompatibility of a novel, patented bioadhesive system for intrarenal embedding and retrieval of residual fragments after endoscopic lithotripsy. Complete stone clearance via active removal of residual fragments (RF) after intracorporeal laser lithotripsy may be time-consuming and fail in many cases. Therefore, the novel adhesive has been developed and evaluated for the first time in an in vivo pig model in the present work. METHODS: Four female domestic pigs underwent flexible ureteroscopy (RIRS) or percutaneous nephrolithotomy (PNL) under general anesthesia (8 kidneys, 4 × RIRS, 4 × PNL) evaluating the bioadhesive system. INTERVENTIONS: RIRS without adhesive system (sham procedure, kidney I); 3 × RIRS using the bioadhesive system (kidneys II-IV); and 4 × PNL using the bioadhesive system (V-VIII). We endoscopically inserted standardized human stone probes followed by comminution using Ho:YAG lithotripsy. The bioadhesive (kidney II-VIII) was then applied and the adhesive-stone fragment complex extracted. After nephrectomy, all kidneys were evaluated by two independent, blinded pathologists. Endpoints were the procedure's safety and adhesive system's biocompatibility. RESULTS: We observed no substantial toxic effects. We were able to embed and remove 80-90% of fragments. However, because of the pig's hampering pyelocaliceal anatomy, a quantified, proportional assessment of the embedded fragments was compromised. CONCLUSIONS: For the first time, we demonstrated the proven feasibility and safety of this novel bioadhesive system for embedding and endoscopically removing small RF in conjunction with a lack of organ toxicity in vivo.

New for Old-Coagulum Lithotomy vs a Novel Bioadhesive for Complete Removal of Stone Fragments in a Comparative Study in an Ex Vivo Porcine Model.

OBJECTIVES: To evaluate a recently reported new bioadhesive system for the retrieval of small residual fragments (RFs) after intracorporeal lithotripsy, we systematically compared this system with coagulum lithotomy in retrograde intrarenal surgery. MATERIALS AND METHODS: We extracted 30 human stone fragments (≤1 mm) in an ex vivo porcine kidney model using a flexible ureteroscope for three groups: (1) the novel bioadhesive, (2) autologous blood as a natural adhesive, and (3) (control group) a conventional retrieval basket. Each group consisted of 15 test runs. Outcomes were evaluated regarding the macroscopic stone-free rate (SFR), retrieval time, and number of ureteral passages. RESULTS: For groups 1 and 2, a significant advantage in stone clearance, mean retrieval time, and number of retrievals was detected compared to the control group (p = 0.001). The time and number of retrievals were significantly lower in group 1 (10:36 minutes, p = 0.001) than in group 2 (26:12 minutes, p = 0.001), with shorter clotting time and better visibility. CONCLUSIONS: These data show the general feasibility of intrarenal RF embedding to improve the SFR. Our data furthermore suggest the superiority of the artificial bioadhesive embedding agent over the application of native blood. Further in vivo studies and other research are necessary to confirm the adhesive's effect in patients.

Endoscopically Determined Stone Clearance Predicts Disease Recurrence Within 5 Years After Retrograde Intrarenal Surgery.

OBJECTIVE: To assess stone-related events (SREs) requiring retreatment in a series of 100 consecutive patients treated by retrograde intrarenal surgery (RIRS) for renal stones and to evaluate potential risk factors thereof. PATIENTS AND METHODS: The primary outcome was incidence of SRE (medical or surgical treatment). Secondary outcomes included side of SRE, time to SRE, and late complications. Analysis of potential risk factors included high-risk stone formers (HRSFs), obesity, high stone burden, and lower pole stones. In addition, we evaluated endoscopically determined small residual fragments (SRF) of <1 mm (i.e., fragments too small for retrieval) as an independent risk factor. RESULTS: Eighty-five of the 99 patients were followed up for a mean of 59 months (31-69), among whom 26 (30.1%) had SRE. Thirty-four of the 85 (40%) patients were HRSFs, 22 of whom experienced SRE (both sides) during follow-up (64.7%, p < 0.001). Eight of the 17 patients (47.1%) with SRF experienced ipsilateral side SRE compared with 13 (19.1%) of the 68 without SRF (p = 0.022, hazard ratio 2.823, 95% confidence interval [95% CI] 1.16, 6.85). Risk for ipsilateral SRE was unaffected by the presence of SRF among HRSFs (p = 0.561). Of low-risk patients with SRF, 33.3% experienced ipsilateral SRE, while those without SRF experienced no ipsilateral SRE (p < 0.001). CONCLUSION: Endoscopically determined stone clearance predicts disease recurrence within 5 years after RIRS. Even SRF are an important risk factor for future stone-related (ipsilateral) events; therefore, patients with residual fragments of any size should not be labeled "stone free" and endoscopic stone treatment should aim at complete stone clearance.

Level of evidence, sponsorship, conflict of interest policy and commercial impact of PubMed-listed clinical urolithiasis-related trials in 2014.

OBJECTIVES: To evaluate published trials on urolithiasis regarding level of evidence, type of sponsorship and declared conflicts of interest (COIs), and to elucidate a potential commercial impact. MATERIALS AND METHODS: We performed a systematic PubMed(®) literature search using a predefined Boolean search term to identify PubMed-listed clinical research studies on urolithiasis in 2014 (fourth quarter). All authors screened the results for eligibility criteria and two independent reviewers evaluated and performed data extraction of predefined endpoints, including level of evidence, declaration of COI and sponsorship/funding (as indicated in the published print version), and commercial impact. RESULTS: A total of 110 clinical trials in urolithiasis listed in PubMed met the inclusion criteria. Levels of evidence 1, 2, 3 and 4 were found in 15%, 14%, 21% and 51% of trials, respectively. A COI was indicated in a total of 90% of publications, 93% of which declared no existing conflict of interest. Sponsorship was indicated in 36% of publications, 55% of which stated public funding, 33% institutional funding, 10% industrial funding and 2% both public and industrial funding. A total of 11% of the published trials were rated as having a high commercial impact. CONCLUSION: The present study provides evidence of increasing levels of evidence for published clinical trials on urolithiasis in 2014 (as compared with earlier data). Ninety percent of publications indicated conflicts of interest, whereas sponsoring of studies was declared only by one-third. A considerable number of trials involved issues of high commercial impact. Recently established legal programmes and voluntary acts on self-reporting of financial relationships will enhance transparency in the future; however, increased public funding will be needed to further promote the quality of trials on urolithiasis.