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Szilvia Berkó,1 Stella Zsikó,1 Gábor Deák,2 Attila Gácsi,1 Anita Kovács,1 Mária Budai-Szűcs,1 László Pajor,2 Zoltán Bajory,2 Erzsébet Csányi1 1Institute of Pharmaceutical Technology and Regulatory Affairs, University of Szeged, Szeged, Hungary; 2Department of Urology, University of Szeged, Szeged, Hungary Purpose: Papaverine hydrochloride (PaHCl) is an old, well-known drug with spasmolytic activity but it has therapeutic effect in erectile dysfunction, too. As an intracavernous injection, it is not used in urologic clinics today because the side effects of the injection are pain, scarring or priapism. Our aim was to develop and test a topical semi-solid preparation containing PaHCl that would provide an alternative administration option by eliminating the undesirable side effects of the injection.Materials and methods: Lyotropic liquid crystal (LLC) systems were formulated as a semi-solid preparation with different concentrations of PaHCl. The characterization of the LLC structure was performed by polarization microscopy using a Leica image analyzer and rheological measurements. The drug diffusion and penetration tests were performed with in vitro synthetic membrane and an ex vivo human epidermis, using Franz diffusion cell to test the skin penetration of PaHCl. Human skin was investigated by Raman microscope to visualize the Active Pharmaceutical Ingredient (API) in different skin layers.Results: The results of diffusion and penetration showed reverse concentration dependency. The in vitro and ex vivo studies correlated with each other and the results of Raman microscopy. The LLC structure influenced the penetration results, the lower viscosity and lamellar structure increased penetration through the skin.Conclusion: Based on our results, a PaHCl containing topically used LLC formulation may be a suitable and effective alternative to the injectable formulation. Keywords: nanocarrier, dermal penetration, impotence, Raman microscopy

Background: The prognosis of patients with synchronous metastatic renal cell carcinoma (mRCC) is poor. Whereas single-agent tyrosine kinase inhibition (TKI) is clearly insufficient, the effects can be enhanced by combinations with immune checkpoint inhibitors. Innovative treatment options combining TKI and other immune-stimulating agents could prove beneficial. Objective: To evaluate the clinical effects on metastatic disease when two doses of allogeneic monocyte-derived dendritic cells (ilixadencel) are administrated intratumorally followed by nephrectomy and treatment with sunitinib compared with nephrectomy and sunitinib monotherapy, in patients with synchronous mRCC. Design, setting, and participants: A randomized (2:1) phase 2 multicenter trial enrolled 88 patients with newly diagnosed mRCC to treatment with the combination ilixadencel/sunitinib (ILIXA/SUN; 58 patients) or sunitinib alone (SUN; 30 patients). Outcome measurements and statistical analysis: The primary endpoints were 18-mo survival rate and overall survival (OS). A secondary endpoint was objective response rate (ORR) assessed up to 18 mo after enrollment. Statistic evaluations included Kaplan-Meier estimates, log-rank tests, Cox regression, and stratified Cochran-Mantel-Haenszel tests. Results and limitations: The median OS was 35.6 mo in the ILIXA/SUN arm versus 25.3 mo in the SUN arm (hazard ratio 0.73, 95% confidence interval 0.42–1.27; p = 0.25), while the 18-mo OS rates were 63% and 66% in the ILIXA/SUN and SUN arms, respectively. The confirmed ORR in the ILIXA/SUN arm were 42.2% (19/45), including three patients with complete response, versus 24.0% (six/25) in the SUN arm (p = 0.13) without complete responses. The study was not adequately powered to detect modest differences in survival. Conclusions: The study failed to meet its primary endpoints. However, ilixadencel in combination with sunitinib was associated with a numerically higher, nonsignificant, confirmed response rate, including complete responses, compared with sunitinib monotherapy. Patient summary: We studied the effects of intratumoral vaccination with ilixadencel followed by sunitinib versus sunitinib only in a randomized phase 2 study. The combination treatment showed numerically higher numbers of confirmed responses, suggesting an immunologic effect.

Background: Nitric oxide (NO) plays a role in inflammation. Our aim was to investigate the role of NO in the microcirculatory changes after ischemia-reperfusion (I/R) of the bladder using intravital videomicroscopy (IVM). Methods: In rats, 60 min of bladder ischemia followed by 30 min of reperfusion was performed in the presence of NG-nitro-L-arginine methyl ester (L-NAME), the NO precursor L-arginine, or saline pre-treatments. Venular red blood cell velocity (RBCV), functional capillary density (FCD), vessel diameters, and leukocyte-endothelial cell interactions in postcapillary venules were determined. Concentrations of nitrite/nitrate in the plasma and myeloperoxidase (MPO) levels in the lungs and the bladder were measured. Results: Elevations of the numbers of rolling and adherent leukocytes, and of plasma nitrite/nitrate levels were found, while FCD and RBCV decreased. L-NAME pretreatment ameliorated the enhanced leukocyte-endothelial cell interactions without influencing the microcirculatory perfusion. In contrast, the L-arginine pretreatment further increased plasma nitrite/nitrate levels and preserved the FCD and RBCV, but did not affect leukocyte-endothelial interactions. None of these treatments influenced MPO activities. Conclusion: Our results suggest that NO plays an enhancing role in the I/R-induced neutrophil-endothelial interactions of the bladder. Supplementation of NO ameliorates the microcirculatory perfusion deficit without influencing the postischemic microcirculatory inflammatory reactions. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: A large number of studies have proved that prostate-specific membrane antigen-positron emission tomography/computer tomography (PSMA-PET/CT) provides excellent accuracy in primary staging and restaging of prostate cancer. Less data exist with PSMA-single photon emission computed tomography (SPECT)/CT investigations., Objective: The aim of this study was to evaluate the performance of [ 99m Tc]Tc-PSMA-I&S (for imaging and surgery) in prostate cancer., Design and Methods: We retrospectively analysed PSMA-SPECT/CT scans of 20 healthy volunteers and 100 male patients with prostate cancer. All of them had histologically confirmed prostate cancer. In all, 28 patients were examined for primary staging and 72 for biochemical recurrence or progressive disease. Whole body SPECT/CT imaging was carried out 6 h after the intravenous administration of 666 ± 102 MBq [ 99m Tc]Tc-PSMA-I&S. Images were evaluated visually and semi-quantitatively., Results: Patient-based sensitivity, specificity, positive predictive value, negative predictive value and accuracy for primary prostate cancer were 86%, 100%, 100%, 83% and 92%, respectively. For detecting metastases in primary staging, these values were 88%, 100%, 100%, 85% and 93%, respectively. The radiopharmaceutical uptake of primary prostate cancer was significantly higher than in normal prostate. The patient-based sensitivity, specificity, positive predictive value, negative predictive value and accuracy of the method in the visualization of local recurrence were 67%, 100%, 100%, 86% and 89%, and for detecting metastases in restaging were 91%, 92%, 98%, 75% and 91%, respectively. In restaging, detection rates were 37% under prostate-specific antigen level of 1 ng/mL, 74% between 1 and 5 ng/mL and 80% >5 ng/mL., Conclusion: [ 99m Tc]Tc-PSMA-I&S-SPECT/CT can be easily integrated into the routine diagnostic practice, and it provides usable data in primary staging and restaging of prostate cancer. Quantitative assessment of PSMA-SPECT/CT has the potential to be used to differentiate between physiological and pathological intraprostatic tracer uptake., Competing Interests: The authors declare that there is no conflict of interest., (© The Author(s), 2024.)

Background: Penile melanoma (PM) is a rare tumor, accounting for less than 2% of all penile cancers. PM can occur on the surface of the glans, foreskin, and opening of the urethra. Furthermore, PM primarily affects older individuals and is not associated with sun exposure. Currently, there is no specific staging system for genitourinary tract melanomas, so these tumors are typically staged using the criteria for cutaneous melanoma. Limited data in the literature suggests that PM generally has a poor clinical prognosis., Case Presentation: Here, we describe two cases of PM. The first case affected a 62-year-old male who presented with hematuria and a painful tumor in the distal urethra, leading to a suspicion of penile cancer. The second case involved a 68-year-old male who noticed a rapidly evolving dark spot on his foreskin. Histological analysis confirmed the presence of melanoma in both patients. The tumors showed a diffuse and strong PRAME-positivity and lacked BRAF mutation in both cases. Additionally, the second tumor harbored an activating CKIT mutation. An enhanced PD-L1 expression was observed in both tumors., Conclusions: We presented two rare forms of mucosal melanoma and highlighted the entities in the differential diagnosis. Based on our experience PRAME is a helpful marker for making the diagnosis of PM, and PD-L1 can predict the success of the immunotherapy. We also emphasize the need for an organ-specific staging system for PMs., (© 2023. The Author(s).)

Introduction: Prostate-specific membrane antigen (PSMA) is a transmembrane protein that may be expressed on the surface of prostate cancer (PC) cells. It enables a more sensitive and specific diagnosis PC, compared to conventional anatomical imaging., Aim: The integration of PSMA-based imaging in the personalized radiotherapy of PC patients and the evaluation of its impact on target volume definition if stereotactic body radiotherapy (SBRT) is planned for locally recurrent or oligometastatic disease., Patients and Methods: The data from 363 examinations were analyzed retrospectively. Inclusion criteria were histologically verified PC and clinical data suggesting local recurrence or distant metastasis. Whole-body 99m Tc-PSMA-I&S single-photon emission computed tomography (SPECT)/CT or 18 F-JK-PSMA-7 positron emission tomography/computer tomography (PET/CT) was carried out, and the evaluation of the scans and biological tumor volume contouring was performed at the Department of Nuclear Medicine. The target volume delineation on topometric CT (TCT) scan was performed at the Department of Oncotherapy. The comparison of the two volumes was performed by image fusion and registration., Results: From 363 PSMA isotope-based examinations, 84 lesions of 64 patients were treated with SBRT. In 50 patients, 70 lesions were examined for intermodality comparison. The target volume defined by the PSMA density was significantly smaller than the tumor size defined by the TCT scan: GTV CT (gross tumor volume on the TCT), 27.58 ± 46.07 cm 3 ; BTV PSMA (biological target volume on the PSMA-based examination), 16.14 ± 29.87 cm 3 . During geometrical analyses, the Dice similarity coefficient (DSC) was 0.56 ± 0.20 (0.07-0.85). Prostate-specific antigen (PSA) control was performed to evaluate the response: mean pre-radiotherapy (pre-RT) PSA was 16.98 ng/ml ( ± SD: 33.81), and post-RT PSA at 3 months after SBRT was 11.19 ng/ml ( ± SD: 32.85). Three-month post-therapy PSMA-based imaging was performed in 14 cases, in which we observed a decrease or cessation of isotope uptake. Conventional imaging control was performed in 42 cases (65.6% of all cases): 22 (52.4%) complete remissions, 14 (33.3%) partial remissions, four (9.5%) stable diseases, and two (4.8%) progressive diseases were described., Conclusion: PSMA-based imaging is a promising diagnostic method for specifying the stage and detecting the low-volume progression. Our results suggest that PSMA-based hybrid imaging can influence treatment decisions and target volume delineation for SBRT., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Varga, Besenyi, Paczona, Farkas, Urbán, Sipka, Pávics, Varga, Fodor, Hideghéty, Olah, Bajory and Maráz.)

Applying lung protective mechanical ventilation (LPV) during general anaesthesia even in patients with non-injured lungs is recommended. However, the effects of an individual PEEP-optimisation on respiratory mechanics, oxygenation and their potential correlation with the inflammatory response and postoperative complications have not been evaluated have not been compared to standard LPV in patients undergoing major abdominal surgery. Thirty-nine patients undergoing open radical cystectomy were enrolled in this study. In the study group (SG) optimal PEEP was determined by a decremental titration procedure and defined as the PEEP value resulting the highest static pulmonary compliance. In the control group (CG) PEEP was set to 6 cmH2O. Primary endpoints were intraoperative respiratory mechanics and gas exchange parameters. Secondary outcomes were perioperative procalcitonin kinetics and postoperative pulmonary complications. Optimal PEEP levels (median = 10, range: 8-14 cmH2O), PaO2/FiO2 (451.24 ± 121.78 mmHg vs. 404.15 ± 115.87 mmHg, P = 0.005) and static pulmonary compliance (52.54 ± 13.59 ml cmH2O-1 vs. 45.22 ± 9.13 ml cmH2O-1, P < 0.0001) were significantly higher, while driving pressure (8.26 ± 1.74 cmH2O vs. 9.73 ± 4.02 cmH2O, P < 0.0001) was significantly lower in the SG as compared to the CG. No significant intergroup differences were found in procalcitonin kinetics (P = 0.076). Composite outcome results indicated a non-significant reduction of postoperative complications in the SG. Intraoperative PEEP-optimization resulted in significant improvement in gas exchange and pulmonary mechanics as compared to standard LPV. Whether these have any effect on short and long term outcomes require further investigations. Trial registration: Clinicaltrials.gov, identifier: NCT02931409.

Xp11.2 translocation carcinoma is a distinct subtype of renal cell carcinoma characterized by translocations involving the TFE3 gene. Our study included the morphological, immunohistochemical and clinicopathological examination of 28 Xp11.2 RCCs. The immunophenotype has been assessed by using CA9, CK7, CD10, AMACR, MelanA, HMB45, Cathepsin K and TFE3 immunostainings. The diagnosis was confirmed by TFE3 break-apart FISH in 25 cases. The ages of 13 male and 15 female patients, without underlying renal disease or having undergone chemotherapy ranged from 8 to 72. The mean size of the tumors was 78.5 mm. Forty-three percent of patients were diagnosed in the pT3/pT4 stage with distant metastasis in 6 cases. Histological appearance was branching-papillary composed of clear cells with voluminous cytoplasm in 13 and variable in 15 cases, including one tumor with anaplastic carcinoma and another with rhabdoid morphology. Three tumors were labeled with CA9, while CK7 was negative in all cases. Diffuse CD10 reaction was observed in 17 tumors and diffuse AMACR positivity was described in 14 tumors. The expression of melanocytic markers and Cathepsin K were seen only in 7 and 6 cases, respectively. TFE3 immunohistochemistry displayed a positive reaction in 26/28 samples. TFE3 rearrangement was detected in all the analyzed cases (25/25), including one with the loss of the entire labeled break-point region. The follow-up time ranged from 2 to 300 months, with 7 cancer-related deaths. In summary, Xp11.2 carcinoma is an uncommon form of renal cell carcinoma with a variable histomorphology and rather aggressive clinical course.

Thirty-one cases of low-grade renal cell carcinoma (RCC) with clear cells and tubulopapillary/papillary architecture were analyzed retrospectively with immunohistochemical and genetic markers to gain more experience with the differential diagnosis of such cases. All samples coexpressed CK7 and CA9; the TFE3 or TFEB reactions were negative; the CD10 and the AMACR stainings were negative in 27 cases and 30 cases, respectively. The FISH assays for papillary RCC, available in 27 cases, and deletion of chromosome 3p, available in 29 cases, gave negative results. The results for 3p deletion, VHL gene mutation or VHL gene promoter region hypermethylation testing, along with the diffuse CD10-positivity in 2 cases confirmed 21 cases as clear cell papillary RCC (CCPRCC; CK7+, CA9+; no 3p loss, no VHL abnormality) and 10 cases as clear cell RCC (CCRCC; CK7+, CA9+; no 3p loss, VHL abnormality mutation/hypermethylation present). In CCPRCCs, the representative growth pattern was branching tubulo-acinar, commonly accompanied by cyst formation. The linear nuclear arrangement or cup-shaped staining of CA9 did not necessarily indicate CCPRCC, and the absence of these did not exclude the diagnosis of CCPPRC. One tumor infiltrated the renal sinus; the others exhibited pT1 stage; and metastatic outcome was not recorded. The CCRCC cases were in pT1 stage; 6 exhibited cup-shaped staining of CA9, and 1 displayed lymph node metastasis at the time of surgery. Distant metastatic disease was not observed. In summary, the VHL abnormalities distinguished the subset of CCRCC with diffuse CK7-positivity and no 3p loss from cases of CCPRCC.

Purpose: In the integrated analysis of phase III head-to-head trials in patients with advanced solid tumors, denosumab demonstrated superiority over zoledronic acid in preventing skeletal-related events (SREs). Regular and continued drug use (persistence) is a precondition of clinical efficacy; persistence in real-life is yet undetermined for denosumab., Methods: This was a single-arm, prospective, observational, non-interventional study in 598 patients with bone metastases from breast, prostate, lung, or other solid tumors treated with denosumab every four weeks in real-world clinical practice in Austria, Czech Republic, Hungary, Slovakia, and Bulgaria. Persistence was defined as denosumab administration at ≤ 35-day intervals over 24 or 48 weeks, respectively., Results: Previous SREs were found in 10.9% of patients. 62.6% were persistent over 24 weeks and 40.1% over 48 weeks. The Kaplan-Meier median (95% CI) time to non-persistence was 274.0 days (232.0, 316.0). The most frequent reason for non-persistence was delayed administration. There was a trend towards weaker analgesics over time, with approximately 60% of patients not requiring any analgesics. Serum calcium remained within the normal range throughout the study. Adjudicated osteonecrosis of the jaw was documented in three patients with an incidence per patient-year (95% CI) of 0.012 (0.004, 0.029)., Conclusions: Most patients received denosumab regularly once every four weeks over 24 weeks of treatment. Non-persistence was mainly due to delayed administration. The incidence of adverse drug reactions, especially of osteonecrosis of the jaw, was in line with expectations from previous studies.

Purpose: Investigate the short-term effect of sildenafil on microcirculation, especially the velocity, the pattern of the flow and the recruitment of the leukocyte in postcapillaries., Methods: In male Sprague-Dawley rats, the microcirculatory consequences of 60 min experimental testicular torsion, followed by 240 min of reperfusion, were examined. Using fluorescence intravital microscopy, changes in red blood cell velocity in post-capillary venules and rolling as well as adhesion of leukocytes in the postcapillary venules were examined before the torsion and every hour during the reperfusion period. Sildenafil was given 10 min prior to reperfusion (iv 0.7 mg/kg, n = 6), while control animals received saline vehicle (n = 5)., Results: The characteristic flow motion disappeared in the affected testicular during the torsion. Red blood cell velocity values were dramatically decreased (by > 50%) and both rolling and adhesion of leukocytes increased during the reperfusion phase. Sildenafil treatment resulted in significantly higher red blood cell velocity values during the entire reperfusion period, but exerted only a temporary positive effect on the plost-ischaemic leukocyte-endothelial interactions., Conclusions: Intraoperative administration of sildenafil during surgical detorsion may provide marked testicular microperfusion benefits, but failed to influence the overall leukocyte-driven microcirculatory inflammatory reactions.

Introduction: The prostate-specific membrane antigen (PSMA) is a transmembrane protein, that is highly expressed on the surface of prostate cancer cells. In the last few years, several PSMA-specific ligands have been developed, that can be successfully used to detect primary prostate cancer, tumor recurrences and metastases as well., Aim: The goal of our work was to examine the clinical application of a 99m technetium-labeled PSMA-radiopharmaceutical as part of the routine diagnostics of prostate cancer., Method: We examined 15 male patients with verified prostate adenocarcinoma with suspicion of progression or recurrence of the disease. We performed whole-body PSMA-SPECT/CTs and multiparametric MRIs of the prostate and the pelvic regions within a week. We used 99m Tc-mas3-y-nal-k(Sub-KuE) for the PSMA-SPECT scans. The images were visually evaluated by independent observers. The results were compared with the follow-up bone scintigraphies as well., Results: Twenty-two PSMA-positive lesions were found. Nine of them were localized outside, 13 were within the MRI's field of view. From these 13 lesions, 7 matched with the SPECT/CT results and in 5 cases the MRI images showed no abnormalities. In one case, bone metastasis was suspected on the MRI scan but there was no corresponding pathological tracer uptake on the SPECT images. In two patients, none of the examinations showed signs of prostate malignancy. Four patients had PSMA-positive bone metastases. One of them had a matching PSMA/SPECT and bone scintigraphy result and in one case the PSMA examination showed metastasis in contrast to the negative bone scintigraphy., Conclusion: PSMA-SPECT/CT with 99m Tc-mas3-y-nal-k(Sub-KuE) is a promising diagnostic tool. This technique is capable of visualizing bone metastases and it can detect local recurrences and visceral metastases as well. Orv Hetil. 2018; 159(35): 1433-1440.

Introduction: Mortality of prostate carcinoma can be significantly decreased by the use of modern diagnostic and therapeutic options. Patients in early stages can be cured by radical surgery or radiotherapy., Aim: Overview and comparison of previous and present diagnostic and therapeutic methods regarding accuracy of diagnosis, improvement of efficiency and decrease of toxicities. We also aimed to explore general correlations in case of serious complications., Method: By the help of two prostate cancer patients we demonstrate the importance of accuracy and change of histological diagnosis, significance of proper imaging techniques, and also show parameters of conventional and modern radiotherapy and their acute and chronic complications. Differences of previous and present methods and their consequences were analyzed., Results: By now, histological findings in the patients' diagnosis have changed. Both patients received conventional three-dimensional definitive radiotherapy in 2009-2011, and their prostate cancer was cured. In one case, urinary bladder also received radiotherapy because prostate carcinoma had infiltrated it. In the other case, the contemporary radiotherapy involved urinary bladder's fundus due to safety margins. Although acute grade 2 cystitis developed in both cases and recovered in several weeks, as late complication bladder shrinkage developed, which after the ineffectiveness of conventional therapies had to be cured by radical cystoprostatectomy - in order to cease bleeding and to cure incontinence., Conclusions: In case of prostate carcinomas, serious complications can be avoided by the improvement of diagnostic and therapeutic options. Synthesis of data could be more successful if they were analyzed in the light of previous experiences. Orv Hetil. 2018; 159(32): 1317-1325.

Background: This study aims to explore the feasibility of anchoring a four-arm transvaginal mesh (TVM) to the mid-urethra to correct an anterior compartment POP-Quantification stage II-III (Q II-III) and concomitant genuine SUI., Methods: We analysed clinical data from 248 patients with stage II-III anterior prolapse and concomitant SUI who had undergone surgery at a tertiary referral centre in Hungary between January 2008 and June 2010. One hundred and twenty-four women treated with anterior colporrhaphy and 62 patients implanted with a conventional permanent TVM were selected as historical matched controls. Sixty-two patients received a modified permanent TVM, where the mesh was fixed to the mid-urethra with two stitches for the purpose of potentially correcting SUI. Surgical complications were classified using the Clavien-Dindo (CD) classification system., Results: The anti-SUI efficacy was minimally higher in the mTVM group than in the original TVM group (p = 0.44, 96.8% vs 91.9%, respectively), while prosthesis surgery was more effective than anterior colporrhaphy in improving the anterior compartment POP-Q status (96.8, 90.3% vs 64.5%, respectively). Anchoring the mesh did not increase the extrusion rate (p = 0.11). The de novo urge symptoms were not more prevalent among those who had received additional periurethral stitches (p = 1.00, 11.3% vs 12.9%). The incidence of reoperation observed in the mTVM group was non-significantly lower than that in the TVM group (p = 0.15, 6.5% vs 16.1%); however, the difference did not reach the level of significance. The early postoperative complication profile was more favourable among the mTVM patients (classified as CD I: 8.1%; CD II: 1.6%; and CD IIIb: 1.6%) as compared to the TVM group (p = 0.013)., Conclusions: The new, modified mesh surgery represents an effective procedure for prolapse and concomitant SUI with a decreased risk of short- and long-term complications.

Background: Patients undergoing general anesthesia and mechanical ventilation during major abdominal surgery commonly develop pulmonary atelectasis and/or hyperdistention of the lungs. Recent studies show benefits of lung-protective mechanical ventilation with the use of low tidal volumes, a moderate level of positive end-expiratory pressure (PEEP) and regular alveolar recruitment maneuvers during general anesthesia, even in patients with healthy lungs. The purpose of this clinical trial is to evaluate the effects of intraoperative lung-protective mechanical ventilation, using individualized PEEP values, on postoperative pulmonary complications and the inflammatory response., Methods/design: A total number of 40 patients with bladder cancer undergoing open radical cystectomy and urinary diversion (ileal conduit or orthotopic bladder substitute) will be enrolled and randomized into a study (SG) and a control group (CG). Standard lung-protective ventilation with a PEEP of 6 cmH 2 O will be applied in the CG and an optimal PEEP value determined during a static pulmonary compliance (Cstat)-directed PEEP titration procedure will be used in the SG. Low tidal volumes (6 mL/Kg ideal bodyweight) and a fraction of inspired oxygen of 0.5 will be applied in both groups. After surgery both groups will receive standard postoperative management. Primary endpoints are postoperative pulmonary complications and serum procalcitonin kinetics during and after surgery until the third postoperative day. Secondary and tertiary endpoints will be: organ dysfunction as monitored by the Sequential Organ Failure Assessment Score, in-hospital stay, 28-day and in-hospital mortality., Discussion: This trial will assess the possible benefits or disadvantages of an individualized lung-protective mechanical ventilation strategy during open radical cystectomy and urinary diversion regarding postoperative pulmonary complications and the inflammatory response., Trial Registration: ClinicalTrials.gov, ID: NCT02931409 . Registered on 5 October 2016.

The morphotype and grade of renal cell carcinoma (RCC) in 928 nephrectomies were reclassified according to the 2016 WHO classification in order to analyze the distribution and outcomes of RCC subtypes in Hungary, to assess whether microscopic tumor necrosis is an independent prognostic factor in clear cell RCC, and to study whether a two-tiered grading (low/high) for clear cell and papillary RCC provides similar prognostic information to that of the four-tiered ISUP grading system. 83.4% of the cohort were clear cell, 6.9% papillary, 4.5% chromophobe, 2.3% unclassified, 1.1% Xp11 translocation, 1.1% clear cell papillary, 0.3% collecting duct and 0.1% mucinous tubular and spindle cell RCCs. RCC occurred in 16 patients with end-stage kidney disease and none of them displayed features of acquired cystic kidney disease-associated RCC. The 5-year survival rates were as follows: chromophobe 100%, clear cell papillary 100%, clear cell low-grade 96%, papillary type 1 92%, clear cell high-grade 63%, papillary type 2 65%, unclassified 46%, Xp11 translocation 20%, and collecting duct 0%. The 5-year survival rates in low-grade and high-grade papillary RCC were 95% and 59%, respectively. In clear cell RCC, only the grade, the stage and the positive surgical margin proved to be independent prognostic factors statistically. Overall, papillary RCC occurred relatively infrequently; microscopic tumor necrosis in clear cell RCC did not predict the outcome independently of the tumor grading; and the assignment of clear cell and papillary RCCs into low-grade or high-grade tumors was in terms of survival no worse than the ISUP grading.

Nocturia is a significantly underestimated disorder, resulting in general worsening of patients' quality of life, while morbidity and mortality are increasing. Several urologic and other pathologic causes can be described in the background including relatively severe conditions. Therefore, accurate evaluation and adequate treatment is recommended. In this review the authors summarize the international literature regarding nocturia. PubMed and ScienceDirect databases were accurately reviewed for the relevant information. Epidemiology, etiology, unfavourable effects, diagnosis and possible treatment options were analysed. They found that symptoms can be releaved by lifestyle changes and traditional therapy in several cases, but clinically significant improvement can be reached using desmopressin in patients suffering from nocturnal polyuria. The authors conclude that nocturia may have negative effects on patients' quality of life and also on the society. Early detection and proper treatment is essential. Orv. Hetil., 2016, 157(36), 1419-1426.

Purpose: Testicular torsion without timely intervention causes incurable damage to the testis. We examined the causative role of microcirculatory injury in torsion induced testicular damage with particular regard to endothelin-A receptor activation., Materials and Methods: The microcirculatory consequences of testicular torsion were assessed in the presence or absence of endothelin-A receptor antagonism in rats. Microcirculatory perfusion changes (red blood cell velocity and pulsatile flow pattern alterations) were examined by an orthogonal polarization spectral imaging technique. Microcirculatory inflammatory alterations were assessed by fluorescence intravital video microscopy after 60-minute torsion followed by 240-minute reperfusion. As a specific endothelin-A receptor inhibitor, the antisense homology box derived peptide ETR-p1/fl was applied 10 minutes before reperfusion. Tissue accumulation of leukocytes was estimated by myeloperoxidase activity in tissue biopsies taken at the end of the 4-hour reperfusion period. In further experiments testicular weight as a marker of permanent damage was evaluated 45 days after torsion., Results: The physiological pulsatile flow pattern ceased in the initial phase of reperfusion while leukocyte-endothelial interactions increased throughout the examined reperfusion period. Endothelin-A receptor antagonism caused earlier return of pulsatile flow and recovery of red blood cell velocity, and alleviated microcirculatory inflammatory reactions and atrophy., Conclusions: Results suggest a pathophysiological role of endothelin-A receptor activation in the pathogenesis of testicular torsion. This effect is related to deterioration in testicular perfusion and activation of microcirculatory inflammatory reactions., (Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Bone metastases are a very common problem in prostate cancer. They are associated with considerable morbidity, adversely affect quality of life and frequently lead to advanced bone events (so-called skeletal-related events, SREs); SREs include fractures, spinal cord compression and the requirement for bone surgery or bone radiation. The aim of this paper was to evaluate currently available treatment options in the prevention and management of SREs and bone metastases in men with castration-resistant prostate cancer and to outline the importance of interdisciplinary management strategies. It also discusses the diagnostic workup of osseous metastases and practical considerations for the utilization of bone-targeted therapies in accordance with current guidelines to provide a consensus for special and/or difficult clinical situations., (© 2014 S. Karger AG, Basel.)

Large-conductance Ca(2+) -activated K(+) channels (BKC a ), located on the vascular smooth muscle, play an important role in regulation of vascular tone. In penile corpus cavernosum tissue, opening of BKC a channels leads to relaxation of corporal smooth muscle, which is essential during erection; however, there is little information on the role of BKC a channels located in penile vascular smooth muscle. This study was designed to investigate the involvement of BKC a channels in endothelium-dependent and endothelium-independent relaxation of human intracavernous penile arteries. In human intracavernous arteries obtained in connection with transsexual operations, change in isometric force was recorded in microvascular myographs, and endothelium-dependent [nitric oxide (NO) and endothelium-derived hyperpolarization (EDH)-type] and endothelium-independent (NO-donor) relaxations were measured in contracted arteries. In penile small arteries contracted with phenylephrine, acetylcholine evoked NO- and EDH-type relaxations, which were sensitive to iberiotoxin (IbTX), a selective blocker of BKC a channels. Iberiotoxin also inhibited relaxations induced by a NO-donor, sodium nitroprusside. NS11021, a selective opener of BKC a channels, evoked pronounced relaxations that were inhibited in the presence of IbTX. NS13558, a BKC a -inactive analogue of NS11021, failed to relax human penile small arteries. Our results show that BKC a channels are involved in both NO- and EDH-type relaxation of intracavernous penile arteries obtained from healthy men. The effect of a selective opener of BKC a channels also suggests that direct activation of the channel may be an advantageous approach for treatment of impaired endothelium-dependent relaxation often associated with erectile dysfunction., (© 2013 Nordic Pharmacological Society. Published by John Wiley & Sons Ltd.)

Introduction: Penile girth enhancement by the injection of Vaseline is an existing practice. Many cases develop severe complications that need surgery., Aim: To report on the reconstructive surgical solutions of the complications of Vaseline self-injection and the outcomes. To develop a modification of a one-step reconstruction method involving the use of pedicled scrotal flaps., Main Outcome Measures: The complications and their surgical solutions were classified as regards severity and difficulty. The outcomes were observed and a newly introduced one-step surgical method was investigated., Methods: Seventy-eight consecutive patients (87.2% of them with a history of imprisonment) were divided into three groups. In group A, aesthetic penile defects or phimosis caused by the Vaseline necessitated circumcision or local excision. In group B, the whole penile skin was involved, and total skin removal and two- or (a newly modified) one-step reconstructive surgery were performed. In group C, both the whole penile skin and the scrotum were involved: complete skin removal and skin grafting or skin pedicled flap transplantation were carried out., Results: In five cases in group B, postoperative skin necrosis made a second operation necessary. There was one intraoperative urethral injury, where a urethral fistula developed and a second urethral reconstruction was performed. There was no major complication with the newly developed one-stage pedicled flap procedure. At the end of the therapy, all the cases were healed. All of the patients reported successful sexual intercourse after the operations and 91% were satisfied with the result., Conclusions: The complications depend mainly on the amount of Vaseline injected, the hygienic circumstances, and the personal tolerability. In the worst cases, only radical skin removal and skin transplantation can solve the problem. The newly developed one-step arterial branch-preserving scrotal skin flap reconstruction appears to be a suitable and cost-effective solution for these patients., (© 2013 International Society for Sexual Medicine.)

Introduction: Vaseline self-injection into the penis is currently a popular procedure in prisons. Since such injections are illegal, severe complications of the procedure can often remain hidden., Aim: To identify the incidence, motivation, and morbidity of Vaseline self-injection into the penis among inmates., Methods: A total of 4,735 inmates at the largest Hungarian prisons were asked to complete a questionnaire relating to their sexual life, whether they had self-injected Vaseline into their penis, the motivation leading them to resort to Vaseline self-injection, any complications observed and the level of satisfaction attained., Main Outcome Measures: A 17-point questionnaire on the circumstances, motivations, and complications of Vaseline self-injection among prisoners., Results: Of the 1,905 responders, 15.7% admitted Vaseline self-injection. Only around one-fifth of the Vaseline injected subjects had not been satisfied with the original size of their penis and their sexual life up to the time of the injection, a proportion similar to that among Vaseline nonusers. While the satisfaction with the sexual life became significantly worse after the Vaseline injection, the satisfaction with the penis size did not change and an erectile dysfunction developed de novo in 21.4% of cases. The most common motivation for self-injection was a recommendation by another inmate; it was rarely recommended by a sexual partner. Complications had developed among 25.4% of the Vaseline users and 50.3% of them were not satisfied with the result of the Vaseline injection. Of the Vaseline users, 22.4% regretted the self-injection, while the rate among those who had developed complications was 53%., Conclusions: The self-injection of Vaseline into the penile skin proved to be somewhat of a trend among these inmates. The complications depended mainly on the amount of Vaseline injected, the poor hygienic circumstances, and the personal tolerability. Increased awareness is needed for the prevention of this social, psychological, and physical problem., (© 2012 International Society for Sexual Medicine.)

Testicular torsion is a surgical emergency in urologic practice. Many models have demonstrated the relationship between the degree and duration of the torsion and the subsequent damages of the testis, but there are as yet no suitable methods for visualization of the testicular microcirculation in this condition. We aimed to use orthogonal polarization spectral (OPS) imaging to observe the microcirculatory changes in the testis after ischemia-reperfusion (I/R) challenge, and to compare this technique with that of fluorescence intravital video microscopy (IVM). Twelve rats subjected to 60-minute ischemia following 720° testicular torsion were divided into two groups for IVM or OPS imaging examinations of the microcirculatory network of the testis at 60, 120, 180, and 240 minutes after reestablishment of perfusion. Significant microcirculatory failure was demonstrated after I/R in both groups. The absolute values of the microcirculatory parameters recorded with the OPS and IVM imaging methods did not differ statistically. The microcirculatory disturbances are present during the later phases of testicular torsion. OPS imaging technique represents an accurate noninvasive method to detect physiologic and pathophysiologic changes in the microcirculation of the testis.

Aim: To report a reconstructive technique of large vesicovaginal fistula repairs, which is a rare complication of the most modern anti-incontinence procedures (tension-free tapes) using the "oldie but goodie" Lehoczky's island flap., Methods: Women with large vesicovaginal fistulas caused by mid-urethral transobturator tape were operated in our department. The transobturator tape was removed and the large fistula was closed using the skin island flap. The flap was created from the regional skin and subcutaneous tissue and pulled with intact vascular supply through a paravaginal tunnel to the site of the vaginal defect., Results: No complications occurred after the reconstructions. The patients have become permanently continent and free from fistulas., Conclusions: Mid-urethral transobturator sling is a successful procedure evidenced worldwide with a very low rate of fistula formation. Lehoczky's island flap can be a reasonable and safe surgical option in the repair of large defects of the vaginal wall., (Copyright © 2011 Wiley Periodicals, Inc.)

Objectives: To determine the microcirculatory disturbances in a rat model of ischemia-reperfusion-induced cystitis using intravital fluorescence videomicroscopy., Methods: Twenty male Sprague-Dawley rats were used for the experiments. In 10 animals, warm ischemia of the bladder was induced for 60 minutes. After 30 minutes of reperfusion, microvascular macromolecular leakage, leukocyte-endothelial cell interactions, venular red blood cell velocity, functional capillary density, and the arteriolar and venular diameters were determined by intravital videomicroscopy. In addition, the intravesical pressure and macrohemodynamic parameters were assessed during the experiments. Sham-operated animals served as the controls (n = 10)., Results: After ischemia-reperfusion, the numbers of rolling and firmly adherent leukocytes in the postcapillary venules were significantly increased. Venular red blood cell velocity and functional capillary density, as well as the arteriolar and venular diameters, were significantly decreased. The macromolecular leakage had increased in both arterioles and venules., Conclusions: After ischemia-reperfusion, inflammatory reactions and microcirculatory failure were observed in the urinary bladder. This study targeted the microcirculatory consequences of cystitis using intravital videomicroscopy. Because the parameters investigated are relevant not only for ischemia-reperfusion of the urinary bladder but also for cystitis caused by other stimuli, this model represents a novel tool in the field of inflammation research in urology.

Purpose: Endothelin (ET)-1 is causatively involved in ischemia-reperfusion induced acute inflammatory reactions and microcirculatory disturbances in many organs. We investigated the role of endothelin-1 in the microcirculatory consequences of ischemia-reperfusion of the bladder using intravital fluorescence videomicroscopy., Materials and Methods: Male Sprague-Dawley rats were used in the experiments. The animals were randomly assigned to a sham operated group or to 1 of 2 ischemia-reperfusion groups that underwent 60 minutes of ischemia followed by 30 minutes of bladder reperfusion. In 1 ischemia-reperfusion group the animals were pretreated with BQ 610, a specific ET-A receptor blocker. The bladder was placed on an especially designed stage for intravital fluorescence videomicroscopy measurements. Venular red blood cell velocity, functional capillary density, venular and arteriolar diameter, venular and arteriolar macromolecular leakage, and leukocyte-endothelial cell interactions in postcapillary venules were determined using a computer assisted analyzing system., Results: Functional capillary density, red blood cell velocity, venular and arteriolar diameter were significantly decreased and macromolecular leakage was significantly enhanced after bladder ischemia-reperfusion. The number of rolling and adherent leukocytes was significantly increased in postcapillary venules. Pretreatment with BQ 610 was effective for attenuating the effects of ischemia-reperfusion induced inflammation but could not completely prevent microcirculatory failure., Conclusions: Ischemia-reperfusion induced cystitis leads to significant impairment of the microcirculation and ET-1 is suggested to have an important role in this process. Pretreatment with an ET-A receptor antagonist reduces ischemia-reperfusion related microvascular disturbances in the bladder.

Intravital fluorescence microscopy (IVM) is a widely used method to study the microcirculation in several organs. Our aim was to develop a standard rat model to evaluate the microcirculatory characteristics of the urinary bladder under physiological pressure conditions using the most advanced fluorescence videomicroscopic techniques. Spraque-Dawley rats were used after filling their bladders with a constant volume of saline solution. The intravesical pressure was continuously monitored. The bladder was positioned on a specially designed stage and IVM measurements were made at the beginning, the 90th, 120th and 180th min. Arteriolar and venular diameters, functional capillary density, venular red blood cell velocity, arteriolar and venular macromolecular leakage and leukocyte-endothelial cell interactions (observation of rolling and firmly adherent leukocytes) were quantitatively assessed by a computer assisted analysis system. Neither microcirculatory parameters nor the intravesical pressure changed significantly during the observation period of 180 min using constant filling volume. We successfully established a new, well functioning and reproducible model to study the microcirculation of the rat bladder using intravital fluorescent microscopy.