Upper Urinary Tract Urothelial Cancer After Radical Cystectomy for Bladder Cancer: Survival Outcomes After Radical Nephroureterectomy.

BACKGROUND: Systemic and local recurrences of urothelial bladder cancer (UBC) significantly impair survival after radical cystectomy (RC), but little is known about the impact of the recurrence of urothelial cancer in the upper urinary tract (UTUC). This report describes survival outcomes and their predictors for patients who underwent RC followed by radical nephroureterectomy (RNU) for UTUC. METHODS: The Surveillance, Epidemiology, and End Results database was queried to identify patients who underwent RC for UBC and subsequent RNU for UTUC. The Kaplan-Meier method and competing-risk Cox regression (CRR) were used for the survival analysis. RESULTS: Overall, 102 patients have undergone RNU within a median of 49 months (interquartile range [IQR], 27-76 months) since RC. Muscle-invasive UTUCs were predominant at RNU (n = 58; 56.7%), but organ-confined bladder tumors were most frequent at RC (n = 42, 41.5%). After RNU, the estimated 5-year overall survival (OS) was 25.9%, the cancer-specific survival (CSS) was 35.6%, the median OS was 23 months (IQR, 11-63 months), and the CSS was 34 months (IQR, 13-132 months). In the multivariable CRR, the factors predictive for CSS after RNU included male gender (hazard ratio [HR], 2.36; 95% confidence interval [CI], 1.03-5.42; p < 0.05), muscle-invasive UTUC (HR, 2.20; 95% CI, 1.13-4.28; p < 0.05), and the presence of distant metastasis (HR,11.59; 95% CI, 5.33-25.2; p < 0.001). CONCLUSIONS: In conclusion, the patients who underwent RNU for UTUC after RC for UBC experienced poor OS and CSS. The majority of RNUs were performed for locally advanced tumors. The independent risk factors for worse OS and CSS after RNU were UTUC T stage, presence of metastasis, and male gender.

Cancer-Specific Survival of Patients with Non-Muscle-Invasive Bladder Cancer: A Population-Based Analysis.

BACKGROUND AND PURPOSE: Non-muscle-invasive bladder cancer (NMIBC) constitutes a heterogeneous group of tumors with different prognoses. This population-based study aimed to report real-world cancer-specific survival (CSS) of NMIBC and create a prognostic nomogram based on the identified risk factors. METHODS: The Surveillance, Epidemiology, and End Results database was searched for patients diagnosed with NMIBC from 2004 to 2015, who underwent transurethral resection of the bladder tumor. The dataset was divided into development and validation cohorts. Factors associated with CSS were identified using Cox proportional hazards and used to develop a prognostic nomogram. RESULTS: In total, 98,238 patients with NMIBC were included. At the median follow-up of 124 months (IQR 81-157 months), cancer-specific mortality (CSM) was highest for T1HG (19.52%), followed by Tis (15.56%), similar for T1LG and TaHG (10.88% and 9.23%, respectively), and lowest for TaLG (3.76%). Multivariable Cox regression for CSS prediction was utilized to develop a nomogram including the following risk factors: tumor T category and grade, age, tumor size and location, histology type, primary character, race, income, and marital status. In the validation cohort, the model was characterized by an AUC of 0.824 and C-index that reached 0.795. CONCLUSIONS: To conclude, NMIBC is associated with a significant risk of long-term CSM especially, but not only, in patients with T1HG. Rarely diagnosed TaHG and T1LG tumors should be regarded as high-risk due to approximately 10% CSM. T category, grading, and age remain the most powerful determinants of CSS in NMIBC, but sociodemographic factors might also influence its prognosis.

Fournier's Gangrene: Clinical Presentation of 13 Cases.

BACKGROUND Fournier's gangrene (FG) is a fulminant form of infective, polymicrobial, necrotizing fasciitis of the perineal, genital, and perianal regions. It commonly affects men, but women and children may also develop this type of tissue necrosis. MATERIAL AND METHODS This study is a retrospective analysis of the management of 13 cases of Fournier's gangrene, diagnosed from among about 45 000 patients (men, women, and children) treated in the Department of General, Oncological, and Functional Urology (Medical University of Warsaw) from 1995 to 2013. All patients with Fournier's gangrene underwent adequate surgical debridement of the necrotic tissues. Additional procedures (suprapubic cystostomy and orchiectomy) were necessary in 10 out of 13 (77.0%) patients. Seven out of 13 (53.8%) patients required subsequent reconstructive surgery of the scrotum. RESULTS All 13 patients were males, with a median age of 59.6 years (range: 42-68 years). The average hospital stay was 31.9 days (range: 16-46 days). None of our patients died due to Fournier's gangrene. Bacteriological cultures of samples from the wounds showed polymicrobial flora, including the following genera of aerobes and anaerobes: Escherichia, Proteus, Klebsiella, Moraxella, Gemella, Enterococcus, Streptococcus, Staphylococcus, Bacteroides, Pseudoflavonifractor, Parabacteroides, Porphyromonas, Prevotella, Peptoniphilus, Peptostreptococcus, Actinomyces, Collinsella, and Lactobacillus. CONCLUSIONS Favorable outcome of FG treatment with low morbidity and no mortality can be achieved with rapid diagnosis, urgent surgical debridement of all necrotic tissues, and broad-spectrum empirical antimicrobial therapy, usually with combined antibiotics, against aerobic and anaerobic bacteria. Prevention of uroseptic shock by treating localized infection is compulsory.

Evolution in the approach to overlooked ureteral injuries after gynecological surgery.

OBJECTIVES: To analyzed the therapeutic results for patients with overlooked iatrogenic ureteral injuries after gynecological surgery, treated at the department since 1990. Before the era of endourology, ureteral injuries were operated on immediately after making a diagnosis. This approach was changed after the popularization of percutaneous nephrostomy (PN) and ureteral stenting using a JJ stent. MATERIAL AND METHODS: 27 patients who were diagnosed with a ureteral injury between the first and sixty-fourth day after injury were included. Only PN was performed in 21 patients (group A). In 6 patients, a JJ stent was introduced either immediately after making a diagnosis or after PN (group B). RESULTS: In group A, a good therapeutic result was obtained in only 6 patients (28.6%). Of the 12 patients subjected to PN up to two weeks after injury, 5 had a good result without a need for repair surgery. Of the 9 patients with an injury diagnosed after 3 weeks, only one had a good therapeutic outcome. In Group B, a good result was achieved in 5 out of 6 patients. In 2 patients, a JJ stent was introduced immediately after making the diagnosis, and, in 3 patients, after PN. A successful attempt to "tunnelize" a complete and long obstruction in the sixth patient failed. CONCLUSIONS: Attempting to introduce a JJ stent should be the treatment of choice in patients with an overlooked iatrogenic ureteral injury. If an attempt to introduce the JJ stent fails, PN should be performed as a first step to manage the injury.

The presence of prostate cancer at biopsy is predicted by a number of genetic variants.

Several single nucleotide polymorphisms (SNPs) have been associated with an elevated risk of prostate cancer risk. It is not established if they are useful in predicting the presence of prostate cancer at biopsy or if they can be used to define a low-risk group of men. In this study, 4,548 men underwent a prostate biopsy because of an elevated prostate specific antigen (PSA; ≥4 ng/mL) or an abnormal digital rectal examination (DRE). All men were genotyped for 11 selected SNPs. The effect of each SNP, alone and in combination, on prostate cancer prevalence was studied. Of 4,548 men: 1,834 (40.3%) were found to have cancer. A positive association with prostate cancer was seen for 5 of 11 SNPs studied (rs1800629, rs1859962, rs1447295, rs4430796, rs11228565). The cancer detection rate rose with the number of SNP risk alleles from 29% for men with no variant to 63% for men who carried seven or more risk alleles (OR = 4.2; p = 0.002). The SNP data did not improve the predictive power of clinical factors (age, PSA and DRE) for detecting prostate cancer (AUC: 0.726 vs. 0.735; p = 0.4). We were unable to define a group of men with a sufficiently low prevalence of prostate cancer that a biopsy might have been avoided. In conclusion, our data do not support the routine use of SNP polymorphisms as an adjunct test to be used on the context of prostate biopsy for Polish men with an abnormal screening test.

Lack of usefulness of ureteral reconstruction with free bladder mucosa flap in dogs confirmed by microangiography.

BACKGROUND: There is a paucity of data addressing the blood supply in the surgically reconstructed ureter, and complete lack of microangiographic studies of the reconstructed ureter with the use of a free bladder mucosa flap. The present study evaluated the blood supply in the reconstructed dog ureter after a 5-centimeter segment resection, supplemented by a tube constructed from a free bladder mucosa flap. MATERIAL AND METHODS: Female mongrel dogs (n=29) were used in this study. Under general anaesthesia, a 5-centimeter autologous free bladder mucosa flap was used to construct a tube, which was afterwards grafted to replace a 5-centimeter ureter resection. After a period of 3 months (n=2) and after 1 year (n=2), microangiography was performed to assess the revascularization of the grafted ureter. RESULTS: In our study, we observed the continuity of the ureter, but the grafted reconstruction was narrowed by the cicatrization in about 86% (n=25) of cases. This resulted in the development of hydronephrosis, as described in previous publications. The ureteral wall was covered by a normal urothelium, but consisted of fibrous connective tissue, which failed to restore a regular (normal) coat. The reconstructed segment showed no smooth muscle cells. A few smooth monocytes were found only at the border with intact portions of the ureter. The microangiography performed at the end of the experiments showed no vascularization of the restored segment of the ureter. CONCLUSIONS: The experiments showed a whole regeneration of urothelium in the transected and reanastomosed ureters. However, there was no regeneration of the muscular coat and a complete lack of revascularization.

Fournier's gangrene--current concepts.

Fournier's gangrene (FG) is a rapidly progressive form of infective necrotising fasciitis of the perineal, genital, or perianal regions, leading to thrombosis of the small subcutaneous vessels and necrosis of the overlying skin. It is believed that the occurrence of the disease in women is underreported and may be unrecognised by some clinicians. Fournier's gangrene is a life-threatening condition, constituting an urological emergency. Many patients with Fournier's gangrene have medical or surgical conditions, which are predisposing factors to this disease or its more severe or fatal course. These comprise diabetes mellitus, hypertension, alcoholism and advanced age. Recent reports in the literature point to changes in the epidemiology of FG, comprising an increasing age of patients. Several authors reported that the mean age of FG patients is at present 53-55 years. Prognosis in FG patients is based on FGSI (Fournier's gangrene severity index) score. Despite the progress in medical care for FG patients, the mortality rate reported in the literature remains high--most often 20-40%, but ranges from 4% to 80%. The most common isolates cultured from FG lesions are both Gram-positive and Gram-negative, as well as strictly anaerobic bacteria. Recently community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) has emerged as an etiological agent of FG with severe clinical course and even fulminant sepsis. Rarely FG may have a fungal etiology, being caused by yeast-like fungi Candida spp. or by moulds. Antibiotics should be administered parenterally and in doses high enough to reach an effective concentration in the infected tissues.

The G84E mutation in the HOXB13 gene is associated with an increased risk of prostate cancer in Poland.

BACKGROUND: The G84E mutation in the HOXB13 gene has been associated with a high lifetime risk of prostate cancer in North America (about 20-fold). The geographical and ethnic extent of this recurrent allele has not yet been determined. METHODS: We assayed for the presence of the G84E mutation in 3,515 prostate cancer patients and 2,604 controls from Poland and estimated the odds ratio for prostate cancer associated with the allele. RESULTS: The G84E mutation was detected in 3 of 2,604 (0.1%) individuals from the general population in Poland and in 20 of 3,515 (0.6%) men with prostate cancer (Odds ratio [OR] = 5.0; 95% CI: 1.5-16.7; P = 0.008). The allele was present in 4 of 416 (1.0%) men with familial prostate cancer (OR = 8.4, 95% CI: 1.9-37.7; P = 0.005). CONCLUSIONS: The G84E mutation predisposes to prostate cancer in Poland, but accounts for only a small proportion of cases. We expect that the G84E founder mutation might be present in other Slavic populations.

Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial.

BACKGROUND: Bone metastases are a major cause of morbidity and mortality in men with prostate cancer. Preclinical studies suggest that osteoclast inhibition might prevent bone metastases. We assessed denosumab, a fully human anti-RANKL monoclonal antibody, for prevention of bone metastasis or death in non-metastatic castration-resistant prostate cancer. METHODS: In this phase 3, double-blind, randomised, placebo-controlled study, men with non-metastatic castration-resistant prostate cancer at high risk of bone metastasis (prostate-specific antigen [PSA] ≥8·0 µg/L or PSA doubling time ≤10·0 months, or both) were enrolled at 319 centres from 30 countries. Patients were randomly assigned (1:1) via an interactive voice response system to receive subcutaneous denosumab 120 mg or subcutaneous placebo every 4 weeks. Randomisation was stratified by PSA eligibility criteria and previous or ongoing chemotherapy for prostate cancer. Patients, investigators, and all people involved in study conduct were masked to treatment allocation. The primary endpoint was bone-metastasis-free survival, a composite endpoint determined by time to first occurrence of bone metastasis (symptomatic or asymptomatic) or death from any cause. Efficacy analysis was by intention to treat. The masked treatment phase of the trial has been completed. This trial was registered at ClinicalTrials.gov, number NCT00286091. FINDINGS: 1432 patients were randomly assigned to treatment groups (716 denosumab, 716 placebo). Denosumab significantly increased bone-metastasis-free survival by a median of 4·2 months compared with placebo (median 29·5 [95% CI 25·4-33·3] vs 25·2 [22·2-29·5] months; hazard ratio [HR] 0·85, 95% CI 0·73-0·98, p=0·028). Denosumab also significantly delayed time to first bone metastasis (33·2 [95% CI 29·5-38·0] vs 29·5 [22·4-33·1] months; HR 0·84, 95% CI 0·71-0·98, p=0·032). Overall survival did not differ between groups (denosumab, 43·9 [95% CI 40·1-not estimable] months vs placebo, 44·8 [40·1-not estimable] months; HR 1·01, 95% CI 0·85-1·20, p=0·91). Rates of adverse events and serious adverse events were similar in both groups, except for osteonecrosis of the jaw and hypocalcaemia. 33 (5%) patients on denosumab developed osteonecrosis of the jaw versus none on placebo. Hypocalcaemia occurred in 12 (2%) patients on denosumab and two (<1%) on placebo. INTERPRETATION: This large randomised study shows that targeting of the bone microenvironment can delay bone metastasis in men with prostate cancer. FUNDING: Amgen Inc.

Radiation after radical prostatectomy in elderly patients - a SEER database-derived competing-risk survival analysis of propensity score-matched age groups.

Introduction: This study aimed to evaluate cancer-specific (CSM) and other-cause mortality (OCM) in elderly patients with prostate cancer treated with radical prostatectomy (RP) and postoperative radiotherapy (RT). Material and methods: The Surveillance, Epidemiology, and End Results (SEER) database was searched for clinically non-metastatic prostate cancer (PCa) treated with RT after RP between 2010 and 2015. Patients were stratified according to age groups and underwent propensity score (PS) matching. The Kaplan-Meier method and competing-risk Cox regression (CRR) were used for survival analysis. Results: In total, 5385 patients were analysed, including 738 (13.7%) elderly patients (≥70 years old) and 4647 (86.29%) younger individuals. A total of 54 (7.32%) and 69 (9.35%) patients aged ≥70 years died due to PCa and competing reasons, respectively. Among younger patients these included 275 (5.92%) and 208 (4.48%) deaths, respectively. At a median follow-up of 80 months, patients ≥70 years old had significantly shorter OCM (p <0.0001) than PS-matched younger controls without significant impairment of cancer-specific survival when compared to controls (p = 0.19). In CRR analysis older patients were at significantly higher risk of OCM (HR = 2.24, p = 0.0002 and HR = 3.3, p = 0.011 for patients aged ≥70 and ≥75 years, respectively). Simultaneously, the CRR revealed no increased risk of CSM for patients older than 70 and 75 years (HR = 1.2, p = 0.33 and HR = 1.53, p = 0.29, respectively). Conclusions: Elderly patients with PCa are at high risk of dying due to competing reasons, which might prevent the survival benefit of RT after RP. Selection for salvage and adjuvant RT in these individuals should be cautious.

Palladium(0) deposited on PAMAM dendrimers as a catalyst for C-C cross coupling reactions.

PAMAM dendrimers of generations G2-G3 as well as a partially substituted derivative of generation G4 and a low-molecular-weight tricyclic ligand 4 were used to bind Pd(0) nanoparticles. The obtained adducts were tested as catalysts for C-C cross-coupling reactions, such as the Suzuki-Miyaura, Hiyama, Heck and Sonogashira reaction. The highest yields of the coupling product, diphenylacetylene, were obtained with all the catalysts studied in the Sonogashira coupling performed in ethanol with K2CO3 as base. Very good results, 85-100%, were also found in the Suzuki-Miyaura cross-coupling, while the efficiency of the Hiyama coupling appeared lower, with 38-52% of 2-methylbiphenyl formed. In all reactions, the G2-Pd(0) catalyst, containing an unmodified dendrimer, afforded the highest yields of the cross-coupling products.

Feasibility of active surveillance in small testicular mass: a mini review.

INTRODUCTION: Widespread use of scrotal ultrasonography has led to the detection of incidental, non-palpable small testicular masses (STMs). Historically, all intratesticular masses were treated radically, however more conservative strategies are now being applied with growing evidence that up to 80% of STMs are benign lesions. Testis-sparing surgery is deemed a gold standard in STMs. However, the high probability of the benign nature of STMs and the excellent cure rate of localized testicular cancer has led to emerging attempts to use an active surveillance (AS) strategy for selected groups of patients. MATERIAL AND METHODS: We conducted a non-systematic review of the literature in the PubMed and Embase databases for articles associated with AS strategy in STMs. RESULTS: The main inclusion criteria for AS in patients with STMs were lack of risk factors of testicular cancer, no features of disseminated disease, negative tumor markers, non-palpable lesion that did not exceed 10 mm. Mean follow-up time of AS across the studies ranged from 9.6 to 29.6 months. Surveillance protocols were based on regular physical examination, scrotal ultrasonography and measurement of tumor markers. The change rate to active treatment ranged from 0% to 8% without reported deterioration of oncological outcomes. Patients have proceeded to surgical treatment based on their preference, lesion growth, change in echogenicity, tumor marker growth and the need for testicular exploration for other reasons. CONCLUSIONS: Active surveillance is a reasonable conservative strategy in the management of STMs in selected groups of patients with minimal risk of deteriorating impact on oncological outcomes.

Human kidney injury molecule-1 as a urine biomarker differentiating urothelial and renal cell carcinoma.

INTRODUCTION: Urine concentration of human kidney injury molecule-1 (KIM-1) is suggested to be increased in patients with renal cell carcinoma (RCC). However, it has never been tested in patients with urothelial tumors, while preoperative differentiation between RCC and upper tract urothelial carcinoma (UTUC) plays an essential role in therapeutic decisions.The aim of the study was to evaluate the role of urinary KIM-1 expression in preoperative differentiation between RCC and urothelial carcinoma (UC). MATERIAL AND METHODS: Sixty-four participants were enrolled in the study, including 30 patients with RCC and 27 with UC (16 with UTUC and 11 with bladder tumor). Preoperative urinary KIM-1 levels were measured using a commercially available ELISA kit and normalized to urinary creatinine levels. RESULTS: The median concentration of urinary KIM-1 normalized to urinary creatinine was lower in patients with RCC compared to UC (1.35 vs 1.86 ng/mg creatinine, p = 0.04). The comparison between RCC and UTUC shows even more significant difference (1.33 vs 2.23 ng/mg creatinine, p = 0.02). Urinary KIM-1 concentration did not correlate with tumor stage nor grade in any of the groups. ROC analysis to identify UC revealed AUC of 0.657 with sensitivity 33.3% and specificity 96.7% at the cut-off value of 3.226 ng/mg creatinine. Among patients with eGFR ≥60 mL/min/1.73 m², ROC analysis to detect UC achieved AUC of 0.727 with sensitivity 69.5% and specificity 70.2%. CONCLUSIONS: Urine KIM-1 can potentially differentiate UC from RCC. However, a wide range of observed results and limited sensitivity and specificity requires caution in making clinical decisions before confirmatory studies.

Enhanced cardiac hypoxic injury in atherogenic dyslipidaemia results from alterations in the energy metabolism pattern.

OBJECTIVE: Dyslipidaemia is a major risk factor for myocardial infarction that is known to correlate with atherosclerosis in the coronary arteries. We sought to clarify whether metabolic alterations induced by dyslipidaemia in cardiomyocytes collectively constitute an alternative pathway that escalates myocardial injury. METHODS: Dyslipidaemic apolipoprotein E and low-density lipoprotein receptor (ApoE/LDLR) double knockout (ApoE-/-/LDLR-/-) and wild-type C57BL/6 (WT) mice aged six months old were studied. Cardiac injury under reduced oxygen supply was evaluated by 5 min exposure to 5% oxygen in the breathing air under electrocardiogram (ECG) recording and with the assessment of troponin I release. To address the mechanisms LC/MS was used to analyse the cardiac proteome pattern or in vivo metabolism of stable isotope-labelled substrates and HPLC was applied to measure concentrations of cardiac high-energy phosphates. Furthermore, the effect of blocking fatty acid use with ranolazine on the substrate preference and cardiac hypoxic damage was studied in ApoE-/-/LDLR-/- mice. RESULTS: Hypoxia induced profound changes in ECG ST-segment and troponin I leakage in ApoE-/-/LDLR-/- mice but not in WT mice. The evaluation of the cardiac proteomic pattern revealed that ApoE-/-/LDLR-/- as compared with WT mice were characterised by coordinated increased expression of mitochondrial proteins, including enzymes of fatty acids' and branched-chain amino acids' oxidation, accompanied by decreased expression levels of glycolytic enzymes. These findings correlated with in vivo analysis, revealing a reduction in the entry of glucose and enhanced entry of leucine into the cardiac Krebs cycle, with the cardiac high-energy phosphates pool maintained. These changes were accompanied by the activation of molecular targets controlling mitochondrial metabolism. Ranolazine reversed the oxidative metabolic shift in ApoE-/-/LDLR-/- mice and reduced cardiac damage induced by hypoxia. CONCLUSIONS: We suggest a novel mechanism for myocardial injury in dyslipidaemia that is consequent to an increased reliance on oxidative metabolism in the heart. The alterations in the metabolic pattern that we identified constitute an adaptive mechanism that facilitates maintenance of metabolic equilibrium and cardiac function under normoxia. However, this adaptation could account for myocardial injury even in a mild reduction of oxygen supply.

Exogenously administered opioids contract the female rat intrinsic urethral sphincter in vivo.

BACKGROUND AND OBJECTIVE: Previous studies have reported immunoreactive opioid nerve fibers in the detrusor and lower urinary tract sphincters. However, there is a paucity of in vivo studies demonstrating the direct effect of endogenous opioids in these structures. In the present study, we investigated the contractile actions of intra-arterially administered exogenous Dynorphin-A, Met-enkephalin, Leu-enkephalin, morphine, and the opioid antagonist naltrexone on the female rat intrinsic urethral sphincter in vivo. METHODS: Intraurethral pressure was recorded by a catheter placed at the maximum pressure zone of the intrinsic urethral sphincter in anesthetized female Sprague-Dawley rats. The effects of different opioids were studied and expressed as means and as percentages of pressure change (cmH(2)O) of the baseline intraurethral pressure. RESULTS: Dynorphin-A, Met-enkephalin, and Leu-enkephalin evoked rapid, long-lasting contractile effects on the female rat urethra. The greatest intraurethral pressure increase was evoked by Dynorphin-A (89.2 +/- 15.3%). For Met-enkephalin, intraurethral pressure increased by 70.2 +/- 21.8% and for Leu-enkephalin, the pressure increase was 60.6 +/- 20%. Morphine, however, evoked inconsistent intraurethral pressure changes, increasing the urethral pressure in three subjects and lowering the pressure in the remaining six subjects. The opioid antagonist naltrexone reduced the intraurethral pressure by a mean of -19.0 +/- 5.8%. CONCLUSION: Results of the present study suggest that endogenous opioids by their contractile action on the intrinsic urethral sphincter may play a role in the control of continence in rats, additional to cholinergic and noradrenergic pathways.

Phosphodiesterase 9a Inhibition in Mouse Models of Diastolic Dysfunction.

BACKGROUND: Low myocardial cGMP-PKG (cyclic guanosine monophosphate-protein kinase G) activity has been associated with increased cardiomyocyte diastolic stiffness in heart failure with preserved ejection fraction. Cyclic guanosine monophosphate is mainly hydrolyzed by PDE (phosphodiesterases) 5a and 9a. Importantly, PDE9a expression has been reported to be upregulated in human heart failure with preserved ejection fraction myocardium and chronic administration of a PDE9a inhibitor reverses preestablished cardiac hypertrophy and systolic dysfunction in mice subjected to transverse aortic constriction (TAC). We hypothesized that inhibiting PDE9a activity ameliorates diastolic dysfunction. METHODS: To examine the effect of chronic PDE9a inhibition, 2 diastolic dysfunction mouse models were studied: (1) TAC-deoxycorticosterone acetate and (2) Leprdb/db. PDE9a inhibitor (5 and 8 mg/kg per day) was administered to the mice via subcutaneously implanted osmotic minipumps for 28 days. The effect of acute PDE9a inhibition was investigated in intact cardiomyocytes isolated from TAC-deoxycorticosterone acetate mice. Atrial natriuretic peptide together with PDE9a inhibitor were administered to the isolated intact cardiomyocytes through the cell perfusate. RESULTS: For acute inhibition, no cellular stiffness reduction was found, whereas chronic PDE9a inhibition resulted in reduced left ventricular chamber stiffness in TAC-deoxycorticosterone acetate, but not in Leprdb/db mice. Passive cardiomyocyte stiffness was reduced by chronic PDE9a inhibition, with no differences in myocardial fibrosis or cardiac morphometry. PDE9a inhibition increased the ventricular-arterial coupling ratio, reflecting impaired systolic function. CONCLUSIONS: Chronic PDE9a inhibition lowers left ventricular chamber stiffness in TAC-deoxycorticosterone acetate mice. However, the usefulness of PDE9a inhibition to treat high-diastolic stiffness may be limited as the required PDE9a inhibitor dose also impairs systolic function, observed as a decline in ventricular-arterial coordination, in this model.

Urinary Human Kidney Injury Molecule1- (hKIM1-) is not Increased in Patients with Renal Cell Carcinoma.

PURPOSE: Human Kidney Injury Molecule-1 (hKIM-1) was proposed as urinary biomarker of renal cell carcinoma (RCC). The aim of the study was to validate urinary hKIM-1 as a biomarker of RCC. MATERIAL AND METHODS: Forty-six participants were enrolled into the study, including 30 patients with clear-cell or papillary RCC and 16 matched patients in the comparison group. Preoperative urinary hKIM-1 levels were measured using commercially available ELISA kit and normalized to urinary creatinine levels. RESULTS: The concentrations of urinary hKIM-1 normalized to urinary creatinine in patients with RCC and comparison group did not differ significantly (1.35 vs. 1.32 ng/mg creatinine, p=.25). There was also no difference in urinary hKIM-1 concentration regarding stage or grade of renal cancer. Additional analysis of patients without chronic kidney disease (defined as eGFR ≥60mL/min/1.73m²) also did not reveal significant difference in urinary hKIM-1 concentrations between the groups (1.54 vs. 1.37; p=.47). CONCLUSION: Results of our study do not confirm recent suggestions that urinary hKIM-1 may be a biomarker of RCC.

Internal optical urethrotomy is the treatment of choice in stenosis of the bladder neck after open prostate adenectomy.

INTRODUCTION: Open adenomectomy of the prostate, although performed less frequently, is still indicated in patients with prostate adenoma > 100 ml. AIM: This study assessed the frequency of isolated bladder neck stenosis after surgery and the effectiveness of internal optical urethrotomy as monotherapy and in combination with transurethral resection in the treatment of this complication. MATERIAL AND METHODS: One thousand five hundred thirty-eight Millin's operations and 381 trans-vesical adenomectomies were performed in patients with prostate adenoma. In 50 patients, the circular hemostatic suture was applied using the de la Peña technique because of bleeding after surgery. The retrospective analysis compared the incidence of isolated bladder neck stenosis depending on the type of surgery. RESULTS: Isolated bladder neck stenosis or narrowing of the neck combined with partial stenosis of the site after adenomectomy occurred in 0.52% (8/1539) of patients after Millin's operation and in 1.05% of patients (4/381) after trans-vesical adenomectomy. All strictures of the bladder after trans-vesical surgery occurred within 12 month after the procedure, and 25% of stenoses after Millin's operation occurred many years after the surgery. Internal optical urethrotomy as monotherapy or in combination with scar resection resulted in recovery after one treatment in 16 out of 17 patients. CONCLUSIONS: Internal optical urethrotomy as monotherapy or in combination with scar resection was effective in nearly all patients with bladder neck stenosis.

BRCA1 mutations and prostate cancer in Poland.

Evidence to date that BRCA1 mutation carriers are at an increased risk of prostate cancer is mixed - both positive and negative studies have been published. To establish whether or not inherited variation in BRCA1 influences prostate cancer risk we genotyped 1793 men with prostate cancer in Poland and 4570 controls for three founder mutations (C61G, 4153delA and 5382insC). A BRCA1 mutation was present in 0.45% of the cases and 0.48% of the controls (odds ratio=0.9; P=1.0). The odds ratios varied substantially by mutation. The 5382insC mutation is the most common of the three founder mutations. It was detected only in one case (0.06%), whereas it was seen in 0.37% of controls (P=0.06). In contrast, the 4153delA was more common in prostate cancer cases (0.22%) than in controls (0.04%) (odds ratio=5.1; 95% confidence interval: 0.9-27.9; P=0.1). The C61G mutation was also found in excess in cases (0.17%) compared with controls (0.07%) (odds ratio=2.6; 95% confidence interval: 0.5-12.7; P=0.5). Eight men with prostate cancer carried a mutation. Only one of these carried the 5382insC mutation, compared with 17 of 22 individuals with mutations in the control population (P=0.003). These data suggest that the 5382insC mutation is unlikely to be pathogenic for prostate cancer in the Polish population. The presence of one of the other alleles was associated with an increased risk for prostate cancer (odds ratio=3.6; 95% confidence interval: 1.1-11.3; P=0.045); in particular for familial prostate cancer (odds ratio=12; 95% confidence interval: 2.9-51; P=0.0004). We consider that the risk of prostate cancer in BRCA1 carriers varies with the position of the mutation.