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Congestive heart failure (CHF) is often associated with impaired kidney function. Over- activation of the renin-angiotensin-aldosterone system (RAAS) contributes to avid salt/water retention and cardiac hypertrophy in CHF. While the deleterious effects of angiotensin II (Ang II) in CHF are well established, the biological actions of angiotensin 1-7 (Ang 1-7) are not fully characterized. In this study, we assessed the acute effects of Ang 1-7 (0.3, 3, 30 and 300 ng/kg/min, IV) on urinary flow (UF), urinary Na + excretion (UNaV), glomerular filtration rate (GFR) and renal plasma flow )RPF) in rats with CHF induced by the placement of aortocaval fistula. Additionally, the chronic effects of Ang 1-7 (24 µg/kg/h, via intra-peritoneally implanted osmotic minipumps) on kidney function, cardiac hypertrophy and neurohormonal status were studied. Acute infusion of either Ang 1-7 or its agonist, AVE 0991, into sham controls, but not CHF rats, increased UF, UNaV, GFR, RPF and urinary cGMP. In the chronic protocols, untreated CHF rats displayed lower cumulative UF and UNaV than their sham controls. Chronic administration of Ang 1-7 and AVE 0991 exerted significant diuretic, natriuretic and kaliuretic effects in CHF rats, but not in sham controls. Serum creatinine and aldosterone levels were significantly higher in vehicle-treated CHF rats as compared with controls. Treatment with Ang 1-7 and AVE 0991 reduced these parameters to comparable levels observed in sham controls. Notably, chronic administration of Ang 1-7 to CHF rats reduced cardiac hypertrophy. In conclusion, Ang 1-7 exerts beneficial renal and cardiac effects in rats with CHF. Thus, we postulate that ACE2/Ang 1-7 axis represents a compensatory response to over-activity of ACE/AngII/AT1R system characterizing CHF and suggest that Ang 1-7 may be a potential therapeutic agent in this disease state.

Introduction: In 2018, we reported a case series of 47 patients diagnosed with cancer following several years of exposure to high-intensity whole-body radiofrequency radiation (RFR) using the parameter of percentage frequency (PF). Consistent high and statistically significant PFs of hematolymphoid (HL) cancers were found in this group and in four previous reports on RFR-exposed groups in Belgium, Poland and Israel together with increased all-cancers rates. In this paper we report a new series of 46 young cancer patients who were exposed during military service to such radiation., Materials and Methods: The new group of patients comprises Israeli soldiers previously exposed to occupational RFR. The patients were self-selected to enroll in the research in cooperation with an NGO assisting patients with administrative counseling and legal and social services. The new group of patients was studied with respect to distribution (proportion) of cancer types using the method of PF. When possible, cancer risk ratios (RR) were estimated too. The results are compared to those of other occupational groups in three countries., Results: Median age at diagnosis was 23 years; duration of exposure was between 1 and 3 years and the latencies were short, median 4.6 years. The PF of HL cancers was 41.3%, 95% CI (27%-57%), versus 22.7% expected in non-exposed subjects matched for age and gender profiles, p = 0.003; 19 out of the 46 patients had HL cancers. The PF of Hodgkin lymphoma cancers was 21.7%, 95%CI (11%-36%), versus 11.6% expected, p = 0.033. For a subgroup of 6 patients, the number of soldiers in the units was known, and we were able estimate approximately the overall cancer risk ratio (RR) after 8 years as being 8.0 with 95% CI (2.9, 17), p < 0.002, with only 0.75 cases expected from the Cancer Registry data. In this subgroup, there were 3 HL cancer cases and 3 non-HL cases. Sarcoma PF was higher than expected, 7 out of the 46 patients were diagnosed with sarcoma, PF = 15.2%, 95%CI (6.3%-28.9%), p = 0.04 versus the expected PF of 7%., Conclusion: The HL PF was high and consistent with previous reports. Epidemiological studies on excess risk for HL and other cancers, brain tumors in cellphone users, and experimental studies on RFR and carcinogenicity strongly point to a cause-effect relationship. It is mandatory to reduce the RFR exposure of all personnel to that of the typical community levels, including the peak level of radar pulses. Radiation protection, safety instructions, cancer risk warnings and quantitative data on individual exposure together with regular medical monitoring must be instituted for all personnel exposed to such risks. The findings from our study add to the growing body of evidence underscoring the gross inadequacy of the International Commission on Non-Ionizing Radiation Protection (ICNIRP) thermal standards. Based on our findings and on the previous accumulated research, we endorse the recommendations to reclassify RFR exposure as a human carcinogen, International Agency for Research on Cancer (IARC) group 1., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: M.P. is employed by a company producing RFR transmitting equipement. M.D. is a foundder and the CEO of Zoar. E.R. : The Unit of Occupational and Environmental Medicine in the Hebrew University-Hadassah School of Public Health and Community Medicine provided medical opinions to previous cancer patients. The fees went directly into the Unit research budget in the University., (Copyright © 2022 Elsevier Inc. All rights reserved.)

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Purpose: to evaluate a unique subpopulation of radical prostatectomy (RP) candidates with “negative” prostate 68Ga-labeled prostate-specific membrane antigen (PSMA) positron emission tomography (PET) computed tomography (CT) imaging scans and to characterize the clinical implications of misleading findings. Materials and Methods: This case-control retrospective study compared the final histological outcomes of patients with “negative” pre-RP PSMA PET/CT prostate scans (with a prostate maximal standardized uptake value [SUVmax] below the physiologic uptake) to those with an “intense” prostatic tracer uptake (with a SUVmax above the physiologic uptake). The patients underwent an RP between March 2015 and July 2019 in five academic centers. Data on the demographics, comorbidities, prostate-specific antigen (PSA) and rectal exam findings, prior biopsies, imaging results, biopsies, and RP histology results were collected. Results: Ninety-seven of the 392 patients who underwent an RP had PSMA PET/CT imaging preoperatively. Fifty-two (54%) had a “negative” uptake (in the study group), and 45 (46%) had a “positive” uptake (in the control group). Only the lesion size and SUVmax values on the PSMA PET/CT differed between the groups preoperatively. On the histological analysis, only the ISUP score, seminal vesicles invasion, T stage, and positive margin rates differed between the groups (p < 0.05), while 50 (96%) study group patients harbored clinically significant disease (ISUP ≥ 2), with an extra-prostatic disease in 24 (46%), perineural invasion in 35 (67%), and positive lymph nodes in 4 (8%). Conclusions: Disease aggressiveness generally correlated with an intense PSMA uptake on the preoperative PSMA PET/CT, but a subpopulation of patients with clinically significant cancer and aggressive characteristics showed a deceptively weak PSMA uptake. These data raise a concern about the unqualified application of PSMA PET/CT for staging RP candidates.

Objective: This study examined the reliability of the various parameters obtained in diagnostic ureteroscopy for upper-tract urothelial carcinoma (UTUC) in predicting the degree of differentiation in the final pathological report after radical nephroureterectomy (RNU)., Methods: We conducted a retrospective review of patients undergoing RNU at a single tertiary hospital between 2000 and 2020. Only patients who underwent preoperative diagnostic ureteroscopy (URS) were included. The results of urine selective cytology, endoscopic appearance of the tumor, and biopsy taken during ureteroscopy were compared to the final pathological report., Results: In total, 111 patients underwent RNU. A preliminary URS was performed in 54. According to endoscopic appearance, 40% of the "solid"-looking tumors were high grade (HG), while 52% of those with a papillary appearance were low grade (LG). Positive cytology predicted HG tumors in 86% of cases. However, 42% of patients with negative cytology had HG disease. The biopsies acquired during URS showed that HG disease findings matched the final pathology in 75% of cases. However, 25% of patients noted as being HG, based on URS biopsies, were noted to have LG disease based on nephroureterectomy biopsies. Full analyses revealed that 40% of the cases diagnosed as LG based on the URS biopsies actually had HG disease., Conclusions: Direct tumor observation of papillary lesions, negative cytology, and biopsies indicating LG disease are of low predictive value for classifying the actual degree of tumor differentiation. No single test can accurately rule out HG disease. In light of the rising use of neo-adjuvant chemotherapy in UTUC, a reliable predictive model should be developed that accurately discriminates between HG and LG disease.

Objectives: To quantitatively compare the functional renal volume loss, following nephron sparing surgery (NSS) between patients in whom tumor bed closure was done by biological tissue adhesive and those who were managed by standard suture technique., Methods: From our institutional NSS database we retrospectively collected patients who had two sequential quantitative single-photon emission computed tomography of 99m Tc-dimercaptosuccinic acid uptake studies, the first study immediately before surgery and the second one 3-6 months following surgery. The study group included 69 patients: 26 (37.7%) patients in the sealant group (BioGlue®) and 43 (62.3%) patients in the standard suture group., Results: No statistically significant differences were noted in the baseline clinical and pathological characteristics of the studied groups. However, there were several statistically significant differences in operative variables: patients in the suture group had larger amount of blood loss (3-fold), longer ischemia time (26.6 vs. 21 minutes,) and slightly longer operation time. Patients in whom tumor bed was closed by sutures had nearly 3-fold higher parenchymal loss compared to patients managed by sealant (26.28 vs. 8.92 ml, p = 0.048)., Conclusions: The use of tissue sealant during tumor bed reconstruction is associated with reduced devascularized parenchymal mass loss and should be considered among modifiable surgical factors during NSS., (Copyright © 2019 by S. Karger AG, Basel.)

The thiazolidinedione (TZD) class of Peroxisome proliferator-activated receptor gamma agonists has restricted clinical use for diabetes mellitus due to fluid retention and potential cardiovascular risks. These side effects are attributed in part to direct salt-retaining effect of TZDs at the renal collecting duct. A recent study from our group revealed that prolonged rosiglitazone (RGZ) treatment caused no Na+/H 2 O retention or up-regulation of Na + transport-linked channels/transporters in experimental congestive heart failure (CHF) induced by surgical aorto-caval fistula (ACF). The present study examines the effects of RGZ on renal and cardiac responses to atrial natriuretic peptide (ANP), Acetylcholine (Ach) and S-Nitroso-N-acetylpenicillamine (SNAP-NO donor). Furthermore, we assessed the impact of RGZ on gene expression related to the ANP signalling pathway in animals with ACF. Rats subjected to ACF (or sham) were treated with either RGZ (30 mg/kg/day) or vehicle for 4 weeks. Cardiac chambers pressures and volumes were assessed invasively via Miller catheter. Kidney excretory and renal hemodynamic in response to ANP, Ach and SNAP were examined. Renal clearance along with cyclic guanosine monophosphate (cGMP), gene expression of renal CHF-related genes and ANP signalling in the kidney were determined. RGZ-treated CHF rats exhibited significant improvement in the natriuretic responses to ANP infusion. This 'sensitization' to ANP was not associated with increases in neither urinary cGMP nor in vitro cGMP production. However, RGZ caused down-regulation of several genes in the renal cortex (Ace, Nos3 and Npr1) and up-regulation of ACE2, Agtrla, Mme and Cftr along down-regulation of Avpr2, Npr1,2, Nos3 and Pde3 in the medulla. In conclusion, CHF+RGZ rats exhibited significant enhancement in the natriuretic responses to ANP infusion, which are known to be blunted in CHF. This 'sensitization' to ANP is independent of cGMP signalling, yet may involve post-cGMP signalling target genes such as ACE2, CFTR and V2 receptor. The possibility that TZD treatment in uncomplicated CHF may be less detrimental than thought before deserves additional investigations., (© 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Background: This study aims to prospectively evaluate the ability of Neutrophil-to-Lymphocyte ratio (NLR) to forecast recurrence in patients with non-muscle invasive bladder cancer (NMIBC). This is a continuation of our two previous retrospective studies that indicated the NLR > 2.5 criterion as a predictor of recurrence in patients with NMIBC., Methods: Since December 2013, all patients admitted to our department for TUR-BT and agreed to participate, had a blood drawn for cell count and differential 24 h prior to surgery. Patients with pathological NMIBC were followed prospectively for disease recurrence. The end-point of the follow up was either a cancer recurrence or the termination of the study. Univariate and multivariate Cox regressions were performed to assess the NLR > 2.5 predictive capability for recurrence, versus and in conjunction to the pathologically based EORTC score, among additional statistical analyses., Results: The study cohort included 96 men and 17 women with a median age of 72 years. Sixty-four patients (56.6%) have had a recurrence during the study occurring at the median time of 9 months (IQR 6, 13), while the median follow-up time for patients without recurrence was 18 months (IQR 10, 29). Univariate Cox regressions for recurrence demonstrated significance for NLR > 2.5 for the whole cohort (p = 0.011, HR 2.015, CI 1.175-3.454) and for the BCG sub-group (p = 0.023, HR 3.7, CI 1.2-11.9), while the EORTC score demonstrated significance for the 'No Treatment' subgroup (p = 0.024, HR 1.278, CI 1.03-1.58). When analyzed together as a multivariate Cox model, the NLR > 2.5 and EORTC score retained their significance for the aforementioned groups, while also improving the EORTC score significance for the whole cohort., Conclusion: NLR > 2.5 was found to be a significant predictor of disease recurrence and demonstrated high hazard ratio and worse recurrence-free survival in patients with NMIBC, especially in those treated with BCG. Additionally, our data demonstrated statistical evidence that NLR > 2.5 might have an improving effect on the EORTC score's prediction when analyzed together.

Background and Aim: We reexamine whether radio frequency radiation (RFR) in the occupational and military settings is a human carcinogen., Methods: We extended an analysis of an already-reported case series of patients with cancer previously exposed to whole-body prolonged RFR, mainly from communication equipment and radar. We focused on hematolymphatic (HL) cancers. We used analysis by percentage frequency (PF) of a cancer type, which is the proportion of a specific cancer type relative to the total number of cancer cases. We also examined and analyzed the published data on three other cohort studies from similar military settings from different countries., Results: The PF of HL cancers in the case series was very high, at 40% with only 23% expected for the series age and gender profile, confidence interval CI95%: 26-56%, p<0.01, 19 out of 47 patients had HL cancers. We also found high PF for multiple primaries. As for the three other cohort studies: In the Polish military sector, the PF of HL cancers was 36% in the exposed population as compared to 12% in the unexposed population, p<0.001. In a small group of employees exposed to RFR in Israeli defense industry, the PF of HL cancers was 60% versus 17% expected for the group age and gender profile, p<0.05. In Belgian radar battalions the HL PF was 8.3% versus 1.4% in the control battalions as shown in a causes of deaths study and HL cancer mortality rate ratio was 7.2 and statistically significant. Similar findings were reported on radio amateurs and Korean war technicians. Elevated risk ratios were previously reported in most of the above studies., Conclusions: The consistent association of RFR and highly elevated HL cancer risk in the four groups spread over three countries, operating different RFR equipment types and analyzed by different research protocols, suggests a cause-effect relationship between RFR and HL cancers in military/occupational settings. While complete measurements of RFR exposures were not available and rough exposure assessments from patients interviews and from partial exposure data were used instead, we have demonstrated increased HL cancers in occupational groups with relatively high RFR exposures. Our findings, combined with other studies, indicate that exposures incurred in the military settings evaluated here significantly increased the risk of HL cancers. Accordingly, the RFR military exposures in these occupations should be substantially reduced and further efforts should be undertaken to monitor and measure those exposures and to follow cohorts exposed to RFR for cancers and other health effects. Overall, the epidemiological studies on excess risk for HL and other cancers together with brain tumors in cellphone users and experimental studies on RFR and carcinogenicity make a coherent case for a cause-effect relationship and classifying RFR exposure as a human carcinogen (IARC group 1)., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: The aim of this study was to report the impact of patients' baseline characteristics on the incidence of acute kidney injury (AKI) after nephron-sparing surgery (NSS) for localized kidney cancer., Patients and Methods: Data from our kidney cancer database were retrospectively extracted to include 402 patients who underwent NSS between March 2000 and June 2016, and had sufficient data. Definition of AKI was based on the postoperative serum creatinine levels and estimated glomerular filtration rate (eGFR) magnitude, which were measured during the 72 h after surgery., Results: Based on RIFLE and AKIN criteria, the overall rate of postoperative AKI was 35%. The average decrease in eGFR among patients who developed AKI was 20% as compared with the non-AKI subgroup (2%). In univariate analysis, variables that were associated with AKI included right-sided tumors ( p = 0.014), male sex ( p = 0.01), hypertension ( p = 0.003), baseline eGFR ( p = 0.009) and history of nephrolithiasis ( p = 0.039). However, multivariate analysis revealed that the only independent predictors of postoperative AKI were hypertension ( p = 0.009) and cigarette smoking ( p = 0.024)., Conclusion: AKI is a common complication of NSS affecting about one-third of the patients. The most important risk factors are hypertension and smoking., Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest.

Stents are widely use in endoscopic urological procedures. One of the most important indications is the treatment of urinary tract strictures. Allium™ Medical has introduced several types of stents for the treatment of different types of urinary tract strictures, based on anatomic location. All the stents are made of nitinol and coated with a co-polymer that reduces encrustations. These stents are self-expandable and have a large caliber and a high radial force. They have different shapes, designed especially for the treatment of each type of stricture. One of the most important features of Allium-manufactured stents is the ease of removal, due to their special unraveling feature. The company has introduced the Bulbar Urethral Stent (BUS) for treatment of bulbar urethral strictures; a rounded stent available in different lengths. Initial data on 64 patients with bulbar urethral stricture treated with the BUS showed a significant improvement in symptoms, with minimal complications and few adverse events. For treatment of prostate obstruction in patients unfit for surgery or unwilling to undergo a classical prostatic surgery, the Triangular Prostatic Stent (TPS) was introduced, which has a triangular shape that fits in the prostatic urethra. Its body has a high radial force attached to an anchor (which prevents migration) through a trans-sphincteric wire (which reduces incontinence rate). Initial data on 51 patients showed significant improvement in symptoms and in urinary peak flow rate, with a relatively small number of complications. The Round Posterior Stent (RPS) was designed for treatment of post radical prostatectomy bladder neck contracture. This short, round stent has an anchor, which is placed in the bladder neck. This stent being relatively new, the clinical data are still limited. Ureteral strictures can be treated with the Ureteral Stent (URS), which is round-shaped, available in different lengths, and has an anchor option (for very distal or very proximal strictures). We have previously published data on 107 URSs inserted in patients with ureteral stricture due to several etiologies, including patients who failed previous treatment. All patients were asymptomatic for a long period of follow-up after stent removal, with only one case of re-stenosis. In this paper, we review the urological "covered" stents produced by Allium Medical with the relevant clinical data available at the present time.

Despite the high prevalence of acute kidney injury (AKI) and its association with increased morbidity and mortality, therapeutic approaches for AKI are disappointing. This is largely attributed to poor understanding of the pathogenesis of AKI. Heparanase, an endoglycosidase that cleaves heparan sulfate, is involved in extracellular matrix turnover, inflammation, kidney dysfunction, diabetes, fibrosis, angiogenesis and cancer progression. The current study examined the involvement of heparanase in the pathogenesis of ischemic reperfusion (I/R) AKI in a mouse model and the protective effect of PG545, a potent heparanase inhibitor. I/R induced tubular damage and elevation in serum creatinine and blood urea nitrogen to a higher extent in heparanase over-expressing transgenic mice vs. wild type mice. Moreover, TGF-β, vimentin, fibronectin and α-smooth muscle actin, biomarkers of fibrosis, and TNFα, IL6 and endothelin-1, biomarkers of inflammation, were upregulated in I/R induced AKI, primarily in heparanase transgenic mice, suggesting an adverse role of heparanase in the pathogenesis of AKI. Remarkably, pretreatment of mice with PG545 abolished kidney dysfunction and the up-regulation of heparanase, pro-inflammatory (i.e., IL-6) and pro-fibrotic (i.e., TGF-β) genes induced by I/R. The present study provides new insights into the involvement of heparanase in the pathogenesis of ischemic AKI.Our results demonstrate that heparanase plays a deleterious role in the development of renal injury and kidney dysfunction,attesting heparanase inhibition as a promising therapeutic approach for AKI.

Background: To present the operative and post-operative comparison between patients who underwent tumor-bed closure with sutures compared with bovine serum albumin-glutaraldehyde (BioGlue ® ) tissue sealant only., Methods: We retrospectively analyzed data from our ongoing database of 507 eligible patients who underwent open NSS nephron-sparing surgery in our department between January 1995 and May 2014. Patients had tumor-bed closure with sealant adhesive (255 patients) or standard suture technique (252 patients). Demographic, clinical and perioperative data were compared between the two groups, by Chi-square test or by Fisher-Irwin exact test for categorical variables, and by t test for differences in means or by Wilcoxon rank sum test for continuous variables. A multivariate analysis was also done., Results: Patients' baseline characteristics showed similar distribution of the analyzed parameters among both groups, with few differences: younger age in the sealant group (65.4 versus 68.4 years, p = 0.01) and slightly larger mass size in the suture group (4.0 versus 3.9 cm, p = 0.03). Ischemia time was significantly shorter in the sealant group (21.8 versus 27.0 minutes, p = 0001). Blood loss and transfusion rate (0.8% versus 11.9%, p = 0.0001) were significantly less in the sealant group. A multivariate analysis showed date of surgery and blood loss as the major parameters affecting transfusion rate., Conclusions: Closing the tumor bed with BioGlue ® tissue adhesive is feasible, safe, can shorten ischemia time and potentially reduce transfusion rate., Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest.

Background: Pathology of urothelial carcinoma may vary in different populations at diagnosis. Our aim was to evaluate the histopathologic differences between Jewish and Arab patients in Israel at first diagnosis of urothelial cancer., Patients and Methods: We retrospectively collected data of all patients with confirmed urothelial cancer, treated at our department between January 2010 and January 2015. We examined the distribution of the histopathologic data among the studied populations. To compare the categorical variables we used the Chi-Square Pearson test. Comparison of independent variables was made by Student's t -test. P value below 0.05 was considered significant., Results: The study group included 413 patients, 345 Jews and 68 Arabs. The major differences were that Arab patients were younger (62.61 versus 68.55 years, P = 0.001), had more aggressive tumors that were detected at a more advanced stage, and had also a higher rate of metastatic disease (7.4% versus 3.2%, P = 0.05). Nonurothelial cell tumors were 2.3 times more prevalent in Arab population. Unlike Jewish population, Arab women had higher rate of invasive/metastatic disease compared with Arab men (40% versus 22.4%)., Conclusion: At time of diagnosis the tumors were more aggressive in Arab patients, especially in Arab women. The reasons for those differences constitute a target for a separate research. These results should have an impact on prevention medicine and education of physicians treating mixed populations.

Background: Ischemia/reperfusion (I/R) is an important cause of acute renal failure and delayed graft function, and it may induce chronic renal damage by activating epithelial to mesenchymal transition (EMT) of renal tubular cells. Heparanase (HPSE), an endoglycosidase that regulates FGF-2 and TGFβ-induced EMT, may have an important role. Therefore, aim of this study was to evaluate its role in the I/R-induced renal pro-fibrotic machinery by employing in vitro and in vivo models., Methods: Wild type (WT) and HPSE-silenced renal tubular cells were subjected to hypoxia and reoxygenation in the presence or absence of SST0001, an inhibitor of HPSE. In vivo, I/R injury was induced by bilateral clamping of renal arteries for 30 min in transgenic mice over-expressing HPSE (HPA-tg) and in their WT littermates. Mice were sacrificed 48 and 72 h after I/R. Gene and protein EMT markers (α-SMA, VIM and FN) were evaluated by bio-molecular and histological methodologies., Results: In vitro: hypoxia/reoxygenation (H/R) significantly increased the expression of EMT-markers in WT, but not in HPSE-silenced tubular cells. Notably, EMT was prevented in WT cells by SST0001 treatment. In vivo: I/R induced a remarkable up-regulation of EMT markers in HPA-tg mice after 48-72 h. Noteworthy, these effects were absent in WT animals., Conclusions: In conclusion, our results add new insights towards understanding the renal biological mechanisms activated by I/R and they demonstrate, for the first time, that HPSE is a pivotal factor involved in the onset and development of I/R-induced EMT. It is plausible that in future the inhibition of this endoglycosidase may represent a new therapeutic approach to minimize/prevent fibrosis and slow down chronic renal disease progression in native and transplanted kidneys.

While the pro-tumorigenic function of heparanase is well taken, the role of its close homolog, heparanase 2 (Hpa2) in cancer is by far less investigated. Utilizing immunohistochemical analysis we found that Hpa2 is expressed by normal bladder transitional epithelium and its levels are decreased substantially in bladder cancer. Notably, tumors that retain high levels of Hpa2 were diagnosed as low grade (p=0.001) and low stage (p=0.002), suggesting that Hpa2 is required to preserve cell differentiation and halt cell motility. Indeed, migration of 5637 bladder carcinoma cells was attenuated significantly by exogenous addition of purified Hpa2, and over expression of Hpa2 in 5637 cells resulted in smaller tumors that were diagnosed as low grade. We also noted that tumors produced by Hpa2 over expressing cells are abundantly decorated with stromal cells and collagen deposition evident by Masson's/Trichrome staining, correlating with a marked increase in lysyl oxidase (LOX) staining. The association between Hpa2 and LOX was further confirmed clinically, because of the 16 cases that exhibited strong staining of Hpa2, 14 (87.5%) were also stained strongly for LOX (p=0.05). Collectively, our results suggest that Hpa2 functions as a tumor suppressor in bladder cancer, maintaining cellular differentiation and decreasing cell motility in a manner that appears to be independent of regulating heparanase activity., Competing Interests: The authors have no potential conflict of interest to declare.

Background: Erectile dysfunction (ED), a common problem in males of all ages, can be of organic, psychogenic or combined etiology. Organic ED is mainly caused by vascular and neurological disorders. One of the available tests for differentiating organic from inorganic ED is measuring penile tumescence and rigidity during the REM phase of sleep. However, this test lacks the ability to differentiate between a vascular and non-vascular cause of organic ED., Objectives: To compare the results of the EndoPAT test and the nocturnal penile tumescence (NPT) test in patients with erectile dysfunction., Methods: Twenty patients with ED were recruited for the study. Each participant was evaluated by the SHIM score, RigiScan during polysomnography, and two EndoPAT tests (at the beginning and end of the study)., Results: Seventeen patients had a SHIM score 21; 4 of them had organic ED with a mean EndoPAT score of 1.49, significantly lower than the 1.93 mean EndoPAT score of the 11 patients in the psychogenic ED group (P = 0.047). Two participants had a neurological impairment (spinal trauma and herniated disk). The average SHIM score in the vascular organic group was 6.25 points as compared to 11.69 for the psychogenic group (P = 0.027). The positive predictive value was 43% and the negative predictive value 90%., Conclusions: EndoPAT could be helpful in excluding organic ED.

Angiosarcoma of the urinary bladder is an extremely rare and poorly characterized tumor. We are presenting the 13th reported patient who was an 89-year-old man initially presented with massive hematuria. His past medical history included external-beam radiation for prostate cancer 12 years ago. His PSA was 0.26 ng/dL. His CT-Urography demonstrated a highly vascular mass originating from the bladder base. The mass was partially resected, transurethrally. The pathology was consistent with primary angiosarcoma of the urinary bladder. Bone scan and CT-U showed metastasis to spine. The patient was treated with palliative radiotherapy for back pain due to metastasis, and he refused chemotherapy. The patient died 3 months after his initial diagnosis.

Aim. To describe the natural history of small renal mass on active surveillance and identify parameters that could help in predicting the need for intervention in patients with small renal masses undergoing active surveillance. We also discuss the need for renal biopsy in the management of these patients. Methods. A retrospective analysis of 78 renal masses ≤4 cm diagnosed at our Urology Department at Bnai Zion Medical Center between September 2003 and March 2012. Results. Seventy patients with 78 small renal masses were analyzed. The mean age at diagnosis was 68 years (47-89). The mean follow-up period was 34 months (12-112). In 54 of 78 masses there was a growth of at least 2 mm between imaging on last available follow-up and diagnosis. Eight of the 54 (15%) masses which grew in size underwent a nephron-sparing surgery, of which two were oncocytomas and six were renal cell carcinoma. Growth rate and mass diameter on diagnosis were significantly greater in the group of patients who underwent a surgery. Conclusions. Small renal masses might eventually be managed by active surveillance without compromising survival or surgical approach. All masses that were eventually excised underwent a nephron-sparing surgery. None of the patients developed metastases.

Acute kidney injury (AKI) is a common clinical problem that still lacks effective treatment. Phosphodiesterase-5 (PDE5) inhibitors possess anti-apoptotic and anti-oxidant properties, making it a promising therapy for ischemia-reperfusion (I/R) injury of various organs. The present study evaluated the early nephroprotective effects of Tadalafil, a PDE5 inhibitor, in an experimental model of renal I/R. Sprague-Dawley rats were divided into two groups: vehicle-treated I/R (n = 10), and Tadalafil (10 mg/kg po)-treated I/R group (n = 11). After removal of the right kidney and collection of two baseline urine samples, the left renal artery was clamped for 45 min followed by reperfusion for 60, 120, 180, and 240 min. Functional and histological parameters of the kidneys from the various groups were determined. In the vehicle-treated I/R group, glomerular filtration rate was significantly reduced compared with that in normal kidneys. In addition, the ischemic kidney showed remarkable cast formation, necrosis, and congestion, a consistent pattern of acute tubular necrosis. Furthermore, urinary excretion of NGAL and KIM-1, two novel biomarkers of kidney injury, substantially increased following I/R insult. In contrast, Tadalafil treatment resulted in a significant improvement in kidney function and amelioration of the adverse histological alterations of the ischemic kidney. Noteworthy, the urinary excretion of NGAL and KIM-1 markedly decreased in the Tadalafil-treated I/R group. These findings demonstrate that Tadalafil possesses early nephroprotective effects in rat kidneys subjected to I/R insult. This approach may suggest a prophylactic therapy for patients with ischemic AKI.

Background: Bleeding severity, anatomic location, tissue characteristics, and visibility are common challenges encountered while managing intraoperative bleeding, and conventional hemostatic measures (suture, ligature, and cautery) may sometimes be ineffective or impractical. While topical absorbable hemostats (TAH) are useful hemostatic adjuvants, each TAH has associated disadvantages., Methods: We evaluated the safety and hemostatic efficacy of a new advanced biologic combination product-fibrin pad-to potentially address some gaps associated with TAHs. Fibrin pad was assessed as adjunctive hemostat in open partial nephrectomy in single-center, open-label, Phase I study (N = 10), and as primary hemostat in multicenter, single-blind, randomized, standard-of-care (SOC)-controlled Phase I/II study (N = 7) in Israel. It was used to control mild-to-moderate bleeding in Phase I and also spurting arterial bleeding in Phase I/II study. Phase I study assessed safety and Phase I/II study, proportion of successes at 10 min following randomization, analyzed by Fisher exact tests at 5% significance level., Results: Phase I (N = 10): All patients completed the study. Hemostasis was achieved within 3-4 min (average = 3.1 min) of a single application in all patients. Fibrin pad was found to be safe for human use, with no product-related adverse events reported. Phase I/II (N = 7): Hemostatic success at 10 min (primary endpoint) was achieved in 3/4 patients treated with fibrin pad versus 0/3 patients treated with SOC. No clinically significant change in laboratory or coagulation parameters was recorded, except a case of post-procedural hemorrhage with fibrin pad, which was considered serious and related to the fibrin pad treatment, and required re-operation. Although Data Safety Monitoring Board authorized trial continuation, the sponsor decided against proceeding toward an indication for primary treatment of severe arterial hemorrhage as a replacement for sutures. The study was suspended after 7/30 planned subjects were enrolled., Conclusions: The first-in-man trial of fibrin pad demonstrated its safety and efficacy as an adjunctive hemostatic technique for mild-to-moderate bleeding in partial nephrectomy. The study also suggested that the product should not replace sutures or meticulous surgical techniques for the treatment of severe arterial hemorrhage., Trial Registration: Phase I/II trial, NCT00598130.

T5 is a novel splice variant of heparanase, an endo-β-D-glucuronidase capable of cleaving heparan sulfate side chains at a limited number of sites. T5 splice variant is endowed with pro-tumorigenic properties, enhancing cell proliferation, anchorage independent growth and tumor xenograft development despite lack of heparan sulfate-degrading activity typical of heparanase. T5 is over expressed in the majority of human renal cell carcinoma biopsies examined, suggesting that this splice variant is clinically relevant. T5 is thought to assume a distinct three-dimensional conformation compared with the wild type heparanase protein. We sought to exploit this presumed feature by generating monoclonal antibodies that will recognize the unique structure of T5 without, or with minimal recognition of heparanase, thus enabling more accurate assessment of the clinical relevance of T5. We provide evidence that such a monoclonal antibody, 9c9, preferentially recognizes T5 compared with heparanase by ELISA, immunoblotting and immunohistochemistry. In order to uncover the clinical significance of T5, a cohort of renal cell carcinoma specimens was subjected to immunostaining applying the 9c9 antibody. Notably, T5 staining intensity was significantly associated with tumor size (p = 0.004) and tumor grade (p = 0.02). Our results suggest that T5 is a functional, pro-tumorigenic entity.

Background: One of the major concerns in performing nephron-sparing surgery (NSS) for renal cell carcinoma (RCC) is the risk of tumor recurrence., Objectives: To assess the rate, predictors and mechanisms of oncological failure in patients after NSS for renal cancer., Methods: Between 1993 and 2008 NSS was performed in 229 patients via flank incision. Only patients without metastases at diagnosis and minimal 12 months follow-up were included in the outcome analysis., Results: During a mean follow-up of 45 +/- 34 months (range 6-168 months) tumor recurrence was observed in 13 patients (5.6%). Mean follow-up time for detection of oncological failure was 51 months (range 6-132 months). All patients with oncological failure were males, with a mean age of 61 years (median 58, range 51-74 years). The average size of the enucleated lesion was 5 cm (range 4-7 cm). Intraoperative frozen sections as well as postoperative final pathological examination of the surgical margins were negative in all recurrent cases. Mechanisms of recurrence were distant metastases (n=4), surgical scar implantation (n=2), perirenal fat recurrence (n=2), local renal recurrence at the surgical site (n=1), and new renal lesions (n=4). Predictors of oncological failure included warm ischemia time (P = 0.058), tumor size (P = 0.001), tumor location (central versus peripheral) (P = 0.015), and multifocality (P = 0.001)., Conclusions: Distant dissemination, seeding during surgery, residual disease and new growth are the mechanisms responsible for cancer relapse. Large central lesions, long warm ischemia time and multifocality were significant predictors of oncological failure.

Purpose. In recent years, endoscopic injection became the procedure of choice for the correction of vesicoureteral reflux in the majority of the centers. Unfortunately, endoscopic treatment is not always successful and sometimes requires more than one trial to achieve similar results to that of an open reimplantation surgery. Our aim of this study is to evaluate the feasibility and success rate of open ureteral reimplantation following failed endoscopic procedure. Patients and Methods. During 2004-2010, we evaluated 16 patients with persistent vesicoureteral reflux (grades II-IV) following failed endoscopic treatment. All patients underwent open ureteral reimplantation. All patients were followed with an ultrasound 6 weeks following surgery and every 6 months thereafter for an average of 22 months. Voiding cystography was performed at 3 months after surgery. Results. During unilateral open ureteral reimplantation, the implanted deposit from previous procedures was either excised, drained, or incorporated into the neotunnel with the ureter. Vesicoureteral reflux was resolved in all patients with 100% success rate. No new hydronephrosis or signs of obstruction developed in any of the patients. qDMSA renal scan was available in 8 patients showing improvement of function in 5 and stable function in 3, and no new scars were identified. Conclusions. Open ureteral reimplantation is an excellent choice for the correction of failed endoscopic treatment in children with vesicoureteral reflux.

Purpose. To determine the degree and predictors of renal function loss of the operated kidney following nephron-sparing surgery (NSS). Material and methods. The study group included 113 patients with renal mass who underwent NSS at our institution. QDMSA before and 3-6 months after surgery was used for evaluation differences in renal function of each kidney. Mean change of percent uptake by the kidney was correlated with various clinical and pathological variables. Results. The overall average decrease of renal function of the operated kidney as measured by QDMSA was 10.5% ± 2.6 SER. Among the studied variables, the most important predictors of postoperative ipsilateral residual kidney function were estimated blood loss (EBL), P = 0.0003, duration of warm ischemia, P = 0.008, patient's age at surgery, P = 0.024, method used for tumor bed closure, P = 0.06, and location of the lesion, P = 0.08. Conclusions. Carful hemostasis, minimal duration of arterial clamping, and use of tissue adhesives to seal tumor bed are associated with maximal preservation of postoperative residual renal function after NSS. These variables should be considered by the operative team when planning the surgical procedure .

MicroRNAs (miRNAs) belong to a class of noncoding, regulatory RNAs that is involved in oncogenesis and shows remarkable tissue specificity. Their potential for tumor classification suggests they may be used in identifying the tissue in which cancers of unknown primary origin arose, a major clinical problem. We measured miRNA expression levels in 400 paraffin-embedded and fresh-frozen samples from 22 different tumor tissues and metastases. We used miRNA microarray data of 253 samples to construct a transparent classifier based on 48 miRNAs. Two-thirds of samples were classified with high confidence, with accuracy >90%. In an independent blinded test-set of 83 samples, overall high-confidence accuracy reached 89%. Classification accuracy reached 100% for most tissue classes, including 131 metastatic samples. We further validated the utility of the miRNA biomarkers by quantitative RT-PCR using 65 additional blinded test samples. Our findings demonstrate the effectiveness of miRNAs as biomarkers for tracing the tissue of origin of cancers of unknown primary origin.

Background: Although the current literature attributes most cases of hematospermia to an infectious agent, identification of the specific pathogens involved has been limited., Objectives: To determine the prevalence of different pathogens in patients presenting with hematospermia to our sexually transmitted disease clinic., Methods: Between January 1999 and January 2000, 16 patients presented to our STD clinic with hematospermia after other noninfectious pathologies had been excluded by a referring physician. After obtaining informed consent, subjects completed a questionnaire addressing symptoms and sexual behavior. First-void urine samples, as well as genitourinary and serum specimens were tested for Chlamydia trachomatis, Ureaplasma urealyticum and herpes simplex virus. Standard bacterial cultures were also performed., Results: Laboratory testing detected a pathogen in 12 of the 16 males presenting with hematospermia. The sexually transmitted pathogens detected were herpes simplex virus in 5 patients (42%), Chlamydia trachomatis in 4 (33%), Enterococcus fecalis in 2 (17%), and Ureaplasma urealyticum in 1 (8%). In all cases in which a pathogen was identified, the appropriate antimicrobial agent was administered. Symptoms resolved for each patient following antimicrobial therapy. During a 1 year follow-up, all 12 patients remained free of disease., Conclusions: Recent advances in microbiologic diagnostic techniques have facilitated the detection of pathogens in patients with hematospermia, thereby enhancing the efficacy of treatment.

The incidence of transitional cell carcinoma (TCC), the fourth most common neoplasm diagnosed in men, is rising. Despite the development of several noninvasive diagnostic tests, none have gained full recognition by the clinicians. Gene expression profiling of tumors can identify new molecular markers for early diagnosis and disease follow-up. It also allows the classification of tumors into subclasses assisting in disease diagnosis and prognosis, as well as in treatment selection. In this paper, we employed expression profiling for molecular analysis of TCC. A TCC-derived cDNA microarray was constructed and hybridized with 19 probes from normal urothelium and TCC tissues. Hierarchical clustering analysis identified all normal urothelium samples to be tightly clustered and separated from the TCC samples, with 29 of the genes significantly induced (t-test, P<10(-5)) in noninvasive TCC compared to normal urothelium. The identified genes are involved in epithelial cells' functions, tumorigenesis or apoptosis, and could become molecular tools for noninvasive TCC diagnosis. Principal components analysis of the noninvasive and invasive TCC expression profiles further revealed sets of genes that are specifically induced in different tumor subsets, thus providing molecular fingerprints that expand the information gained from classical staging and grading.

Background: Seroepidemeliogic surveys have provided valuable information on the prevalence and incidence of herpes simplex virus-2 infection in general and in selected populations., Objective: To review the reliability of traditional diagnostic approaches in herpes simplex virus-2 infection., Methods: In this cross-sectional study, 472 patients attending a clinic for sexually transmitted disease in 1998-1999 were evaluated for HSV-2 infection through collection of epidemiologic and clinical data. HSV-2 infection was confirmed by the presence of specific viral glycoprotein, gG-2, antibody in sera., Results: The seroprevalence of HSV-2 among clinic attendees was 9.33%. Of these attendees only 22% presented with or reported a history of typical vesicular lesions in the genital area. Infection rate was higher in patients with multiple sex partners (20.8% vs. 8.7%, P < or = 0.0023), in individuals aged 30 or older (12.6 vs. 6.4%, P = 0.03) and in the Israeli Jewish population as compared to the Israeli Arab population (11.1% vs. 2.4%, P < or = 0.01). Females with multiple sex partners exhibited higher rates of infection than did their male counterparts (50 vs. 16.1%, P < or = 0.0275)., Conclusion: The findings support the need for HSV-2 serologic testing in patients presenting to STD clinics even when typical genital lesions are not evident but where risk factors for HSV-2 infection are identified.

Background: Non-gonococcal urethritis is the most common clinical diagnosis in men seeking care at clinics for sexually transmitted diseases., Objective: To identify the pathogens involved in NGU among males attending an Israeli STD clinic., Methods: During 19 months spanning September 1996 to July 1998 we investigated a cohort of 238 male patients attending the Bnai Zion Medical Center STD clinic with a clinical presentation of urethritis. Intraurethral swab specimens were tested for Neisseria gonorrhea, Ureaplasma urealyticum, Mycoplasma hominis, and Trichomonas vaginalis by culture and for herpes simplex virus by antigen detection. First voiding urine for C. trachomatis was done by polymerase chain reaction. The specific seropositivities of HSV types 1 and 2 were tested by enzyme-linked immunosorbent assay., Results: From among 238 males with dysuria or urethral discharge an etiology for urethritis was found for 71 (29.8%). N. gonorrhea was recovered in only three men (4.2%). In the remaining 68 NGU patients Chlamydia trachomatis (35/68, 51.5%) and U. urealyticum (31/68, 45.6%) were the most common infecting and co-infecting pathogens (P < 0.0001). M. hominis and T. vaginalis were found in 9/68 (13.2%), and 1 patient, respectively. HSV was recovered from the urethra in 7/68 males (10.3%)--3 with HSV-1, 2 with HSV-2, and 2 were seronegative for HSV. None of these males had genital lesions. Although a single etiologic agent was identified in 45/68 infected men (66.2%), co-infection was common: 2 organisms in 15 (22%) and 3 organisms in 8 (11.8%)., Conclusion: C. trachomatis and U. urealyticum were the most common infecting and co-infecting pathogens in this cohort of men with NGU. Unrecognized genital HSV infections are common in males attending our STD clinic, and symptomatic shedding of HSV occurs without genital lesions. Still, the microbial etiology in this group remains unclear in many patients despite careful microbiologic evaluation.

Background: The bladder tumor antigen stat is a simple and fast one-step immunochromatographic assay for the detection of bladder tumor-associated antigen in urine., Objectives: To evaluate the BTA stat in non-bladder cancer patients in order to identify the categories contributing to its low specificity., Methods: A single voided urine sample was collected from 45 patients treated in the urology clinic for conditions not related to bladder cancer. Each urine sample was examined by the BTA stat test and cytology., Results: The overall specificity of the BTA stat test was 44%, which was significantly lower than that of urine cytology, 90%. The false positive rates for the BTA stat test varied among the different clinical categories, being highest in cases of urinary tract calculi (90%), and benign prostatic hypertrophy (73%). Exclusion of these categories from data analysis improved BTA stat specificity to 66%., Conclusions: Clinical categories contributing to low BTA stat specificity can be identified, and their exclusion improves the specificity of this test.