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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.

This study aimed to determine whether fatalistic beliefs were associated with elevated levels of glycated hemoglobin (HbA1c) and to establish the role of religiosity in this relationship. A cross-sectional survey was conducted on a sample of 183 Jewish adults with diabetes visiting a large medical center in northern Israel. Self-administered questionnaires assessed level of religiosity, fatalistic beliefs, diabetes management behaviors, and demographic/personal characteristics; laboratory tests were used to measure HbA1c. Multivariate regression indicated that fatalism was significantly associated with HbA1c (β = 0.51, p = 0.01). The association was no longer statistically significant after including self-reported religiosity in the model (β = 0.31, p = 0.13). This phenomenon is likely due to a confounding relationship between the religious/spiritual coping component of the fatalism index and self-reported religiosity (r = 0.69). The results indicate that addressing fatalistic attitudes may be a viable strategy for improving diabetes management, but call for a better understanding of the interplay between religiosity and fatalism in this context.

Introduction: Several prostatic stents were developed in the last three decades, none of which were able to provide a real alternative in patients unfit or unwilling to undergo classical prostatic surgeries. In this study, we report the results of the use of a newly developed prostatic stent--the Allium™ Triangular Prostatic Stent (TPS)., Patients and Methods: The Allium TPS is a highly flexible, nitinol-built polymer-covered stent, which prevents tissue ingrowth and reduces encrustations. Between 2008 and 2014, at two centers (Israel and Turkey), the stent was inserted under local or regional anesthesia in 51 patients with benign prostatic obstruction (BPO) who are unwilling or unfit for surgery. Patients were followed for 12 months from surgery. The primary outcome was symptom improvement as measured by the international prostate symptom score (IPSS) and improvement in peak urinary flow., Results: Stent insertion was successful in all patients. The mean IPSS decreased from 26.4 to 7.7 on the last follow-up. The mean peak flow increased from 5.5 mL/second before stent insertion to 16.0 mL/second 1 year thereafter. The main adverse effect was transient pain in nine patients. No stent migration or obstruction was seen. Patients reported satisfaction and improvement in quality of life., Conclusion: Our short-term results show that Allium TPS is safe and effective for the treatment of patients with BPO.

Introduction: The increase in the use of imaging studies led to an increase in the diagnosis of small renal masses. However, most of the small renal masses are asymptomatic, grow slowly, and will not metastasize due to their relative benign biology. We still cannot differentiate malignant from benign masses using imaging studies, hence there is a dilemma between excision and follow-up., Objective: To report our intermediate-term results of active surveillance in patients with small renal masses in our urology department at the Bnai-Zion Medical Center., Patients and Methods: Retrospective analysis of 70 patients diagnosed at our department with renal mass < 4cm in its maximal diameter between 2003 and 2012. The maximal diameter of the masses at diagnosis was measured using computed tomography and diameter was recorded during follow-up., Results: Seventy patients with 78 small renal masses met the inclusion criteria. Mean age at diagnosis was 68 years. The mean folow-up period was 34 months; 54 of 78 masses grew in size, of them 8 were excised. All patients who had surgery had a nephron-sparing procedure. The growth rate and the size at diagnosis were both higher in the group of patients who underwent surgery., Conclusion: Most of the small renal masses can be managed safely by active surveillance., Discussion: Only 4% of the masses were upstaged, and none to stage > 2. None of the patients developed metastasis or died from renal cancer during the follow-up period., Summary: Active surveillance is a safe and reliable option for some patients with small renal mass.

Non-muscle invasive bladder cancer (NMIBC) has a high tendency for recurrence and progression. Currently, all known intravesical agents are associated with adverse effects (AEs) and limited efficacy. The combination of hyperthermia (HT) with intravesical Mitomycin C (MMC) chemotherapy has been shown to improve outcomes. The added efficacy of HT to MMC was first shown in preclinical studies. The reports on patients with NMIBC have indicated that the treatment is safe and well tolerated. Several clinical studies reported the efficacy of radiofrequency-induced chemotherapy effect (RITE) in the treatment of patients with NMIBC. This modality was shown to be superior to MMC alone. RITE was effective also in patients with high-risk NMIBC, including those who failed Bacillus Calmette-Guérin (BCG). This study provides an updated review of literature regarding the use of RITE in patients with NMIBC.

Introduction: Chronic ureteral stricture and ureteral fistula are treated with urinary diversion using percutaneous nephrostomy or double pigtail stent. Both of these techniques require replacement of the tube every few months in order to prevent encrustations and obstruction., Objectives: To report the long-term efficacy of the new Allium Ureteral Stent (URS) in the treatment of ureteral stricture and fistula., Methods: The Allium URS is a newly-developed ureteral stent made of nickel-titanium (Nitinol), which is inserted in a small diameter and spontaneously expands into and preserves a large-caliber. The stent is coated with a biochemical co-polymer which prevents tissue ingrowth and incrustations. The stent is inserted antegradely or retrogradely with intraoperative x-ray guidance after dilation of the stricture. The Allium URS stent was inserted into 107 ureters of 92 patients in 5 different centers worldwide; 69 patients carried a percutaneous nephrostomy before the procedure and 38 patients had a ureteral stent. The etiologies underlying the strictures were: gynecological cancer (with or without irradiation), bladder cancer, iatrogenic stricture, ureteroileal stenosis, stricture following uretero-pelvic junction obstruction repair and iatrogenic ureteral fistula., Results: During a mean follow-up of 27 months, only one stent was obstructed after eleven-indwelling months; 21 patients died of their primary disease carrying the stent. Stent migration was seen in 11 patients within 8 months after its insertion, and these stents were removed. In 4 patients with early stent migration, the stents were replaced. In 18 patients the stents were removed as planned after one year of indwelling time, and these patients were asymptomatic in a follow-up period of up to 59 months., Conclusion: The results of our study show that the use of Allium URS for the treatment of ureteral strictures is feasible, safe and effective. The relative ease of its insertion could encourage its use in a wide range of other indications., Discussion: Due to its unique structure, the Allium URS is superior to the regular pigtail stents in the treatment of ureteral strictures. Stent migration was seen in only 10.7% of the patients, mainly in patients with stricture of the mid-ureter., Summary: The use of the Allium URS stent in the treatment of proximal and distaL ureteral strictures is safe and effective.

Purpose: Interruption of renal blood flow is often necessary during nephron sparing surgery (NSS) and can induce renal injury. This study examines whether tadalafil, a phosphodiesterase-5 (PDE-5) inhibitor and well-known vasodilator, exerts nephroprotective effects in patients undergoing NSS., Methods: This non-randomized study included 49 patients with enhancing solid renal mass. All patients were subjected to open NSS during which clamping the renal artery was performed. Twenty-two patients were pretreated with tadalafil 1 day prior NSS and 2 days following surgery. The other 27 patients underwent the same surgical procedure but did not receive tadalafil (controls). Urine samples were collected before surgery and following renal pedicle clamp removal. Urine levels of NGAL and KIM-1, two novel biomarkers for acute kidney injury (AKI), were determined., Results: Clamping the renal artery induced kidney dysfunction as reflected by increases in urinary NGAL and KIM-1 in all participants. These increases in urinary NGAL and KIM-1 excretion were evident 1 h after renal ischemia and lasted for 72 and 24 h, respectively. Pretreatment with tadalafil reduced the absolute urinary excretion of KIM-1, but not of NGAL. Although the incidence of AKI was comparable between tadalafil-treated and untreated NSS subjects, the elevation in serum creatinine (SCr) was significantly attenuated in tadalafil-treated group as compared with NSS controls., Conclusions: Tadalafil exerts nephroprotective effects in AKI following NSS, as was evident by reduced urinary excretion of KIM-1 and attenuation of SCr elevation. Carefully controlled large clinical studies are needed before defining the role of PDE-5 inhibition therapy in these patients.

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.

Objective: To present our long-term functional and oncological outcomes in open nephron-sparing surgery for complex renal masses., Patients and Methods: We enrolled 584 patients who underwent open partial nephrectomy between January 1995 and May 2014 at our institution; 108 (18.4%) patients had hilar or completely intraparenchymal tumors or both. We compared change in renal function, perioperative complications, and survival outcomes between complex and noncomplex renal masses., Results: Mean tumor diameter was 4.3 and 3.5cm in patients with hilar and completely intraparenchymal lesions, respectively. R.E.N.A.L. nephrometry scores were significantly higher in patients with complex tumors as compared with patients with exophytic tumors. There was no significant difference between mean estimated glomerular filtration rate at last follow-up compared with preoperative mean estimated glomerular filtration rate in any of the groups. The incidence of perioperative complications was similar across all patients groups. Estimated 10-year cancer-specific survival probabilities were 100% in patients with hilar and intraparenchymal tumors. The 10-year recurrence-free survival probabilities were 96% and 95% in patients with hilar and intraparenchymal tumors, respectively. The main limitations include retrospective design and the lack of kidney-specific functional scan., Conclusion: Open nephron-sparing surgery should be considered for complex renal masses yielding excellent functional and oncological outcomes without higher incidence of complications., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: Neutrophil-to-lymphocyte ratio (NLR) predicts advanced stage disease and decreased survival in patients undergoing radical cystectomy for urothelial carcinoma of the bladder. The predictive value of NLR in non-muscle-invasive bladder cancer (NMIBC) has not been well studied. We aimed to evaluate whether NLR predicted disease recurrence and progression in NMIBC., Materials and Methods: The medical records of 122 consecutive, newly diagnosed, patients with NMIBC treated with transurethral tumor resection, between the years 2003 and 2010, were reviewed. Patients with hematological malignancies (n = 4) and without preoperative NLR (n = 11) were excluded. Cutoff points for NLR were tested separately for recurrence and progression using the standardized cutoff-finder algorithm. Univariate and multivariate Cox regression analyses were used to evaluate the association between NLR and disease recurrence and progression., Results: The study cohort comprised 91 men and 16 women at a median age of 68 years. The median NLR was 2.85 (interquartile range: 2-3.9). In total, 68 patients (64%) had an NLR>2.41. Patients with NLR>2.41 were more often men (P = 0.02) and had T1 category tumors (P = 0.034). Analyzed as a continuous variable, higher NLR showed a weak positive association with high tumor grade (R = 0.21, P = 0.028). The median follow-up for patients without disease recurrence was 40 months (interquartile range: 23-51). The estimated 3-year progression-free survival rate in patients with an NLR>2.41 was 61%, compared with 84% in patients with an NLR≤2.41 (P = 0.004). On multivariate analysis, an NLR>2.41 (hazard ratio [HR] = 3.52; 95% CI: 1.33-9.33; P = 0.012) and high-risk tumors compared with low-intermediate-risk tumors (HR = 4.83; 95% CI: 1.31-17.77; P = 0.018), as defined by the European Organization for Research and Treatment of Cancer risk tables, were associated with disease progression. An NLR>2.43 (HR = 1.75; 95% CI: 1.05-2.92; P = 0.032) and treatment with intravesical instillations (HR = 0.49; 95% CI: 0.28-0.85; P = 0.011) were associated with disease recurrence on multivariate analysis., Conclusions: NLR is an independent predictor of disease progression and recurrence in patients with NMIBC without hematological malignancies. Prospective studies are required to validate the role of NLR as a prognostic marker in NMIBC., (Copyright © 2014 Elsevier Inc. All rights reserved.)

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.

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.

Purpose: NGAL and KIM-1 are suggested to play a key role in the carcinogenesis and progression of renal cell carcinoma. Attention is currently focused on the potential use of the urinary level of NGAL and KIM-1(uNGAL and uKIM-1, respectively) in making an early diagnosis, establishing a prognosis and determination of the histologic characteristics., Methods: Forty-six patients underwent surgical treatment for renal lesions (n = 37) and for non-functioning kidney (n = 9). uNGAL and uKIM-1 levels were evaluated for clear cell, papillary and chromophobe subtypes of renal cancer patient and also for the control patients. The concentrations were determined by ELISA., Results: uNGAL and uKIM-1 in the control group were not significantly different from those of the patients with kidney cancer. There was no association between tumor size or histologic grade and the uNGAL and uKIM-1 levels. All patients with papillary type RCC had KIM-1 level below 2 ng/mgUcr and uNGAL concentration above 50 ng/mgUcr. Using the same threshold values enables prediction of 100% of patients with chromophobe subtype; 91.6% of the patients with clear cell histology have uNGAL concentration below 50 ng/mgUcr and KIM-1 concentration below 5 ng/mgUce., Conclusion: Combined analysis of uNGAL and uKIM-1 allowed high prediction rate of the histologic subtype of the radiographic-detected masses among cases with kidney cancer. These biomarkers may enable to select the proper therapeutic agents in cases with metastatic disease without the need of pretreatment biopsy.

Unlabelled: WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Recurrence and progression prediction in urothelial cancer is currently based on clinical and pathological factors: tumour grade, tumour stage, number of lesions, tumour size, previous recurrence rate, and presence of concomitant carcinoma in situ. These factors are not specific enough to predict progression and ∼50% of patients diagnosed as high risk in fact do not progress within 3 years. Patient follow-up is both expensive and unpleasant (frequent invasive cystoscopies). Molecular biomarkers, including microRNAs have been studied to provide additional prognostic information for these patients, but to date no molecular biomarker has become the 'gold standard' for patient diagnosis and follow-up. We used Rosetta Genomics' highly specific microRNA expression profiling platforms to study the prognostic role of microRNAs in bladder cancer. Using microdissection we chose specific tumour microRNAs to study in order to avoid background contamination. Tumour progression was associated with altered levels of microRNAs. In particular, high expression levels of miR-29c* were associated with a good prognosis. The study found that the use of microRNAs for determining progression and invasiveness for patients with urothelial cancer could potentially have a substantial impact on the treatment and follow-up individual patients., Objective: To identify microRNAs that could be useful as prognostic markers for non-muscle-invasive (NMI) bladder carcinoma., Patients and Methods: Formalin-fixed, paraffin-embedded samples of 108 NMI bladder carcinomas, and 29 carcinomas invading bladder muscle were collected, and microRNA expression levels were measured using microarrays. For 19 samples, microdissection was performed to compare microRNA expression between the tumour and surrounding tissue. MicroRNAs that were found to be unrelated to the tumour itself were excluded as potential prognostic markers., Results: Expression profiles identified microRNAs that were differentially expressed in NMI tumours from patients who later progressed to carcinoma invading bladder muscle compared with NMI tumours from patients that did not progress. The microRNA profile of tumours invading the bladder muscle was more similar to that of NMI tumours from patients who later progressed, than to that of the same-stage NMI tumours from patients who did not later progress. The expression level of one microRNA, miR-29c*, was significantly under-expressed in tumours that progressed and could be used to stratify patients with T1 disease into risk groups., Conclusions: MicroRNAs can be useful biomarkers for prognosis in patients with urothelial carcinoma. In our study, expression levels of several microRNAs, including miR-29c* identified high- and low-risk groups. These biomarkers show promise for the stratification of patients with bladder cancer., (© 2013 BJU International.)

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.

Purpose: Nephron sparing surgery is considered the treatment of choice in most patients with confined renal cancer. Interrupting renal blood flow is often necessary during such surgery, which can induce significant renal injury. We explored the possibility of using urinary NGAL and KIM-1 excretion as novel biomarkers to assess the extent of acute kidney injury after nephron sparing surgery., Materials and Methods: The study group included 27 patients who underwent open nephron sparing surgery for enhancing solid renal tumors. During surgery the renal artery was clamped for between 6 and 47 minutes. Urine samples were collected before surgery, and 1, 3, 8, 24, 48 and 72 hours after renal pedicle clamp removal. Urinary levels of NGAL and KIM-1 were determined., Results: Renal artery clamping induced renal injury, as reflected by increased urinary NGAL and KIM-1 in all participants. These increases in urinary NGAL excretion were evident after 1 hour of renal ischemia and lasted for 72 hours. Urinary NGAL correlated with the serum creatinine increase and ischemia duration. Compared with patients without significantly increased serum creatinine, those with significantly increased serum creatinine after nephron sparing surgery had a greater increase in urinary NGAL but not in KIM-1., Conclusions: Renal injury severity after nephron sparing surgery could be quantitatively assessed by measuring urinary NGAL and KIM-1., (Copyright © 2013 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

A healthy diet and good eating behaviors are essential components of long-term success in weight maintenance after bariatric surgery. Although rates of revised bariatric surgery have increased, data on subsequent behavioral outcomes are sparse. The aim of our study was to investigate behavioral outcomes following revised laparoscopic sleeve gastrectomy (R-LSG) that was indicated for failed laparoscopic adjustable gastric banding and compare with outcomes following primary laparoscopic sleeve gastrectomy (P-LSG). Twelve patients who underwent R-LSG and 25 patients who underwent P-LSG between 2007 and 2009 in our medical center completed a questionnaire that assessed weight loss, eating behaviors, physical activity, food tolerance, and satisfaction. The average time elapsed since the operation was 18 months for both groups. In the R-LSG group, more patients reported non-normative eating patterns and less healthy food selection than in the P-LSG group. Food tolerance and satisfaction were also lower after R-LSG. Engagement in regular physical activity increased from 0 to 16.7 % in the R-LSG group and from 8 to 33 % in the P-LSG group. After R-LSG, 58 % reported eating at scheduled times, compared with 85 % after P-LSG. Levels of healthy food selection, food tolerance, normative eating patterns, and physical activity were lower in the R-LSG group than in the P-LSG group. This study highlights the need to develop pre- and post-surgery treatment that would promote better behavioral outcomes in the growing number of individuals undergoing repeat bariatric surgery.

Purpose: The primary toxic effects of methotrexate (MTX) are myelosuppression and/or intestinal mucositis. The objective of the present study is to investigate the effect of MTX on germ cell apoptosis and spermatogenesis in a rat., Methods: Male Sprague-Dawley rats were divided into three experimental groups: control rats treated with vehicle; MTX-2 rats treated with one dose (20 μg/kg) of MTX given IP and killed on the second day; and MTX rats treated with IP MTX (20 μg/kg) and killed on day 4. Johnsen's criteria and the number of germinal cell layers in the testes were used to categorize the spermatogenesis. TUNEL assay was used to determine germ cell apoptosis. Western blotting was used to determine Bax and Bcl-2 protein levels. Statistical analysis was performed using the non-parametric Kruskal-Wallis ANOVA test, with p less than 0.05 considered statistically significant., Results: On day 2, MTX-treated animals demonstrated minimal changes in the histological parameters of spermatogenesis, but germ cell apoptosis increased significantly (threefold increase, p = 0.002) compared to control rats. On day 4, MTX-treated rats demonstrated a trend toward a decrease in germ cell apoptosis, compared to day 2, and showed histological signs of impaired spermatogenesis (decreased number of germ cell layers and Johnsen's criteria). A significant increase in cell apoptosis in MTX-treated rats was correlated with higher Bax/Bcl-2 protein levels., Conclusions: MTX induced germ cell apoptosis and impaired spermatogenesis in rat testes.

Background and Purpose: Ureteral strictures (US) can be a recurrent chronic illness that leads to severe side effects and poor quality of life. Several options to treat US exist, including repeated dilations, stents, minimally invasive reconstructive surgeries, and urinary diversion or nephrectomy. Placement of an ureteral stent is a good minimally invasive option but has major limitations, such as stent migration, mucosal in-growth, incrustations, and stent obstruction. Our study aim was to evaluate the safety and the efficacy of a new self-expanding, large caliber ureteral stent (Allium(®))., Patients and Methods: During 2005 to 2011, 49 stents were inserted in 49 renal units (40 patients) for a mean indwelling time of 17 months (range 1-63 mos)., Results: Migration was observed in seven (14.2%) patients, mandating stent removal. Only one stent was occluded. In eight renal units, the stents were removed as scheduled, and no reobstruction was detected during follow-up. Twenty-eight patients currently have a patent stent., Conclusions: The Allium stent provides an attractive solution for long-term internal ureteral drainage. Its design allows good anchoring, prevents intraluminal ingrowth, and has the ability of rapid disintegration for extremely easy removal.

Aim: Owing to the limited efficacy and significant toxicity of most topical intravesical agents for the management of nonmuscle invasive bladder cancer (NMIBC), a search for new therapeutic modalities continues. This study evaluates the safety and efficacy of a relatively new modality, combined intravesical chemotherapy and hyperthermia, using the intravesical chemohyperthermia system., Methods: The data summarize our 10 years of experience in the Department of Urology at Bnai Zion Medical Center, Israel. Ninety two patients with NMIBC (88 evaluable) were treated according to the adjuvant (66 patients) and the neoadjuvant (26 patients) protocols, with up to 7 years follow-up., Results: Over the follow-up period, 56 out of 64 patients (72%) treated according to the adjuvant protocol remained free from recurrences. The progression rate was 4.7% (three out of 64 patients). An initial complete response was documented in 19 out of 24 patients (79%) treated according to the neoadjuvant protocol. During the follow-up period, 16 out of these 19 patients (84%) remained free from recurrences. All of the recurrences in this group had stage Ta grade 1 tumors., Conclusion: Microwave-induced chemohyperthermia is a safe and effective treatment option for patients with NMIBC, both in the adjuvant and neoadjuvant settings. The use of this treatment modality did not expose the patients to an increased risk of progression.

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.

Context: Due to the suboptimal clinical outcomes of current therapies for non-muscle-invasive bladder cancer (NMIBC), the search for better therapeutic options continues. One option is chemohyperthermia (C-HT): microwave-induced hyperthermia (HT) with intravesical chemotherapy, typically mitomycin C (MMC). During the last 15 yr, the combined regimen has been tested in different clinical settings., Objective: To perform a systematic review to evaluate the efficacy of C-HT as a treatment for NMIBC., Evidence Acquisition: The review process followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. An electronic search of the Medline, Embase, Cochrane Library, CancerLit, and ClinicalTrials.gov databases was undertaken. Relevant conference abstracts and urology journals were also searched manually. Two reviewers independently reviewed candidate studies for eligibility and abstracted data from studies that met inclusion criteria. The primary end point was time to recurrence. Secondary end points included time to progression, bladder preservation rate, and adverse event (AE) rate., Evidence Synthesis: A total of 22 studies met inclusion criteria and underwent data extraction. When possible, data were combined using random effects meta-analytic techniques. Recurrence was seen 59% less after C-HT than after MMC alone. Due to short follow-up, no conclusions can be drawn about time to recurrence and progression. The overall bladder preservation rate after C-HT was 87.6%. This rate appeared higher than after MMC alone, but valid comparison studies were lacking. AEs were higher with C-HT than with MMC alone, but this difference was not statistically significant., Conclusions: Published data suggest a 59% relative reduction in NMIBC recurrence when C-HT is compared with MMC alone. C-HT also appears to improve bladder preservation rate. However, due to a limited number of randomized trials and to heterogeneity in study design, definitive conclusions cannot be drawn. In the future, C-HT may become standard therapy for high-risk patients with recurrent tumors, for patients who are unsuitable for radical cystectomy, and in cases for which bacillus Calmette-Guérin treatment is contraindicated., (Copyright © 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Objectives: Non-muscle invasive bladder cancer (NMIBC) classified as T1G3 represents one of the most challenging issues in urologic oncology. Although it is still considered a lesion amenable for conservative management, the risk for recurrence and progression remains high. The aim of this study was to define both recurrence and progression rate in patients with T1G3 UCC treated by complete transurethral resection (TURT) and adjuvant thermochemotherapy approach., Materials and Methods: We retrospectively evaluated the clinical data of patients with T1G3 NMIBC who underwent TURT followed by thermochemotherapy (TCT) treatment. Data recorded included age, gender, previous resections, previous intravesical treatment, time to tumor recurrence, and progression. TCT was given once weekly for 6 consecutive weeks, followed by 6 maintenance sessions at 4 to 6 weeks intervals. During each treatment session, 40 mg of mitomycin C (MMC) was instilled into the bladder in combination with bladder wall hyperthermia of 42 ± 2 °C for 60 minutes. Follow-up cystoscopy and urinary cytology were performed every 3 months for the first 2 years and than biannually., Results: A total of 56 T1G3 patients were treated with adjuvant TCT treatment at 7 urologic centers. Mean age was 68 years (range 35-91), 10 were females and 46 were males. Twenty-six patients failed on at least 1 previous intravesical treatment. Five patients who dropped out due to adverse events before reaching the first outcome evaluation cystoscopy were referred to another intravesical therapy, and were therefore excluded from the current analysis. A total 51 patients were available for analysis. Median follow-up time of tumor-free patients was 18 months (average 20, range 2-49 months). Seventeen patients (33.3%) had tumor recurrence and 4 of them progressed to muscle invasive disease. The median time to recurrence was 9 months (average 11, range 2-31 months). The Kaplan-Meier estimated recurrence rate for this group is: 42.9% at 2 years, 51.0% at 4 years., Conclusions: TCT can be an effective adjuvant treatment option after TURT to prevent recurrence in patients with T1G3 NMIBC. Progression rate after this treatment was low (7.9%). TCT treatment was documented to be effective also in those who failed previous intravesical BCG. Treatment was confirmed to be safe and well tolerated., (Copyright © 2011 Elsevier Inc. All rights reserved.)

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.

Background: Success in maintaining weight loss after bariatric surgery requires the ability to implement long-term changes in eating habits and lifestyle. However, no data are available on patients' eating ability and behavioral aspects after laparoscopic sleeve gastrectomy., Methods: A total of 60 patients who had undergone laparoscopic sleeve gastrectomy from 2007 to 2009 completed a questionnaire on habits, weight loss, health behaviors (e.g., physical activities, meal schedules), food selection, food tolerance, eating style, and satisfaction with personal changes. The patients were divided into 2 groups: those with <1 year of postoperative follow-up (group 1, n = 35) and those with >1 year of postoperative follow-up (group 2, n = 25)., Results: The percentage of excess weight loss was 66.9% ± 21.6% and 70.9% ± 15.3% for groups 1 and 2, respectively. Most of the patients reported changing their eating habits, eating regular solid food, engaging in physical activity, and taking multivitamins. A trend was seen toward greater rates of healthy food consumption on a daily basis and significantly better food tolerance over time. The data showed lower rates of health-promoting behavior and diet restraint with longer follow-up. Both groups reported high satisfaction with the results of their surgery. Group 1 demonstrated a greater level of self-confidence than group 2 about controlling their new weight., Conclusion: Patients have the ability to maintain a healthy diet beyond the first year after laparoscopic sleeve gastrectomy. These findings also underline the importance of long-term maintenance programs., (Copyright © 2011 American Society for Metabolic and Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)

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 .

Heparanase up-regulation was documented in an increasing number of human carcinomas, associated with poor prognosis. The purpose of the current study was to identify mechanisms responsible for heparanase induction. We provide evidence that heparanase expression is regulated at the post-transcriptional level by sequences at the 3' untranslated region (3' UTR) of the gene. Constructing the 3' UTR immediately following the heparanase cDNA reduces heparanase enzymatic activity and protein levels, resulting in decreased cellular invasion capacity. We further identified a 185-bp sequence within the 3' UTR that mediates heparanase down-regulation, and characterized an adenine (A)/uracil (U)-rich consensus element (ARE) within this region. Deletion of the entire 185-bp region or the ARE eliminated the inhibitory effect of the 3' UTR, resulting in elevated heparanase levels and formation of larger tumor xenografts indistinguishable from those produced by heparanase-overexpressing cells in terms of size, vascularization, and Akt activation. These results suggest that loss of the ARE is an important regulatory mechanism contributing to heparanase induction in human cancer.

There is an abundant literature on the adverse effects of solvents on the neurobehavioral performance, higher brain functions, and chronic solvent-induced encephalopathy. However, the occurrence of solvent-related schizophrenia is rare, with few reports on the link between solvent exposure and schizophrenia. Here, we report on a patient with schizophrenia, presenting after a sustained period of 6 months of everyday exposure to neurotoxic solvents in an unprotected occupational setting in Haifa, Israel. In light of the similarity of symptoms of schizophrenia and chronic solvent encephalopathy, we call for further epidemiologic studies to examine the potential contribution of solvent exposure to the etiology and evolution of schizophrenia in selected cases. This case study and review of relevant literature underscores the importance of obtaining detailed histories on occupational exposures to search for agents which can trigger psychotic episodes. In the meantime, policies to prevent such exposures at the source can be expected to contribute to the prevention of a non-trivial proportion of neurotoxic diseases, including, possibly, schizophrenia in worker populations., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Heparanase is a mammalian endo-beta-d-glucuronidase that can cleave heparan sulfate side chains, an activity strongly implicated in tumor cell dissemination. The current study aimed to identify and characterize heparanase splice variants. LEADS, Compugen's alternative splicing modeling platform (Compugen, Tel Aviv, Israel), was used to search for splice variants in silico; tumor-derived cell lines (i.e., CAG myeloma) and tumor biopsies were utilized to validate T5 expression in vivo; signaling (i.e., Src phosphorylation) was evaluated following T5 gene silencing or overexpression and correlated with cell proliferation, colony formation, and tumor xenograft development. A novel spliced form of human heparanase, termed T5, was identified. In this splice variant, 144 bp of intron 5 are joined with exon 4, which results in a truncated, enzymatically inactive protein. T5 overexpression resulted in increased cell proliferation and larger colonies in soft agar, mediated by Src activation. Furthermore, T5 overexpression markedly enhanced tumor xenograft development. T5 expression is up-regulated in 75% of human renal cell carcinoma biopsies examined, which suggests that this splice variant is clinically relevant. Controls included cells overexpressing wild-type heparanase or an empty plasmid and normal-looking tissue adjacent the carcinoma lesion. T5 is a novel functional splice variant of human heparanase endowed with protumorigenic characteristics.-Barash, U., Cohen-Kaplan, V., Arvatz, G., Gingis-Velitski, S., Levy-Adam, F., Nativ, O., Shemesh, R., Ayalon-Sofer, M., Ilan, N., Vlodavsky, I. A novel human heparanase splice variant, T5, endowed with protumorigenic characteristics.

Background: The occurrence of positive surgical margins (PSMs) after partial nephrectomy (PN) is rare, and little is known about their natural history., Objective: To identify predictive factors of cancer recurrence and related death in patients having a PSM following PN., Design, Setting, and Participants: Some 111 patients with a PSM were identified from a multicentre retrospective survey and were compared with 664 negative surgical margin (NSM) patients. A second cohort of NSM patients was created by matching NSM to PSM for indication, tumour size, and tumour grade., Measurements: PSM and NSM patients were compared using student t tests and chi-square tests on independent samples. A Cox proportional hazards regression model was used to test the independent effects of clinical and pathologic variables on survival., Results and Limitations: Mean age at diagnosis was 61+/-12.5 yr. Mean tumour size was 3.5+/-2 cm. Imperative indications accounted for 39% (43 of 111) of the cases. Some 18 patients (16%) underwent a second surgery (partial or total nephrectomy). With a mean follow-up of 37 mo, 11 patients (10%) had recurrences and 12 patients (11%) died, including 6 patients (5.4%) who died of cancer progression. Some 91% (10 of 11) of the patients who had recurrences and 83% of the patients (10 of 12) who died belonged to the group with imperative surgical indications. Rates of recurrence-free survival, of cancer-specific survival, and of overall survival were the same among NSM patients and PSM patients. The multivariable Cox model showed that the two variables that could predict recurrence were the indication (p=0.017) and tumour location (p=0.02). No other variable, including PSM status, had any effect on recurrence. None of the studied parameters had any effect on the rate of cancer-specific survival., Conclusions: PSM status occurs more frequently in cases in which surgery is imperative and is associated with an increased risk of recurrence, but PSM status does not appear to influence cancer-specific survival. Additional follow-up is needed., (2009 European Association of Urology. All rights reserved.)

Purpose: Despite an initial adequate response many patients with nonmuscle invasive urothelial cell carcinoma of the bladder eventually have recurrence after intravesical bacillus Calmette-Guerin treatments. We evaluated the efficacy of combined bladder wall hyperthermia and intravesical mitomycin C instillation (thermo-chemotherapy) in cases of recurrence after bacillus Calmette-Guerin., Materials and Methods: A total of 111 patients with recurrent papillary nonmuscle invasive urothelial cell carcinoma of the bladder after previous bacillus Calmette-Guerin treatment underwent complete bladder tumor resection and were referred for prophylactic adjuvant treatment with thermo-chemotherapy. Treatment was received on an outpatient basis weekly for 6 weeks, followed by 6 maintenance sessions at 4 to 6-week intervals. Each treatment included 2, 30-minute cycles of 20 mg mitomycin C and bladder wall hyperthermia to 42C +/- 2C. Cystoscopy and urine cytology were performed after the completion of induction treatment and every 3 months thereafter., Results: The Kaplan-Meier estimated disease-free survival rate was 85% and 56% after 1 and 2 years, respectively. No maintenance treatment was associated with decreased efficacy, that is the recurrence rate was 61% at 2 years vs 39% in those with maintenance treatments (p = 0.01). The progression rate was 3%., Conclusions: Thermo-chemotherapy may be effective for papillary nonmuscle invasive urothelial cell carcinoma of the bladder that recurs after BCG treatment without increasing the risk of tumor progression. Maintenance therapy is important and improves the outcome.

Objectives: To study the results of chemotherapy combined with intravesical hyperthermia in patients with mainly BCG-failing carcinoma in situ (CIS)., Methods: Patients with histologically confirmed CIS were included retrospectively. Outpatient thermochemotherapy treatment was done with mitomycin-C (MMC) and the Synergo system SB-TS 101 (temperature range between 41 and 44 degrees C), weekly for 6-8 weeks, followed by 4-6 sessions every 6-8 weeks., Results: Fifty-one patients were treated between 1997 and 2005 from 15 European centers. Thirty-four were pre-treated with BCG. Mean age was 69.9 years. Twenty-four patients had concomitant papillary tumors. The mean number of hyperthermia/MMC treatments per patient was 10.0. Of the 49 evaluable patients 45 had a biopsy and cytology proven complete response. In two patients CIS disappeared, but they had persistent papillary tumors. Follow-up of 45 complete responders showed 22 recurrences after a mean of 27 months (median 22): T2 (4), T1 (4), T1/CIS (1), CIS (5), Ta/CIS (2), Ta (5) and Tx (1). Side effects (bladder complaints) were generally mild and transient., Conclusions: In patients with primary or BCG-failing CIS, treatment with intravesical hyperthermia and MMC appears a safe and effective treatment. The initial complete response rate is 92%, which remains approximately 50% after 2 years.

Objective: To evaluate the diagnostic possibilities of CT virtual pneumoendoscopy, in various vesical and extra-vesical urinary tract abnormalities and suggest possible indications for this examination., Patients and Methods: Thirty-three patients (26 men and 7 women, aged 30-91, mean-61 years) were referred by the urologists for specific further evaluation of the urinary tract with virtual pneumoendoscopy for various indications. All patients except three underwent conventional endoscopy within a week either before or after the virtual examination, but the endoscopy was either equivocal or limited. The urinary tract was insufflated with room air., Results: Successful CT pneumoendoscopy was achieved in 31 of the 33 patients. The indications for the virtual study included obstructive uropathy (22), hematuria (15), and suspected fistula (2). The virtual examination findings included urethral stricture, recto-urethral fistula, multiple bladder tumors, bladder tumor invading the distal ureter or urethra, bladder diverticula containing a tumor, ureteral stricture, renal transitional cell carcinoma, and renal calculi with inflammation. Virtual CT endoscopy had added value to the diagnostic process in all our patients., Conclusion: In selected cases virtual CT pneumoendoscopy may serve as an important adjunctive diagnostic aid for urologic pathologies.

Purpose: The current use of cystoscopy for screening and detecting bladder cancer is invasive and expansive. Various urine based biomarkers have been used for this purpose with limited success. Metabolomics, ie metabonomics, is the quantitative measurement of the metabolic response to pathophysiological stimuli. This analysis provides a metabolite pattern that can be characteristic of various benign and malignant conditions. We evaluated high performance liquid chromatography coupled online with a mass spectrometer metabolomic approach to differentiate urine samples from healthy individuals and patients with bladder cancer., Materials and Methods: Urine specimens were collected from 48 healthy individuals and 41 patients with transitional cell carcinoma, and stored at -80C. Samples were analyzed using an Agilent 1100 Series high performance liquid chromatography system (Agilent Technologies, Santa Clara, California) coupled online with a hybrid triple-quad time-of-flight QSTAR XL mass spectrometer. At the time of analysis samples were thawed and centrifuged. The resulting total ion chromatograms of each sample were submitted for statistical analysis. For data interpretation in this study 2 statistical methods were used, that is principal component analysis and orthogonal partial least square-discriminate analysis., Results: Using positive ionization mass spectrometry orthogonal partial least square-discriminate analysis correctly predicted 48 of 48 healthy and 41 of 41 bladder cancer urine samples, while principal component analysis, which is an unsupervised profiling statistical method, confirmed these results and correctly predicted 46 of 48 healthy and 40 of 41 bladder cancer urine samples., Conclusions: The results of this proof of concept study in a relatively small number of subjects indicate that metabolomics using high performance liquid chromatography-mass spectrometry has the potential to become a noninvasive early detection test for bladder cancer.

Purpose: We assessed the efficacy of papaverine hydrochloride, a commonly used smooth muscle relaxant, for the treatment of renal colic as a single agent and in combination with sodium diclofenac., Materials and Methods: A prospective, single-blind clinical study was performed at 2 centers. A total of 86 patients with acute renal colic were randomized to 3 treatment groups of 120 mg intravenous papaverine hydrochloride (29), 75 mg intramuscular sodium diclofenac (30), and papaverine hydrochloride plus sodium diclofenac (27). Pain intensity was assessed with the Visual Analog Scale at 0, 20 and 40 minutes after treatment. Further analgesia given at patient request consisted of 1 mg/kg intramuscular meperidine. Urinalysis, complete blood evaluation and imaging were performed in all patients. All adverse effects were recorded., Results: Baseline characteristics were similar in the 3 groups. Pain intensity decreased significantly (p <0.01) after 20 and 40 minutes in all groups. Papaverine hydrochloride was as effective as sodium diclofenac in alleviating pain and the combined treatment group showed a slight trend of more rapid relief. Significantly more patients in the papaverine group required further analgesia and 4 patients (14.8%) reported minor adverse effects (dizziness in 3, sleepiness in 1)., Conclusions: Papaverine hydrochloride is as effective as sodium diclofenac for the short-term relief of acute renal colic pain and may be advantageous in patients with contraindications for nonsteroidal anti-inflammatory drugs. However, sodium diclofenac appears to provide a longer effective analgesia.

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.

Recent evidence suggests that apoptosis is involved in germ cell loss following testicular ischemia-reperfusion (IR) injury. Allopurinol (Allo) is as a free radical scavenger which prevents tissue damage caused by reperfusion and oxygenation after ischemia; however, its effect on apoptosis in this type of injury has not been studied. To examine the effect of allopurinol on germ cell apoptosis following testicular IR in a rat. Forty rats were divided randomly into 4 experimental groups of 10 rats each: group A (Sham)-Sham operated animals; group B (Sham-Allo)-Sham operated rats treated with allopurinol given PO (by gavage) at a dose of 200 mg/kg, once daily, immediately before and 24 h following operation; group C (IR)-rats underwent 90 min of unilateral testicular ischemia and 48 h of reperfusion; group D (IR-Allo)-rats underwent IR and were treated with allopurinol similar to group B. The ipsilateral and contralateral testes were harvested 48 h following operation. Johnsen's criteria and the number of germinal cell layers were used to categorize spermatogenesis. TUNEL assay was used to determine germ cell apoptosis. Statistical analysis was performed using one-way ANOVA test, with P < 0.05 considered statistically significant. Testicular ischemia in rats led to histological damage in the ipsilateral testis. In the contralateral testis minimal damage was observed. Treatment with allopurinol increased significantly Johnsen's score in both the ischemic (7.3 +/- 0.5 vs 5.6 +/- 0.5, P < 0.05) and contralateral (8.9 +/- 0.1 vs 8.3 +/- 0.2, P < 0.05) testis, compared to IR-animals. Germ cell apoptosis in both the ischemic and the contralateral testis increased significantly after IR. Treatment with allopurinol resulted in a significant decrease in germ cell apoptosis in the ipsilateral testis, expressed as the number of positive tubules per 100 tubules (AI-1, (apoptotic index) threefold decrease, P < 0.005) and the number of apoptotic cells per 100 tubules (AI-2, fivefold decrease, P < 0.005) as well as a significant decrease in germ cell apoptosis in the contralateral testis (AI-1, 3.5-fold decrease, P < 0.05, AI-2- sixfold decrease, P < 0.005) compared to IR animals. In a rat model of testicular IR, treatment with allopurinol decreases germ cell apoptosis in both ischemic and contralateral testes and improves spermatogenesis.

Objectives: To compare changes in renal function following nephron-sparing surgery (NSS) using tissue adhesive only versus NSS using standard suturing technique, as measured by quantitative SPECT of 99m Tc-dimercaptosuccinic acid uptake by the kidney (QDMSA)., Materials and Methods: QDMSA was done before and 3-6 mo after the operation in 32 patients who underwent standard suturing technique and in 24 patients in whom tissue adhesive sealant (19 with albumin glutaraldehyde tissue adhesive [BioGlue]; 5 with CoSeal) was used to close the parenchymal defect. Individual kidney uptake was measured and retrospectively compared between the two groups., Results: Average tumor diameter was 3.4cm (range: 2.2-6) in the suture group and 3.56 (range: 1.7-6) in the tissue sealant group. In the tissue sealant group following surgery, we observed an average individual renal function loss of 11.49% compared with the suture group in whom an average individual renal function loss of 20.36% (p = 0.02) was measured by 99m Tc-DMSA., Conclusions: The use of tissue sealant to close the parenchymal defect during NSS demonstrated a statistically significant advantage in reducing functioning renal loss as measured by the absolute uptake of QDMSA. Further clinical studies are required to establish the role of tissue sealants in NSS., (European Association of Urology.)

Objectives: Temporary occlusion of the renal artery during nephron-sparing surgery may facilitate complete tumor resection and reduce operative bleeding. However, it may also entail a greater risk of ischemic kidney damage. In contrast, when vascular occlusion is not applied, the risk of bleeding, as well as the risk of positive margins, may be increased. To study these issues, we retrospectively evaluated our results with nephron-sparing surgery for kidney masses using renal artery occlusion compared with patients in whom vascular occlusion was not applied., Methods: From 1988 to 2003, 301 consecutive patients underwent nephron-sparing surgery for a kidney mass at our institutions. At the surgeons' discretion, the renal artery was temporarily occluded in 181 patients (60%) and was not in 120 (40%)., Results: No statistically significant differences were found between the two groups regarding blood loss, transfusion rates, and overall complication rates. The loss of the renal unit because of ischemia was noted in 2 patients (1.2%) after renal artery occlusion and in none of the nonoccluded group. Positive tumor margins were found in 5 patients (4.2%) in the nonoccluded group and in 1 patient (0.6%) in the vascular occlusion group., Conclusions: Our results suggest that although vascular occlusion during nephron-sparing surgery may increase the risk of permanent kidney damage, patients with no vascular occlusion may have a greater risk of positive tumor margins after surgery. These two factors should be taken into consideration and could be discussed with the patient when attaining informed consent.

Aim: The aim of this study was to determine the effect of intravesical EDTA instillation on the development of intravesically implanted tumor cells in normal mice., Methods: The mouse bladder tumor (MBT-2) model was used in female C3H/eb mice to evaluate the amount of normal urothelial cell shedding, and the degree of tumor growth inhibition following intravesical EDTA instillation in comparison with phosphate-buffered saline (PBS) instillation., Results: At 1 h after instillation, the number of urothelial cells aspirated was 500-1000 per PBS-treated mouse and 10,000-20,000 per EDTA-treated mouse (P < 0.00001). The bladder weight, which reflected the effect of the agent on the tumor, was similar in the untreated and PBS-treated mice (105.46 +/- 46 mg and 106.2 +/- 50 mg, respectively). It was significantly lower in the EDTA-treated mice (80.4 +/- 42 mg) (P = 0.0045)., Conclusions: Intravesical administration of EDTA results in significant normal and neoplastic urothelial cell shedding. Intravesical irrigation with EDTA may prevent adherence of the malignant cells to the bladder wall following tumor resection.

Objectives: To determine the feasibility of using serum albumin glutaraldehyde tissue adhesive (BioGlue) to achieve hemostasis and prevent urine leakage during nephron-sparing surgery (NSS)., Methods: From February 1993 to April 2005, 174 NSS operations were performed for renal cell carcinoma at our institute. A total of 143 patients underwent NSS with the traditional suturing technique (suture group) and 31 patients underwent a sutureless BioGlue sealing-only procedure (BioGlue group). We compared the two groups for clinical and tumor characteristics and surgical outcome., Results: The patient and tumor characteristics were similar in both groups. The average maximal tumor diameter was 4.21 cm (range 2.2 to 7) for the suture group and 3.67 cm (range 2 to 6.8) for the BioGlue group. The use of BioGlue reduced the mean warm ischemic time by 8.8 minutes (17.2 versus 26 minutes, P = 0.002). The mean estimated blood loss was 45.1 mL in the BioGlue group and 111.7 mL in the suture group (P = 0.001). Blood transfusion was required in 1 patient (3.2%) of the BioGlue group and 24 (17%) in the suture group (P = 0.014). None of the patients treated with BioGlue developed urinary fistula compared with three (2%) in the suture group., Conclusions: Albumin glutaraldehyde tissue adhesive (BioGlue) alone provided adequate hemostasis during NSS, significantly decreasing the blood loss and transfusion rate, as well as the renal ischemic and operative times. BioGlue was easy to use and safe for sealing the kidney during partial nephrectomy. Future prospective clinical trials are necessary to validate its role during renal surgery.

Purpose: To measure the effect of PCNL on global and regional renal function using quantitative single-photon emission CT (SPECT) measurement of Tc-dimercaptosuccinic acid (DMSA) uptake by the kidneys (QDMSA)., Patients and Methods: A series of 47 male and 41 female patients with a mean age of 47 +/- 16 years were studied by sequential QDMSA examinations before and 1.5 to 24 months after PCNL. Among the 67 patients (76%) in whom PCNL was performed using upper- or lower-pole access, the function of the affected and nonaffected poles of the treated kidney was calculated separately., Results: There was no statistically significant difference in the uptake by the treated kidneys before versus after PCNL (11.9% +/- 5% v 11.6% +/- 5%; t = 0.9; P = 0.368). The total functional volume of the treated kidney was slightly decreased, from 235 cc +/- 62 cc to 224 cc +/- 59 cc (t = 2.7; P = 0.011). The percent of the injected isotope dose per cubic centimeter of tissue of the treated kidney was not affected (0.051 +/- 0.02 v 0.053 +/- 0.02; t = 0.86; P = 0.296). Regional assessment revealed a statistically significant decrease in the functional volume at the PCNL port of entry (91 cc +/- 30 cc v 82 cc +/- 27 cc; t = 2.64; P = 0.013). Regarding the percent of the injected dose per cubic centimeter of renal tissue, no statistically significant difference was found between the area of the kidney that underwent PCNL and the untreated area of the same kidney (0.049 +/- 0.02 v 0.05 +/- 0.02; t = 0.693; P = 0.494). The function of the contralateral kidneys remained unchanged (13.4% +/- 5.2% v 13.6% +/- 4.8%; t = 0.68; P = 0.5)., Conclusions: Despite the statistically significant decrease in the functional volume of the surgically treated region, neither total percent uptake nor percent of injected dose were reduced significantly. Further studies with long-term follow-up of treated kidneys are required.

Recent evidence suggests that enhanced cell apoptosis is responsible for germ cell loss following testicular ischemia-reperfusion (IR) injury. A nonsteroidal anti-inflammatory drug diclofenac sodium (Voltaren) is a prostaglandin-synthesis inhibitor, which is widely used in many testicular disorders. The purpose of the present study was to examine the effect of diclofenac (DIC) on germ cell apoptosis in the ischemic and contralateral testes following testicular IR in a rat. Forty rats were divided randomly into four experimental groups of ten rats each: group A (Sham)-Sham operated animals; group B (Sham-DIC)-Sham operated rats that were treated with DIC given subcutaneously at a dose of 10 mg/kg, once daily, 24, 48 and 72 h following operation; group C (IR) underwent 90 min of unilateral testicular IR; group D (IR-DIC)-rats underwent 90 min of unilateral testicular IR and were treated with DIC similarly to group B. Ninety-six hours following operation, the rats were sacrificed and testes were harvested. Johnsen's criteria and the number of germinal cell layers were used to categorize the spermatogenesis. TUNEL assay was used to determine germ cell apoptosis in both the ischemic and contralateral testes. Statistical analysis was performed using the non-parametric Kruskal-Wallis ANOVA test, with P less than 0.05 considered statistically significant. Testicular ischemia in rats led to histological damage in the ipsilateral testis. In the contralateral testis, minimal damage was observed. Germ cell apoptosis in both the ischemic and the contralateral testes increased significantly after IR. Treatment with DIC did not change histologic parameters of spermatogenesis in both the ischemic and contralateral testes, but decreased germ cell apoptosis in both testes following testicular IR. We conclude that testicular ischemia causes an increase in germ cell apoptosis in the contralateral testis. Diclofenac may be beneficial for spermatogenesis following testicular IR by decreasing germ cell apoptosis.

Prostate cancer is the most common neoplasm and the second cause of cancer death. It is an excellent target for primary chemopreventive strategies for the following reasons: it is highly prevalent and has a long latency period, there are identifiable risk factors and a precursor lesion and it produces a biochemical marker (serum PSA) which can serve as an intermediate end point in chemoprevention studies. The goal of primary prevention strategies is to prevent development of clinical life-threatening neoplasms in asymptomatic patients with no evidence of clinical disease. Identification of populations at risk for developing cancer is the cornerstone of chemoprevention. Well-established risk factors for prostate cancer include African-American race, older age and family history. Data on diet and obesity are less clearly defined. Since high grade prostatic intraepithelial neoplasia (PIN) is an early predictor of prostate cancer, preventive strategies focusing on men with high grade PIN are being explored. It was demonstrated that finasteride could significantly reduce prostate cancer in asymptomatic men with normal PSA and no abnormalities on rectal examination. Elevated prostaglandin levels, and upregulation of cyclooxygenase-2 (COX-2) are found in prostate cancer cell lines. There is some epidemiologic evidence that regular use of NSAIDs, which inhibit COX-2, may be associated with a lower risk of prostate cancer. In the field of nutrition, data from prospective large-scale studies demonstrated that increased consumption of lycopene-rich tomato-based foods referred to a reduction in the risk for prostate cancer. Vitamin E was also found to reduce prostate cancer risk. Prospective data showed that vitamin D has an inhibitory effect on prostate cancer development while increased calcium consumption, independent from dietary intake, might increase the risk. Dietary fat intake, particularly from animal sources, may also increase the risk for prostate cancer. Whether this effect is strictly due to the already identified compounds or to other compounds, remains to be explored. Further study will hopefully help to establish a core set of nutritional and dietary factors that can positively or negatively affect prostate cancer development, as well as a set of pharmacologic agents that can reduce the risk of prostate cancer development and/or progression in selected patients.

Objective: There is no consensus concerning the indications for active treatment (selective angioembolization (SAE) or surgery) versus observation alone, and the treatment modality for patients with renal angiomyolipoma (AML). Our study aimed to analyze the results of long-term follow-up of patients with renal AML treated by nephron-sparing surgery (NSS)., Materials and Methods: The medical records of thirteen patients with renal AML were retrospectively reviewed for clinical and histopathologic features. There were twelve women and one man (mean age 55 years) who were treated by NSS in our medical center between the years 1993-2001., Results: One patient with tuberous sclerosis had bilateral multifocal tumors, another patient that presented with shock and retroperitoneal bleeding underwent an urgent NSS. Overall, eight patients were symptomatic at diagnosis. The mean tumor diameter was 5.5 cm (range 2.5-13 cm). There was no need to perform nephrectomy in any of the patients. Two patients had enucleation of more than one tumor in the same session. In one case the adrenal gland was surrounded by the AML and was removed with the specimen. No other serious complications were recorded. Four patients required blood transfusions. The mean follow-up period was 26 months (range: 6-62 months) and during that time there was no evidence of recurrence or decreased renal function. Only one patient developed AML in the contralateral kidney, there was one case of incisional hernia and another patient continued to suffer from flank pain., Conclusions: The results of the present study suggest that NSS is a safe and effective treatment modality for renal AML.

Background: Although the current literature attributes most cases of hematospermia to an infectious agent, identification of the specific pathogens involved has been limited., Objective: To determine the prevalence of different pathogens, in patients presenting with hematospermia to our sexually transmitted disease clinic., Patients and Methods: We retrospectively examined the laboratory results of 30 patients who presented to our clinic with hematospermia after other non-infectious pathologies had been excluded by a referring physician. Firstly, void urine samples as well as genitourinary and serum specimens were tested for Herpes simplex, Chlamydia trachomatis and Ureaplasma urealyticum. Standard bacterial cultures were also performed., Results: In 12 of the 18 patients a possible pathogenic cause for the hematospermia was found. Evidence for Herpes simplex virus (Type 2) was found in 5 of the patients (16.6%), for Chlamydia trachomatis in 3 patients (10%) and for Ureaplasma urealyticum in 2 of the patients. Enterococcus fecalis was detected in 2 (6.6%) of the patients and in 1 patient Herpes simplex virus (Type 1) antigen and antibodies were detected. In all cases in which evidence of a pathogen was identified, the appropriate antimicrobial agent was administered, with recurrence in two patients only., Conclusions: Recent advances in microbiologic diagnostic techniques have facilitated the detection of pathogens in patients with hematospermia, thereby enhancing the efficacy of treatment.