Preoperative neutrophil to lymphocyte ratio improves recurrence prediction of non-muscle invasive bladder cancer.

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.

Method Used for Tumor Bed Closure (Suture vs. Sealant), Ischemia Time and Duration of Surgery are Independent Predictors of Post-Nephron Sparing Surgery Acute Kidney Injury.

INTRODUCTION: The aim of our study was to examine the influence of tumor complexity and operative variables on the degree and rate of post-nephron sparing surgery (NSS) acute kidney injury (AKI). METHODS: We retrospectively reviewed the records of 477 patients who underwent NSS for enhancing renal masses in our institution. AKI was determined using the latest definition by AKIN and RIFLE criteria. Serum creatinine was assessed daily starting from day 1 post-surgery and until discharge (usually on postoperative day 3). Estimated glomerular filtration was determined using the Modification of Diet in Renal Disease equation. RESULTS: Overall, 191 patients (40%) developed postoperative AKI, and most of them (88%) were grade 1. Multivariate analysis revealed that the most significant and independent variables associated with AKI were operation time (p = 0.02), ischemia time (p = 0.02), and the use of tissue adhesive for tumor bed closure (p = 0.02). Other important factors (by univariate analysis) were the need for blood transfusion (p = 0.003) and estimated blood loss (p = 0.007). CONCLUSIONS: Operative time, ischemia, and tumor bed closure method are independent predictors of post-NSS AKI. Efforts should be made to limit prolonged ischemia and to reduce viable parenchymal loss. Further studies concerning the functional impact of AKI in these patients will be required.

Nephron Sparing Surgery for Renal Mass: Is There Any Difference between Oncocytoma and Malignant Lesions.

INTRODUCTION: A relatively high proportion of patients who undergo partial or radical nephrectomy for enhancing renal mass actually have oncocytoma, a benign renal tumor. Several parameters have been shown to be typical for oncocytoma, but only a small number of patients present with these parameters. The aim of our study was to report the clinical, operative and postoperative characteristics of patients who underwent nephron-sparing surgery in our center with a histopathological diagnosis of oncocytoma compared to patients with malignant renal tumor. PATIENTS AND METHODS: Sixty-three out of 530 patients who underwent nephron-sparing surgery for enhancing renal mass were diagnosed with oncocytoma. Clinical and radiological features and operational data of these patients were compared with patients who had malignant renal tumors. RESULTS: Mean age of patients with histologically proven non-malignant oncocytoma was significantly higher than that in patients with malignant renal cell carcinoma (66.7 vs. 61.4 years). All other analyzed variables showed no significant difference between the 2 groups. CONCLUSIONS: No reliable clinical, operative or radiological parameters can differentiate preoperatively between oncocytoma and malignant renal neoplasms.

[INTERMEDIATE-TERM FOLLOW-UP OF PATIENTS UNDERGOING ACTIVE SURVEILLANCE FOR SMALL RENAL MASS: INDICATIONS FOR SURGICAL INTERVENTION].

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.

[KIDNEY DISEASES IN NORTH ISRAEL ACCORDING TO KIDNEY BIOPSIES - BNAI-ZION MEDICAL CENTER 14 YEARS' EXPERIENCE].

INTRODUCTION: Little is known about the prevalence of kidney diseases according to renal biopsy in Israel. Since updated literature worldwide emphasizes changing etiologies of chronic kidney disease, it is crucial to research and define the epidemiology and pathology of kidney disease in Israel. Hereby, we introduce an original review of the prevalence of kidney diseases in our study population, which we believe reflects the prevalence of kidney diseases in the population of Israel. AIMS: To investigate the prevalence of kidney diseases diagnosed by renal biopsy, according to age, gender, race and clinical symptoms. METHODS: A total of 155 kidney biopsies were conducted in the years 2000-2014 in Bnai-Zion Medical Center in Haifa, according to formal accepted indications. Most of the biopsies (65%) were needle aspirations in a retroperitoneal approach, in which 90% were ultrasound guided and the rest computed tomography guided, while the other 35% of biopsies involved laparoscopic approaches. RESULTS: The most common indications for kidney biopsy were nephrotic syndrome, nephritic syndrome and proteinuria (37.4%, 25.8% and 24.5%, respectively). Average glomeruli number per biopsy was 17.5 vs. 82.2 for needle aspiration and laparoscopic approach, respectively (statistically significant). The most common diagnosis was focal segmental glomerulosclerosis (FSGS), followed by chronic glomerulonephritis, IgA nephropathy, lupus nephritis, minimal change disease (MCD), membranous nephropathy and tubulointerstitial disease (20%, 11.5%, 11.5%, 10.1%, 9.5%, 8.1% and 6.1%, respectively). CONCLUSIONS: FSGS was the most common diagnosis in patients presented with nephrotic syndrome or proteinuria, men, and patients above 60 years of age. Patients below 30 years of age were mainly diagnosed with IgA nephropathy. DISCUSSION: In recent years, FSGS is becoming more prevalent compared with other chronic kidney disease especially in the older population. IgA nephropathy is still the most common diagnosis in young patients and in patients presented with hematuria. To the best of our knowledge, no data exists on the prevalence of kidney diseases in Israel, and our study is an important contribution to the epidemiological and clinical knowledge on the subject.

Effects of phosphodiesterase-5 inhibitor on ischemic kidney injury during nephron sparing surgery: quantitative assessment by NGAL and KIM-1.

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.

Endothelial Function Assessment in Patients with Erectile Dysfunction.

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.

[MULTICENTER EXPERIENCE WITH ALLIUM URETERAL STENT FOR THE TREATMENT OF URETERAL STRICTURE AND FISTULA].

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.

Performance of standard systematic biopsy versus MRI/TRUS fusion biopsy using the Navigo® system in contemporary cohort.

INTRODUCTION: The introduction of multi parameter magnetic resonance imaging (mpMRI) of the prostate in combination with MRI/TRUS fusion and systematic biopsy resulted in improved detection of prostate cancer. The aim of the current study was to document the performance of MRI/TRUS fusion biopsy of the prostate using the Navigo™ software in a contemporary cohort of patients from nonreferral centers. MATERIAL AND METHODS: We performed a two centers prospective data collection (2014-2020) for men with clinically suspected Pca and patients on active surveillance for low-risk Pca that were referred for TRUS biopsy after performing mpMRI of the prostate with a visible lesion. The primary outcome was detection of clinically significant cancer (csPca) defined as ISUP grade group ≥2. Patients were stratified according to biopsy technique and PI-RADS category. RESULTS: The study group included 236 patients of whom 129 (54.9%) were diagnosed with Pca and 82 (34.7%) with csPca (GG ≥ 2) on combined biopsy. The overall detection of csPca was 31% for targeted vs. 25.4% for systematic biopsy with an absolute difference of 5.6% in favor of the fusion technique. No significant difference between the two techniques was observed for detection of benign prostate or GG1 disease. The improved performance of the targeted approach was noted only in patients with PI-RADS 4 and 5 lesions. Of the patients with csPca 10 (12%) were diagnosed only by the systematic biopsy while 20 (24%) were detected only in the fusion biopsy. Systematic biopsy of prostate lobe without MRI lesion detected only 2 cases (∼1%) with high grade disease. CONCLUSIONS: Detection of csPca by mpMRI/TRUS fusion biopsy using the 3D Navigo™ system is feasible. The targeted approach outperforms the systematic one, however the later technique also detects high risk disease and should be included in the biopsy procedure. The overall detection rate (34.9%) of clinically significant prostate cancer by both targeted and systematic sampling is relatively low.

Phosphodiesterase-5 inhibition attenuates early renal ischemia-reperfusion-induced acute kidney injury: assessment by quantitative measurement of urinary NGAL and KIM-1.

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.

Urinary NGAL and KIM-1: biomarkers for assessment of acute ischemic kidney injury following nephron sparing surgery.

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.

Predicting progression of bladder urothelial carcinoma using microRNA expression.

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.

Urinary NGAL and KIM-1: potential association with histopathologic features in patients with renal cell carcinoma.

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.

Methotrexate induces germ cell apoptosis and impairs spermatogenesis in a rat.

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.

Performance of CellDetect for detection of bladder cancer: Comparison with urine cytology and UroVysion.

OBJECTIVE: To compare the performance of CellDetect, a new biomarker with urine cytology and UroVysiontechnology for bladder cancer detection. PATIENTS AND METHODS: We performed an IRB approved prospective, blinded single center study in patients on routine surveillance for nonmuscle invasive bladder cancer and those scheduled for transurethral resection of bladder tumor or radical cystectomy. Patients with bladder catheters, neobladder, ileal conduit, urinary stones, or those with upper tract carcinoma were excluded from the study. Voided urine sample was collected from the participants and each sample was divided into three equal aliquots (CellDetect, Urine cytology and Urovysion). Pathology of the operative specimen was considered the gold standard to which the three markers were compared. RESULTS: The study group included 93 patients with median age was 68 years (range: 34-92 years) with male to female ratio of 12:1. Pathologic evaluation revealed malignancy in 43 cases (46%) of whom 81% had previous history of urothelial bladder cancer. Among all studied markers CellDetect exhibited the best performance followed by urine cytology and U-FISH with diagnostic odds ratio of 4.33, 3.85, and 2.5 respectively. The overall sensitivity, specificity, negative predictive value, and positive predictive value for this test were 84%, 80%, 88%, and 74% respectively. The advantage of this new biomarker was observed both in high grade and low-grade cases. CONCLUSIONS: This study demonstrates the advantage of CellDetect as a urine-based assay to detect urothelial bladder cancer over urine cytology and U-FISH test. The high performance was maintained across all cancer grades and stages without compromising the assay specificity. Additional studies are required to test if it can be a noninvasive alternative to cystoscopy.

10-year single-center experience of combined intravesical chemohyperthermia for nonmuscle invasive bladder cancer.

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.

Safety and hemostatic efficacy of fibrin pad in partial nephrectomy: results of an open-label phase I and a randomized, standard-of-care-controlled phase I/II study.

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.

Post-transcriptional regulation of heparanase gene expression by a 3' AU-rich element.

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.

A novel human heparanase splice variant, T5, endowed with protumorigenic characteristics.

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.

Predictors and mechanisms of oncological failure following nephron-sparing surgery for renal cancer.

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.