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.

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.

Very Low Prostate PET/CT PSMA Uptake May Be Misleading in Staging Radical Prostatectomy Candidates.

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

Can Endoscopic Appearance, Selective Cytology, and Pathological Sampling During Ureteroscopy Accurately Predict Tumor Grade of Upper-Tract Urothelial Carcinoma?

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

Impact of Pneumoperitoneum on the Development of Acute Kidney Injury: Comparison Between Normal and Diabetic Rats.

BACKGROUND: Minimally invasive surgery is considered the gold-standard approach for many surgical procedures. However, it requires CO2 insufflation and elevated intra-abdominal pressure (IAP), which may result in adverse pulmonary, cardiovascular, gastrointestinal, and renal changes. The kidneys are highly sensitive to pressure changes, where risk factors such as severe infection, dehydration, older age, and chronic kidney disease may aggravate the likelihood for the development of acute kidney injury (AKI). Unfortunately, the impact of diabetes mellitus on the deleterious effects of elevated IAP-induced AKI was not fully studied so far. The present study was designed to examine the effect of pneumoperitoneum on renal function and the development of AKI in diabetic rats. MATERIALS AND METHODS: Sprague Dawley rats were divided into 2 groups: control (nondiabetic) rats (n=7) and diabetic rats (n=10). A Veress needle was introduced through the supravesical incision where inflating CO2 allowing the IAP to be increased to the desired pressures 7, 10, and 14 mm Hg for 45 minutes each and at the end of the experiment, the pressure was deflated to zero. During each pressure point, hemodynamic parameters were recorded and urine and blood samples were collected for analysis. RESULTS: The baseline values of renal hemodynamic were significantly lower in diabetic rats. There were no major statistically significant changes from baseline in urinary flow, urinary sodium excretion (UNaV), glomerular filtration rate, and renal plasma flow during 7 mm Hg pressure in both groups. When the IAP was further elevated, a significant deterioration of these parameters was recorded. This trend was more pronounced among diabetic rats. When examining urinary neutrophil gelatinase-associated lipocalin, a linear correlation was observed between the IAP and the biomarker level. This correlation was more significant in the diabetic group. CONCLUSION: The present study demonstrated a direct correlation between IAP elevation and the development of AKI. Diabetic rats were more sensitive to the deleterious effect of pneumoperitoneum, where urinary neutrophil gelatinase-associated lipocalin levels may be used as a future biomarker to predict postoperative AKI, especially in patients with diabetes.

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.

Involvement of heparanase in the pathogenesis of acute kidney injury: nephroprotective effect of PG545.

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

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.

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.

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.

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.