Management strategies and outcome of ureterovaginal fistulae: A systematic review and meta-analysis.

BACKGROUND: Genitourinary fistula is a distressful condition involving mental, social, marital, and financial repercussions. OBJECTIVE: The objective of this study is to systematically evaluate etiology, clinical presentation, diagnosis, the timing of repair, and perform a meta-analysis evaluating the success rate of various treatment modalities with respect to time taken to seek treatment. SEARCH STRATEGY: We performed a critical review of PubMed/Medline, Embase, and the Cochrane Library in April 2020 according to the PRISMA statement. Seventeen studies were included in the final analysis and all were retrospective in design. SELECTION CRITERIA: Each article was rated by the evidence-based medicine levels of evidence scale and the Methodological Index for Nonrandomized Studies scale for assessment of bias among nonrandomized studies. MAIN RESULTS: Of the 799 fistulae reported in 17 studies, endoscopic management was done in 35.6% (12 studies), whereas surgical management was preferred in 85.6% fistulae (15 studies). The pooled success of endoscopic stenting was 32% (95% confidence interval [CI]: 7-64) and 100% (95% CI: 98-100) in operated patients. Patients who underwent stenting within 2 weeks (20%), 2-6 weeks (21%), and >6 weeks (40%) had pooled success rates of 95% (95% CI: 87-100), 46% (95% CI: 0-100), and 20% (95% CI: 1-49), respectively. Patients who underwent surgical management <6 weeks (15.9%) and >6 weeks (22%) of diagnosis had pooled success rates of 100% (95% CI: 99-100) and 100% (95% CI: 99-100), respectively. CONCLUSIONS: Stent placement as early as <6 weeks (preferably < 2 weeks) had better outcomes as compared to >6 weeks. Proceeding to surgery regardless of timing in cases of stent failure seems to be a feasible option.

Safety and efficacy of bipolar versus monopolar transurethral resection of bladder tumor: a systematic review and meta-analysis.

PURPOSE: Transurethral resection of bladder tumor is the standard of care for the management of patients with bladder mass. Primary objective of this study was to compare safety and efficacy of the two energy modalities used for TURBT (monopolar and bipolar). MATERIALS AND METHODS: Systematic literature search of various electronic databases was conducted to include all the randomized studies comparing two groups. Standard PRISMA (Preferred reporting Items for Systematic reviews and Meta-analysis) guidelines were pursued for this review and study protocol was registered with PROSPERO (CRD42019139987). RESULTS: In the present review, eight RCTs including 1147 patients were included. Resection time, hospital stay and catheter duration were significantly shorter with bipolar group. There was no significant difference in incidence of obturator reflex (OR 0.65, CI [0.35, 1.2], p = 0.17), whereas incidence of bladder perforation was significantly higher in the monopolar group (6.4% versus 3.3%, p = 0.01. However, sensitivity analysis including 3 high quality studies revealed equal incidence of bladder perforations. Need for blood transfusion was similar in the two groups but fall in hemoglobin was significantly lower in bipolar group (MD - 0.45 CI [- 0.72, - 0.18], p = 0.0009). Bipolar group was found to have significantly lower incidence of tissue artifacts due to thermal energy on pathological examination (OR 0.27 CI [0.15, 0.47], p < 0.00001). CONCLUSIONS: Bipolar and monopolar devices are equally safe in terms of obturator jerk and bladder perforation. Bipolar group was significantly better as compared to monopolar for hospital stay, catheter duration and fall in hemoglobin; however, the clinical relevance of most of these parameters is little.

Role of phosphodiesterase inhibitors in stent-related symptoms: a systematic review and meta-analysis.

PURPOSE: Stent-related symptoms are frequent following stent placement for various indications. Use of PDE inhibitors has expanded beyond their classical indication and has been tried in patients with stent-related symptoms. The systematic review was conducted to ascertain the efficacy of PDE inhibitors in ameliorating stent-related symptoms. METHODS: We performed systematic review and metanalysis on the use of PDE inhibitors for stent-related symptoms in patients who underwent stent placement for various reasons (postpercutaneous nephrolithotomy or ureterorenoscopy). We followed PRISMA guidelines while conducting this review and study protocol was registered with PROSPERO (CRD42019121781) RESULTS: Three studies with 280 participants were included in this review. There was considerable heterogeneity across all the outcome parameters assessed; thus, random-effect model was used for analysis. Comparison of PDE inhibitors with control arm revealed that PDE inhibitors were significantly more effective than placebo in all but one domain (Work performance) of the USSQ. On comparison with alfa blockers, PDE inhibitors were found to be equally effective for urinary symptoms, general health, and body pain parameters, but sexual health parameters improved significantly with PDE inhibitors. CONCLUSION: PDE inhibitors can be considered an option for patients with stent-related symptoms especially in patients with sexual dysfunction. Due to various limitations of the studies included in this review, we recommend conducting further high-quality studies.

Phosphodiesterase inhibitors for lower urinary tract symptoms consistent with benign prostatic hyperplasia.

OBJECTIVES: To assess the effects of phosphodiesterase inhibitors (PDEI) compared to placebo and other standard of care drugs i.e alpha blockers (AB) and 5-alpha reductase inhibitors (5-ARI) in men with LUTS consistent with benign prostatic hyperplasia (BPH). METHODS: We conducted a systematic search of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Web of Science, and clinical trials registries of the World Health Organization (WHO) and the National Institutes of Health (NIH) (updated 2 August 2018). Citation tracking and hand-searching of abstracts and conference proceedings was done. We also attempted to contact the study authors in case additional information was needed. Randomised controlled trials (RCT) comparing PDEI versus placebo, AB, or 5-ARI used for at least four weeks in men with BPH-LUTS were included. Three review authors independently screened the literature and extracted data. Primary outcomes were effects on urinary symptoms as assessed by the International Prostate Symptom Score (IPSS-total; score ranging from 0 to 35, with higher values reflecting more symptoms), urinary bother as assessed by the Benign Prostatic Hyperplasia Impact Index (BPHII; score ranging from 0 to 13, with higher values reflecting more bother), and adverse events (AE). We used GRADE to rate the quality of evidence. We considered short-term (up to 12 weeks) and long-term (12 weeks or longer) results separately. RESULTS: We included a total of 16 randomised trials in this review. Primary outcomes: PDEI versus placebo: PDEI may result in a small improvement in IPSS-total score (mean difference (MD) 1.89 lower, 95% confidence interval (CI) 2.27 lower to 1.50 lower; n = 4293; low-quality evidence) compared to placebo, and may reduce the BPHII score slightly (MD 0.52 lower, 95% CI 0.71 lower to 0.33 lower; n = 3646; low-quality evidence). Rates of AEs may be increased (risk ratio (RR) 1.42, 95% CI 1.21 to 1.67; n = 4386; low-quality evidence). This corresponds to 95 more AEs per 1000 participants (95% CI 47 more to 151 more per 1000). Study results were limited to a treatment duration of six to 12 weeks. PDEI versus AB: PDEI and AB probably provide similar improvement in IPSS-total score (MD 0.22 higher, 95% CI 0.49 lower to 0.93 higher; n = 933; moderate-quality evidence) and may have a similar effect on BPHII score (MD 0.03 higher, 95% CI 1.10 lower to 1.16 higher; n = 550; low-quality evidence) and AE (RR 1.35, 95% CI 0.80 to 2.30; n = 936; low-quality evidence). This corresponds to 71 more AEs per 1000 participants (95% CI 41 fewer to 264 more per 1000). Study results were limited to a treatment duration of six to 12 weeks. PDEI and AB versus AB : The combination of PDEI and AB may provide a small improvement in IPSS-total score (MD 2.56 lower, 95% CI 3.92 lower to 1.19 lower; n = 193; low-quality evidence) compared to AB alone. We found no evidence for BPHII scores. AE may be increased (RR 2.81, 95% CI 1.53 to 5.17; n = 194; moderate-quality evidence). This corresponds to 235 more AE per 1000 participants (95% CI 69 more to 542 more per 1000). Study results were limited to treatment duration of four to 12 weeks. PDEI and AB versus PDEI alone: The combination of PDEI and AB may provide a small improvement in IPSS-total (MD 2.4 lower, 95% CI 6.47 lower to 1.67 higher; n = 40; low-quality evidence) compared to PDEI alone. We found no data on BPHII or AE. Study results were limited to a treatment duration of four weeks. PDEI and 5-ARI versus 5-ARI alone: in the short term (up to 12 weeks), the combination of PDEI and 5-ARI probably results in a small improvement in IPSS-total score (MD 1.40 lower, 95% CI 2.24 lower to 0.56 lower; n = 695; moderate-quality evidence) compared to 5-ARI alone. We found no evidence on BPHII scores or AE. In the long term (13 to 26 weeks), the combination of PDEI and 5-ARI likely results in a small reduction in IPSS-total score (MD 1.00 less, 95% CI 1.83 lower to 0.17 lower; n = 695; moderate-quality evidence). We found no evidence about effects on BPHII scores. There may be no difference in rates of AE (RR 1.07, 95% CI 0.84 to 1.36; n = 695; low-quality evidence). This corresponds to 19 more AE per 1000 participants (95% CI 43 fewer to 98 more per 1000). We found no trials comparing other combinations of treatments or comparing different PDEI for BPH-LUTS. CONCLUSIONS: Compared to placebo, PDEI likely leads to a small reduction in IPSS-total and BPHII sores, with a possible increase in AE. There may be no differences between PDEI and AB with regards to improvement in IPSS-total, BPHII, and incidence of AE. There appears to be no added benefit of PDEI combined with AB compared to PDEI or AB or PDEI combined with 5-ARI compared to ARI with regards to urinary symptoms. Most evidence was limited to short-term treatment up to 12 weeks and of moderate or low certainty.

Protocol-based perioperative antimicrobial prophylaxis in urologic surgeries: Feasibility and lessons learned.

INTRODUCTION: Rational use of antibiotics and strict adherence to practice guidelines is essential to prevent antibiotic resistance. The best surgical prophylaxis protocol requires tailoring of the available guidelines in accordance to the local bacterial flora. We designed a protocol for surgical prophylaxis to check the rampant abuse of antibiotics in the department of urology and evaluated its feasibility. MATERIALS AND METHODS: Patients admitted for elective major surgeries under a single unit of our department over a period of 5 months were included in the study. A protocol for antibiotic prophylaxis was designed based on the European Association of Urology guidelines and the local hospital antibiogram. Single-dose intravenous cefuroxime was administered to the patients undergoing clean and clean-contaminated surgeries. Extended protocols were formulated for contaminated surgeries. Postoperative course and complications were recorded. Effectiveness was defined as adherence to the protocol (without an addition or a change in antibiotic regimen) along with an uneventful postoperative course. Prospectively maintained data were analyzed using descriptive statistics. RESULTS: Data of 277 patients were analyzed. The mean age was 48.37 ± 17.39 years and 27.1% had comorbidities. Majority of the surgeries were clean contaminated (81%), and 60.3% of the total were endoscopic. The protocol was effective in 89.5% of the patients (248/277). The failure rate was higher for the contaminated procedures (41.7%) (odds ratio - 6.43; confidence interval = 1.51-27.2, P < 0.001). Post-operative sepsis with or without shock was the commonest cause (16/29, 55.2%) of protocol failure. Fourteen out of the 16 patients who developed sepsis had undergone endourological surgeries. CONCLUSIONS: Protocol-based perioperative antibiotic prophylaxis in urological surgeries is feasible. Similar protocols should be developed and validated at other major centers to limit the unnecessary use of antibiotics and prevent the emergence of antibiotic resistance.

Phosphodiesterase inhibitors for lower urinary tract symptoms consistent with benign prostatic hyperplasia.

BACKGROUND: Benign prostatic hyperplasia (BPH) refers to non-malignant enlargement of the prostate gland that may cause bothersome lower urinary tract symptoms (LUTS). Alpha-blockers (ABs) and 5-alpha reductase inhibitors (5-ARIs) are the mainstay of medical treatment. Recently, phosphodiesterase inhibitors (PDEIs) that so far have been used mainly to treat erectile dysfunction were introduced to treat male LUTS. OBJECTIVES: To assess the effects of PDEIs compared to placebo and other standard of care drugs (ABs and 5-ARIs) in men with LUTS consistent with BPH. SEARCH METHODS: We conducted a systematic search of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Web of Science, and clinical trials registries of the World Health Organization (WHO) and the National Institutes of Health (NIH) (updated 2 August 2018). We performed citation tracking and handsearching of abstracts and conference proceedings. We also contacted study authors to ask for additional information. SELECTION CRITERIA: We considered for inclusion in this systematic review randomised controlled trials (RCTs) comparing PDEIs versus placebo, ABs, or 5-ARIs for at least four weeks in men with BPH-LUTS. DATA COLLECTION AND ANALYSIS: Three review authors independently screened the literature and extracted data. Primary outcomes were effects on urinary symptoms as assessed by the International Prostate Symptom Score (IPSS-total; score ranging from 0 to 35, with higher values reflecting more symptoms), urinary bother as assessed by the Benign Prostatic Hyperplasia Impact Index (BPHII; score ranging from 0 to 13, with higher values reflecting more bother), and adverse events (AEs). We used GRADE to rate the quality of evidence. We considered short-term (up to 12 weeks) and long-term (12 weeks or longer) results separately. MAIN RESULTS: We included a total of 16 randomised trials in this review. The results for primary outcomes are as follows.PDEI versus placebo: PDEIs may result in a small improvement in IPSS-total score (mean difference (MD) 1.89 lower, 95% confidence interval (CI) 2.27 lower to 1.50 lower; n = 4293; low-quality evidence) compared to placebo, and may reduce the BPHII score slightly (MD 0.52 lower, 95% CI 0.71 lower to 0.33 lower; n = 3646; low-quality evidence). Rates of AEs may be increased (risk ratio (RR) 1.42, 95% CI 1.21 to 1.67; n = 4386; low-quality evidence). This corresponds to 95 more AEs per 1000 participants (95% CI 47 more to 151 more per 1000). Study results were limited to a treatment duration of six to 12 weeks.PDEI versus AB: PDEIs and ABs probably provide similar improvement in IPSS-total score (MD 0.22 higher, 95% CI 0.49 lower to 0.93 higher; n = 933; moderate-quality evidence) and may have a similar effect on BPHII score (MD 0.03 higher, 95% CI 1.10 lower to 1.16 higher; n = 550; low-quality evidence) and AEs (RR 1.35, 95% CI 0.80 to 2.30; n = 936; low-quality evidence). This corresponds to 71 more AEs per 1000 participants (95% CI 41 fewer to 264 more per 1000). Study results were limited to a treatment duration of six to 12 weeks.PDEI and AB versus AB alone: the combination of PDEI and AB may provide a small improvement in IPSS-total score (MD 2.56 lower, 95% CI 3.92 lower to 1.19 lower; n = 193; low-quality evidence) compared to AB alone. We found no evidence for BPHII scores. AEs may be increased (RR 2.81, 95% CI 1.53 to 5.17; n = 194; moderate-quality evidence). This corresponds to 235 more AEs per 1000 participants (95% CI 69 more to 542 more per 1000). Study results were limited to treatment duration of four to 12 weeks.PDEI and AB versus PDEI alone: the combination of PDEI and AB may provide a small improvement in IPSS-total (MD 2.4 lower, 95% CI 6.47 lower to 1.67 higher; n = 40; low-quality evidence) compared to PDEI alone. We found no data on BPHII or AEs. Study results were limited to a treatment duration of four weeks.PDEI and 5-ARI versus 5-ARI alone: in the short term (up to 12 weeks), the combination of PDEI and 5-ARI probably results in a small improvement in IPSS-total score (MD 1.40 lower, 95% CI 2.24 lower to 0.56 lower; n = 695; moderate-quality evidence) compared to 5-ARI alone. We found no evidence on BPHII scores or AEs. In the long term (13 to 26 weeks), the combination of PDEI and 5-ARI likely results in a small reduction in IPSS-total score (MD 1.00 less, 95% CI 1.83 lower to 0.17 lower; n = 695; moderate-quality evidence). We found no evidence about effects on BPHII scores. There may be no difference in rates of AEs (RR 1.07, 95% CI 0.84 to 1.36; n = 695; low-quality evidence). This corresponds to 19 more AEs per 1000 participants (95% CI 43 fewer to 98 more per 1000).We found no trials comparing other combinations of treatments or comparing different PDEI agents. AUTHORS' CONCLUSIONS: Compared to placebo, PDEI likely leads to a small reduction in IPSS-total and BPHII sores, with a possible increase in AEs. There may be no differences between PDEI and AB with regards to improvement in IPSS-total, BPHII, and incidence of AEs. There appears to be no added benefit of PDEI combined with AB compared to PDEI or AB alone or PDEI combined with 5-ARI compared to ARI alone with regards to urinary symptoms. Most evidence was limited to short-term treatment up to 12 weeks and of moderate or low certainty.

STAMPEDEing metastatic prostate cancer: CHAARTing the LATITUDEs.

With the emergence of recent landmark trials, the treatment for hormone-sensitive metastatic prostate cancer (hsMPC) is changing from androgen deprivation therapy (ADT) alone to combination therapy. Both, docetaxel chemotherapy and abiraterone in addition to ADT have been extensively studied in well-conducted randomized controlled trials and were shown to improve outcomes. However, this paradigm shift in the treatment has also raised some queries. This mini review reflects upon the four landmark trials and tries to provide some perspective about the decision-making process for the patients with hsMPC.

Comparison of RENAL, PADUA, and C-index scoring systems in predicting perioperative outcomes after nephron sparing surgery.

INTRODUCTION AND OBJECTIVE: The RENAL, PADUA and centrality index (C-index) nephrometry scoring systems (SS) have been individually evaluated for their role in predicting trifecta outcomes after nephron-sparing surgery (NSS). However, there is little data on their comparative superiority. The present study was designed to evaluate the predictive value of three SS and to assess interobserver reliability. MATERIALS AND METHODS: Fifty patients undergoing NSS at our center between January 2014 and April 2016 were included in the study. The demographic details were noted. Images (computed tomography [CT] scans or magnetic resonance imaging) were reviewed by a urologist and a radiologist independently and RENAL, PADUA, and C-index were calculated. The correlation between these scoring system and trifecta outcomes were calculated. RESULTS: The RENAL and PADUA score did not correlate with any of the perioperative parameters. However, C-index had a significant correlation with operative time (OT) (P = 0.02) and trifecta outcomes (P < 0.05). There was an excellent concordance between the two observers in scoring the RENAL score (α = 0.915; intraclass correlation coefficient [ICC] = 0.814) and PADUA score (α = 0.816; ICC = 0.689 [P < 0.001]). There was lesser although acceptable concordance in the calculation of C-index (ICC -0.552; α -0.711). CONCLUSIONS: There is good correlation among all the 3 SS. C-index has lower reproducibility due to difficult mathematical calculation but correlated best with trifecta outcomes.

Robot-assisted vesicovaginal fistula repair: a safe and feasible technique.

INTRODUCTION AND HYPOTHESIS: Open transabdominal repair of vesicovaginal fistula (VVF) requires a long cystotomy incision, suprapubic drainage and delayed recovery. Laparoscopic repair is limited by difficult suturing in pelvic procedures. Therefore, the utility of robotic assistance is being increasingly explored. We share our initial experience of robot-assisted laparoscopic VVF repair. METHODS: The data from patients who underwent robot-assisted VVF repair from December 2014 to August 2016 were recorded and analyzed. Patients underwent standard preoperative evaluation. After cystovaginoscopy and placement of an access catheter across the fistula, a four-port transperitoneal approach was used. Following adhesiolysis, limited posterior cystotomy was performed. The vaginal and bladder flaps were separated and repaired in the transverse and vertical directions, respectively. V-Loc sutures were used for bladder closure. Omental/sigmoid colon epiploicae or a peritoneal flap was interposed. A pelvic drain was placed. RESULTS: During the study period, 30 patients underwent surgery, of whom 11 (36.7 %) had complex VVF (9 with failure of a previous repair, 1 following radiotherapy, and 1 with a large defect following obstructed labor), and 27 had supratrigonal VVF. The mean age of the patients was 43.5 ± 8.6 years. The mean operative time was 133 ± 48 min. Median blood loss was 50 ml (IQR 50 ml). No suprapubic catheter was placed. The median durations of drain placement and hospital stay were 3 days (IQR 2 days) and 7.5 days (IQR 4.5 days), respectively. The median duration of follow up was 38 weeks (IQR 46 weeks). No recurrence was seen in 28 patients (93.3 %). CONCLUSIONS: Current data suggest that robot-assisted VVF repair is safe and feasible and probides the advantages of minimally invasive surgery.

Initial experience of robotic nephron sparing surgery in cases of high renal nephrometry scores.

INTRODUCTION: The renal nephrometry scoring (RNS) system enables prediction the feasibility of nephron-sparing surgery (NSS) in renal masses. There is insufficient data regarding the outcome of robot-assisted NSS in tumors with RNS ≥10. We reviewed the trifecta outcomes of patients undergoing robotic NSS with high RNS and compare it with tumors of low and intermediate RNS. MATERIALS AND METHODS: Our prospectively maintained data of all robot-assisted NSS were reviewed, and those with RNS of ≥10 were identified. Patient data, outcomes and postoperative estimated glomerular filtration rate were compared between high, intermediate and low RNS patients. RESULTS: In high RNS group, the mean age of the patients was 53 years (male:female = 15:3). Mean diameter of tumors was 6.28 cm (3.0-10.5 cm). Mean operative time was 173.61 ± 52.66 min and mean warm ischemia time was 27.85 ± 5.27 min. Mean estimated blood loss (EBL) was 363.89 ± 296.45 ml. Mean hospital length of stay was 5.39 ± 1.91 days (3-9 days). When compared with low and intermediate RNS, only EBL and need for pelvicalyceal system repair was significantly higher in high RNS group. Postoperative complications, renal function preservation and oncological outcomes at 3 months were comparable in all the three groups. CONCLUSION: Robot-assisted NSS is feasible with comparable outcomes in tumors with high RNS.

Plateau pattern of detrusor contraction: A surrogate indicator of presence of external sphincter dysfunction during micturitional phase of urodynamic study.

INTRODUCTION: Dysfunctional voiding results from a disturbance in the coordination between sphincter relaxation and detrusor contraction. Video urodynamic studies with electromyography (EMG) are used for diagnosis but have limitations of availability and interpretation. We identified a plateau type voiding detrusor pressure tracing pattern in these patients with a potential of helping diagnosis. MATERIALS AND METHODS: Urodynamic data and tracings of adult patients having been diagnosed with external urethral sphincter dysfunction (EUSD) were retrospectively analyzed. The urodynamic studies comprised of pressure flow studies, micturitional urethral pressure profilometry, and voiding cystourethrogram (VCUG). Diagnosis of EUSD was based on the presence of intermittent or continuous narrowing in the region of EUS on VCUG along with a urethral-vesical pressure gradient of >20 cm H2O in males and >5 cm H2O in females. RESULTS: A total of 25 patients (14 men and 11 women) with a mean age 36.6 ± 16.5 years, presented with lower urinary tract symptoms (international prostate symptom score 18 ± 5) and were diagnosed with EUSD on urodynamics/cystourethrography. The cause of EUSD was neurogenic DESD in four, dysfunctional voiding in 20 and voluntary pelvic floor squeeze in one. Resting maximum urethral closure pressure at EUS was 142.2 ± 38.3 cmH2O in both sexes. Three patients had detrusor overactivity. EMG activity during voiding was high in 10 patients, low in three, inconclusive in seven, and not performed in three. A plateau type pattern of detrusor contraction was observed in all the patients. This was qualitatively different from the roughly bell-shaped curve of detrusor contraction in men with prostatic obstruction (n = 14) and women with stress urinary incontinence (n = 11). CONCLUSIONS: Patients with EUSD have a characteristic plateau pattern of detrusor contraction on urodynamics which can be used as a surrogate for urodynamic diagnosis of nonrelaxing EUSD.

Successful management of renal mucormycosis with antifungal therapy and drainage.

We report a case of isolated extensive renal mucormycosis in an immunocompetent adult, who was successfully managed conservatively without surgical debridement. To the best of our knowledge, this is the first case where antifungal therapy alone was sufficient even with such an extensive involvement.

Instrument malfunction during robotic surgery: A case report.

Robotic assistance is the new dimension of minimally invasive surgery. Despite being the state-of-the-art technology, newer technical problems still occur during robotic surgeries which are not addressed in the trouble shooting manual. We report one such problem being encountered with the tip cover accessory of monopolar scissors. In the current report, we discuss the technical fault and its correction. We feel that this problem needs to be registered into the trouble-shooting manual to prevent such incidents in future.

Inhibition of grade dependent autophagy in urothelial carcinoma increases cell death under nutritional limiting condition and potentiates the cytotoxicity of chemotherapeutic agent.

PURPOSE: We evaluated the status of autophagy in different grades of urothelial carcinoma and explored autophagy modulators as a potential adjunctive therapeutic agent for urothelial carcinoma. MATERIALS AND METHODS: The study was performed in tumor tissue from patients with low and high grade urothelial carcinoma, in normal urothelial tissue and in the T24 cell line. Autophagic vesicles and the expression of various autophagic proteins were studied in tissue samples by transmission electron microscopy and Western blot, respectively. The effect of autophagy induction and inhibition was evaluated by measuring AMPK and mTOR expression, cell viability and mitochondrial membrane potential. The therapeutic implication of autophagy was studied using cisplatin alone or combined with an autophagy inhibitor. RESULTS: High grade urothelial carcinoma showed a higher number of autophagic vesicles and significantly higher expression of autophagic proteins. Upon starvation cells cultured from high and low grade urothelial carcinoma demonstrated significant autophagy induction associated with AMPK activation and mTOR inhibition. AMPK inhibition decreased the autophagic response and increased cell death. Autophagy inhibition by wortmannin, 3-methyladenine and chloroquine increased mitochondrial hypopolarization as well as caspase-9 and 3 dependent cell death. Combined treatment with cisplatin and an autophagy inhibitor resulted in greater cell death than cisplatin treatment alone. CONCLUSIONS: Autophagy is related to urothelial carcinoma grade and regulated via the AMPK pathway for tumor cell survival. Autophagy inhibition leads to cancer cell death through an intrinsic apoptotic pathway. The potential application of autophagy inhibitors as an adjunct to chemotherapy for urothelial carcinoma must be explored.

Rationalization of interpretation of uroflowmetry for a non-caucasian (Indian) population: conceptual development and validation of volume-normalized flow rate index.

AIMS: We intended to define volume-normalized flow rates (cQ; VQI) and to construct and validate uroflow (Q)-volume (V) nomograms in our Indian (non-Caucasian) population. METHODS: Prospective observational study. PARTICIPANTS: Group A, male healthy volunteers 18-45 years without LUTS. Group B, men >18 years with LUTS (IPSS > 7; global QOL > 2). The participants voided in standing on normal-to-strong desire into digital gravimetric uroflowmeter. Data of <50 ml void and intermittent flow was discarded. Reference cQ calculated using (i) Von Garrelts equations (=Q/VV(2)), (ii) cubic equations (=Q/VV(3)). Bladder volume (BV) rather than voided volume (VV) was considered for Q-V relation (BV = VV + PVR). VQI derived from present data were compared with the reference-VQI in terms of differences in area-under-curve of receiver operating characteristics. For comparing sensitivity, specificity and predictive values of study nomograms with Caucasian nomograms (Liverpool and Siroky), data of group-A and -B were plotted on each nomogram and no. of observations above and below the cutoffs (defined as equivalent to -1 SD) manually counted. RESULTS: Total 542 voids of group-A and 465 of group-B included for final analysis. Q-V relation was best described as [Q ∝ BV(2.4) ≅ BV(2)]. The derived VQI (=Q/BV(2.4) ≅ Q/BV(2)) fared significantly superior to reference VQI with VV as denominator. Nomograms, constructed on Q ∝ BV(2) , were less sensitive but had higher specificity and positive predictive values compared to Caucasian nomograms. CONCLUSIONS: Volume-normalized flow-rate index with BV as denominator (Q/BV(2)) is has highly discriminative value in screening for voiding dysfunction. Population-specific Q-BV nomograms are more specific and predictive than Caucasian Q-VV nomograms.

Asp299Gly and Thr399Ile polymorphism of TLR-4 gene in patients with prostate cancer from North India.

BACKGROUND: The etiological factors associated with prostate cancer (CaP) have not been completely understood as yet. Genetic predisposition and inflammation is fast emerging as risk factors for CaP is a key player in the innate immune response and plays role in immune- surveillance and inflammation. The present study was conducted to evaluate TLR-4 gene polymorphism in patients with CaP. MATERIAL AND METHODS: DNA was isolated from blood samples of 198 patients with CaP, 200 cases of Benign Prostatic Hyperplasia (BPH) and 119 controls. TLR-4 gene polymorphisms Asp299Gly and Thr399Ile were determined by Restriction Fragment Length Polymorphism (RFLP) technique using Nco1 and Hinf 1 restriction enzymes. All statistical calculations were performed using SPSS for windows, version 13 (SPSS Inc., Chicago, Illinois, USA). RESULTS: A significantly high proportion of patients with CaP had AG genotype (16.6%) as compared to control (4.2%) [OR-4.4, 95% CI (1.57-13.26), P =0.0013] with respect to Asp299Gly single nucleotide polymorphism (SNP). AA genotype showed a protective effect towards CaP development [OR-0.39, 95% CI (0.18-0.83), P=0.007). A trend was observed towards development of BPH with respect to AG genotype (P=0.06). Thr399Ile SNP was not significantly different among the population groups studied. CONCLUSIONS: This finding highlights the genetic predispositions to CaP with respect to TLR-4 gene. Individuals with Asp299Gly polymorphism having AG genotype appear to have four fold higher risk for development of Prostate cancer.

Status of oxidative stress in patients with renal cell carcinoma.

PURPOSE: Although oxidative stress is implicated in renal cell carcinoma pathogenesis, to our knowledge changes in oxidative stress parameters in patients who undergo surgery for renal cell carcinoma have not been studied previously. We investigated the status of oxidative stress in patients with renal cell carcinoma. MATERIALS AND METHODS: Reactive oxygen species, nitric oxide and glutathione were measured in the blood of 68 patients with renal tumor and in 30 age matched normal controls. Levels were measured again 1 week, and 1 and 2 months postoperatively in patients who underwent surgery for renal cell carcinoma. Levels of superoxide dismutase, catalase and lipid peroxidation were measured in tumor tissue and in normal renal parenchyma in 51 patients with renal tumor. RESULTS: Significantly increased reactive oxygen species and nitric oxide, and decreased glutathione were observed in patients with renal cell carcinoma compared to normal subjects and in patients with benign tumors. Superoxide dismutase and lipid peroxidation were increased and catalase was decreased in tumor tissue compared to normal renal tissue. Oxidative stress correlated with renal cell carcinoma grade and stage but decreased after curative resection. Patients with metastatic disease had persistently increased oxidative stress parameters. Antioxidant enzyme levels in benign tumor tissue were significantly higher than in renal cell carcinoma. CONCLUSIONS: Patients with renal cell carcinoma have increased oxidative stress, which is effectively alleviated by curative resection. In patients with benign tumors antioxidant defense mechanisms maintain normal redox status.

Risk factors for urosepsis following percutaneous nephrolithotomy: role of 1 week of nitrofurantoin in reducing the risk of urosepsis.

The purpose of this study was to analyze the various risk factors for urosepsis following percutaneous nephrolithotomy (PNL) and to study the role of 1-week nitrofurantoin before PNL in reducing the risk of urosepsis. All patients undergoing PNL from April 2007 to November 2008 were prospectively included and grouped into four cohorts according to the following inclusion criteria: group A: stones ≤ 2.5 cm, no hydronephrosis, sterile urine; group B: diabetes mellitus, serum creatinine > 2 mg/dl, positive urine culture, stag horn stones, presence of nephrostomy or simultaneous bilateral PNL; group C: stones ≥ 2.5 cm and/or hydronephrosis, sterile urine; group D: similar to group C, but received nitrofurantoin 100 mg bid for 7 days before operation. Preoperative urine culture, intraoperative renal pelvic urine culture and stone cultures were obtained. Fever > 380°C and leukocyte counts > 12,000 were considered as systemic inflammatory response syndrome (SIRS). Endotoxemia was assessed in serum samples. A total of 205 patients were included in the study and grouped into four cohorts as group A (n = 50), group B (n = 54), group C (n = 53) and group D (n = 48). Overall 23% patients had positive renal pelvic urine and/or stone culture, 25% had endotoxemia and 34% developed SIRS. Female gender, chronic renal failure, anemia, hydronephrosis, stones larger than 2.5 cm and prolonged surgery were found to be risk factors associated with urosepsis. Nitrofurantoin prophylaxis resulted in decreased culture positivity (30.2 vs. 8.3%, odds ratio 0.36, p = 0.087), endotoxemia (41.9 vs. 17.5%, odds ratio 0.22, p = 0.001) and SIRS (49 vs. 19%, odds ratio 0.31, p = 0.01). In conclusion, female gender, chronic renal failure, anemia, hydronephrosis, stones larger than 2.5 cm and prolonged surgery were risk factors for urosepsis. Nitrofurantoin is beneficial in the prevention of endotoxemia and urosepsis especially in patients with larger stones and hydronephrosis.