Richmond Owusu

The impact of temperature and urinary constituents on urine viscosity and its relevance to bladder hyperthermia treatment

Abstract Purpose: The aim of this study was to determine the kinematic viscosity of human urine and factors associated with its variability. This value is necessary for accurate modelling of fluid mechanics and heat transfer during hyperthermia treatments of bladder cancer. Materials and methods: Urine samples from 64 patients undergoing routine clinical testing were subject to dipstick urinalysis and measurement of viscosity with a Cannon-Fenske viscometer. Viscosity measurements were taken at relevant temperatures for hyperthermia studies: 20 °C (room temperature), 37 °C (body temperature), and 42 °C (clinical hyperthermia temperature). Factors that might affect viscosity were assessed, including glucosuria, haematuria, urinary tract infection status, ketonuria and proteinuria status. The correlation of urine specific gravity and viscosity was measured with Spearman’s rho. Results: Urine kinematic viscosity at 20 °C was 1.0700 cSt (standard deviation (SD) = 0.1076), at 37 °C 0.8293 cSt (SD = 0.0851), and at 42 °C 0.6928 cSt (SD = 0.0247). Proteinuria appeared to increase urine viscosity, whereas age, gender, urinary tract infection, glucosuria, ketonuria, and haematuria did not affect it. Urine specific gravity was only modestly correlated with urine viscosity at 20 °C (rho = 0.259), 37 °C (rho = 0.266), and 42 °C (rho = 0.255). Conclusions: The kinematic viscosity of human urine is temperature dependent and higher than water. Urine specific gravity was not a good predictor of viscosity. Of factors that might affect urine viscosity, only proteinuria appeared to be clinically relevant. Estimates of urine viscosity provided in this manuscript may be useful for temperature modelling of bladder hyperthermia treatments with regard to correct prediction of the thermal conduction effects.

Hyperthermia as Adjunct to Intravesical Chemotherapy for Bladder Cancer

Nonmuscle invasive bladder cancer remains a very costly cancer to manage because of high recurrence rates requiring long-term surveillance and treatment. Emerging evidence suggests that adjunct and concurrent use of hyperthermia with intravesical chemotherapy after transurethral resection of bladder tumor further reduces recurrence risk and progression to advanced disease. Hyperthermia has both direct and immune-mediated cytotoxic effect on tumor cells including tumor growth arrest and activation of antitumor immune system cells and pathways. Concurrent heat application also acts as a sensitizer to intravesical chemotherapy agents. As such the ability to deliver hyperthermia to the focus of tumor while minimizing damage to surrounding benign tissue is of utmost importance to optimize the benefit of hyperthermia treatment. Existing chemohyperthermia devices that allow for more localized heat delivery continue to pave the way in this effort. Current investigational methods involving heat-activated drug delivery selectively to tumor cells using temperature-sensitive liposomes also offer promising ways to improve chemohyperthermia efficacy in bladder cancer while minimizing toxicity to benign tissue. This will hopefully allow more widespread use of chemohyperthermia to all bladder cancer patients, including metastatic bladder cancer.

Multi-institutional external validation of urinary TWIST1 and NID2 methylation as a diagnostic test for bladder cancer

OBJECTIVES We previously reported a clinical trial in which we were unable to replicate the excellent diagnostic metrics produced in the developmental study of the TWIST1 and NID2 gene methylation assay. In this expanded trial with subjects enrolled from another institution, we reexamine the diagnostic capabilities of the test to externally validate our previous study. MATERIALS AND METHODS TWIST1 and NID2 gene methylation was assessed in DNA isolated from the urine of subjects at risk of bladder cancer undergoing cystoscopy for hematuria or bladder cancer surveillance. The diagnostic gold standard was cystoscopy. Two thresholds of TWIST1 and NID2 gene methylation were used for determining test result positivity, those published by Renard et al. and Abern et al. The sensitivity, specificity, positive and negative predictive values, diagnostic likelihood ratios, and receiver operating characteristic curves were calculated for each gene, as well as their combination. In all, 3 methods were used to combine TWIST1 and NID2 into a single composite test: (1) believe-the-positive decision rule-if either gene is methylated the test result is positive, which maximizes test sensitivity; (2) believe-the-negative decision rule-if either gene is not methylated the test result is negative, which maximizes test specificity; and (3) a likelihood-based logistic regression model approach that balances sensitivity and specificity. Clinical utility was determined using a decision curve analysis. RESULTS A total of 209 subjects were evaluated: 40% for hematuria and 60% for bladder cancer surveillance. Approximately 75% were male, most of the prior cancers being low-grade Ta. Using cystoscopy as the gold standard, areas under the curve were 0.67 for TWIST1, 0.64 for NID2, and 0.66 for combined TWIST1 and NID2. Decision rule results revealed optimization of sensitivity at 67% using Renard thresholds and specificity using the Abern thresholds at 69%. We found improved sensitivity (78%) in current smokers. Decision curve analyses revealed that the methylation assay provided only a modest benefit even at high probabilities of missed cancer. CONCLUSION A urine DNA test measuring TWIST1 and NID2 methylation was externally examined with a larger cohort and its results continue to be poor. These 2 biomarkers are unlikely to replace cystoscopy, but they may be worthy of study in active smokers.

Clinical performance and utility of a DNA methylation urine test for bladder cancer

INTRODUCTION Abnormal gene methylation has been observed in several cancers. A prior study reported methylation of TWIST1 and NID2 as a quantitative biomarker for urothelial carcinoma, but external validation has yet to be performed. We sought to externally validate a urine-based methylation assay combining TWIST1 and NID2 and assess its clinical utility. METHODS A prospective trial was conducted comparing the methylation assay to cystoscopy and biopsy in patients with hematuria or prior non-muscle invasive bladder cancer. Sensitivity, specificity, negative and positive predictive values, and likelihood ratios of the methylation assay were calculated. Area under the receiver operating characteristic curves for each gene and the combined assay were computed. Bayesian analyses were performed to assess utility of the assay for a variety of clinical scenarios. RESULTS Complete data were available for 111 patients. In validating the prior assay definition in the current cohort, sensitivity and specificity were 79% and 63%, respectively, and when optimized for the current cohort were 75% and 71%, respectively. The area under the curve for the assay was 0.73 compared with biopsy and 0.71 compared with cystoscopy. CONCLUSIONS We failed to replicate the excellent performance of the methylation assay in this external validation; however, this assay may have utility for screening or surveillance for non-muscle invasive bladder cancer.

Urinary NID2 and TWIST1 methylation to augment conventional urine cytology for the detection of bladder cancer

BACKGROUND Abnormal methylation of urinary TWIST1 and NID2 conferred high sensitivity and specificity for the detection of urothelial carcinoma. OBJECTIVE We examine the performance of the urine-based TWIST1/NID2 methylation assay with the addition of urine cytology for the detection of urothelial carcinoma. MATERIALS AND METHODS A prospective multi-institutional study was conducted to assess the performance of a methylation assay for patients with hematuria or under surveillance for non-muscle invasive bladder cancer (NMIBC). All patients underwent cystoscopy, a methylation assay, and cytology. Receiver operator characteristic (ROC) curves were constructed for cytology alone, the methylation assay alone, and a combined model. Areas under the curve (AUC) were compared using likelihood ratio tests. RESULTS A total of 172 patients were enrolled (37% for hematuria and 63% NMIBC). The AUC for cytology alone with equivocal cytologies positive was 0.704, and improved to 0.773 with the addition of the DNA methylation assay (p < 0.001). When the equivocal cytologies were considered negative, the AUC improved from 0.558 to 0.697 with the addition of the DNA methylation assay (p = 0.003). CONCLUSIONS Addition of a TWIST1/NID2-based DNA methylation assay adds diagnostic value to urine cytology and the model is sensitive to the classification of equivocal cytology.

MP25-11 THE RISE OF OUTPATIENT PENILE PROSTHESIS SURGERY: A CROSS-SECTIONAL ANALYSIS OF NATIONAL TRENDS

number of IPP devices and procedures performed. The median time to development of infection after most recent IPP surgery was 2 months (IQR 1-3.3 months). No clinical or demographic differences were identified between the infection and non-infection cohorts, including age, DM status, tobacco usage, Charleston Comorbidity Index score, prior prostatectomy, prior hernia repair, or Peyronie0s disease. CONCLUSIONS: Infection rates of revision/salvage IPP surgery increase with each subsequent IPP placement or following IPPrelated surgeries. The majority of patients experience at least one infection by their 4th device. This data could provide relevant information necessary for appropriate patient counseling.

PD73-07 ANALYSIS OF RISK FACTORS ASSOCIATED WITH INFECTIONS COMPLICATIONS FOLLOWING PARTIAL NEPHRECTOMY

INTRODUCTION AND OBJECTIVES: The duration of renal ischemia is the largest modifiable risk factor during partial nephrectomy. The shorter the warm ischemia time during LPN the lower the effect on long-term renal function. Real advantages of offclamping LPN compared with clamping surgery are not yet sufficiently studied. Few studies reported results of off-clamping LPN for high RENAL score cases. We compared Trifecta outcomes of the LPN with and without clamping stratifying cases through nephrometric RENAL score. METHODS: A total of 109 cases classified as low-complexity (54), intermediate-complexity (33) and high-complexity (22) underwent clamping (55) or off-clamping (54) laparoscopic partial nephrectomy and were compared in each group (clamping x off-clamping LPN). Clamping technique was performed with cold scissors intended to obtain 0.5cm of free surgical margins. Off-clamp technique was performed with harmonic scalpel close to the plane of enucleating to achieve minimal surgical margins. Renal function was measured at 1, 6 and 12 months postoperatively. All enrolled patients had normal contralateral kidney. Trifecta (Trifecta criteria: Clavien 2, negative-margins, and warm ischemia time 20 min) outcomes were analyzed and compared between the groups stratified by the nephrometric RENAL score. RESULTS: Trifecta achievement was similar in both groups for low complexity tumors (p < 0.31). The off-clamping group achieved higher trifecta rates for the intermediate (87.5% x 23.5%, p < 0.001) and high (83% x 0%, p < 0.005) complexity tumors. Patients with off-clamp technique had higher mean blood loss (150 X 400 ml) with no difference in blood transfusions. In the clamping group, significant higher proportion did not achieve trifecta (45.5% x 7.4%, p < 0.001). After 1 year, the difference of remnant renal function was 10% more for patients with off clamp surgery with high complexity RENAL score CONCLUSIONS: Off-clamping pure LPN was associated to accomplish higher trifecta rates for intermediate and high complexity RENAL score tumors. Long-term renal function was slightly better for off clamp group. It is unclear if off-clamp technique or differences in the amount resected of renal parenchyma were responsible for observed differences.