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Item Targeting Prostate Cancer with Conditionally Replicative Adenovirus Using PSMA Enhancer(ScienceDirect, 2004-12-01) Lee, Sang-Jin; Zhang, Yanping; Lee, Sang Don; Jung, Chaeyong; Li, Xiong; Kim, Hong-Sup; Bae, Kyung-Hee; Jeng, Meei-Huey; Kao, Chinghai; Gardner, Thomas; Urology, School of MedicineProstate cancer is the second most commonly diagnosed cancer in men and accounts for significant mortality and morbidity in the United States. Initially androgen-dependent, prostate cancer ultimately becomes androgen-independent, which makes the disease extremely difficult to cure. In this study, we examined the use of conditionally replication-competent adenovirus for the treatment of hormone-independent prostate cancer. We utilized PSME, an enhancer element for prostate-specific PSMA expression, to control viral E1A protein expression and achieve exclusive virus replication in prostate. Western blotting confirmed that PSME mediated high E1A protein expression in PSMA-positive, androgen-independent prostate cancer cells (C4-2 and CWR22rv), but was much less active in PSMA-negative cancer cells (PC-3 and A549). Consistent with E1A protein expression, the recombinant adenovirus Ad5-PSME-E1a replicated in C4-2 and CWR22rv almost as efficiently as wild type with low levels of androgen, but its replication was significantly attenuated in PSMA-negative cells. In the in vitro killing assay, Ad5-PSME-E1a lysed all C4-2 and CWR22rv cells 5 days after infection, with minimal effect on PSMA-negative cells. In addition, injections of 1.7 × 108 plaque-forming units in a CWR22rv xenograft model in nude mice induced significant tumor growth delay, with a substantial necrotic area. These studies suggest that PSME-driven replication-competent adenovirus may be a new therapeutic modality for prostate cancer patients after hormone ablation therapy.Item 1021. VP22 Mediates Tumor Vasculature Specific Targeting(Elsevier, 2004-05-01) Raikwar, Sudhanshu P.; Gardner, Thomas A.; Kao, Chinghai; Urology, School of MedicineItem Ossabaw Pig Demonstrates Detrusor Fibrosis and Detrusor Underactivity Associated with Oxidative Stress in Metabolic Syndrome(American Association for Laboratory Animal Science, 2020-10) Powell, Charles R.; Kim, Albert; Roth, Joshua; Byrd, James P.; Mohammad, Khalid; Khalid, Mouhamad; Alloosh, Mouhamad; Vittal, Ragini; Sturek, Michael; Urology, School of MedicineMetabolic Syndrome (MetS) has detrimental effects on the bladder, including detrusor underactivity. The progression and mechanism of disease are poorly understood. A swine model for diabetic bladder dysfunction (DBD) was established because of the pig's human-sized bladder and its ability to develop MetS by dietary modification alone. The hypothesis of this study is that this swine model will demonstrate oxidative stress associated with MetS, which contributes to both bladder fibrosis and detrusor underactivity (DU). Ossabaw pigs underwent dietary modification consisting of a hypercaloric, atherogenic diet for 10 mo to induce MetS, and were compared with a group of control (lean) pigs. Urodynamic studies were performed in both groups to confirm DU. Thiobarbituric acid reactive substances (TBARS) detected in the urine were used to measure oxidative stress activity in the urinary tract, and urinary IL17a was used to detect profibrotic activity. MetS was confirmed by assessing body weight, blood pressure, glucose tolerance, total cholesterol, and triglycerides. The MetS group exhibited an increase in the relative levels of urinary TBARS and IL17a. Bladder pressures at capacity were lower in the MetS group, suggesting DU. Histologic analysis of a cohort of control (lean) and MetS pigs revealed that as compared with the control pigs, the MetS pigs had significantly more collagen in the muscularis layer, but not in the submucosa or mucosa layer. In conclusion, the Ossabaw pig model for diet-induced MetS is associated with oxidative stress and profibrotic activity in the bladder, which results in DU. This has previously been shown in mice and rats, but never in pigs. This novel model will better represent human MetS and DBD because the mechanism and size of the pig bladder more closely resemble that of a human, resulting in a more valid model and facilitating further study into the signaling mechanisms responsible for this impairment.Item Expanded Criteria Same Day Catheter Removal Following Holmium Laser Enucleation of the Prostate (HoLEP)(Liebert, 2022-07-05) Slade, Austen; Agarwal, Deepak; Large, Tim; Sahm, Erica; Schmidt, Jonathan; Rivera, Marcelino E; Urology, School of MedicineIntroduction and Objectives Holmium laser enucleation of the prostate (HoLEP) is a highly effective treatment of benign prostatic hyperplasia (BPH). Technical advances and improved hemostatic properties of Holmium lasers have allowed for increased efficiency and outcomes. Same day catheter removal following HoLEP was described at our institution in 2020 following a 30-patient pilot trial. We now present an expanded update following widespread adoption at our facility. Methods We reviewed patients who underwent same day catheter removal after HoLEP between 1/1/2020 and 3/21/2021. Unlike previous trials, there were no limitations to prostate size. Other changes included catheter removal in phase two of recovery when nursing was available rather than the urology clinic. Descriptive statistics are presented of preoperative, operative, and postoperative data. Univariate and multivariate analysis was performed to assess associations with failure of same day void trial. Results The success rate of same-day catheter removal for the 114 identified patients was 87.7%. Mean age was 69.1 8.6 years and prostate volume was 109.2 61.5cc, 35% were dependent on catheterization for urinary retention preoperatively and 9% were on antiplatelet/anticoagulant therapy. A total of 26.5% of patients with ASA 3 or 4 failed catheter removal compared to 3.9% of patients with ASA 1 or 2 (Likelihood ratio 9.32, p=0.002), ASA status lost significance on multivariate analysis (p=0.076). Successful catheter removal was not significantly associated with age, BMI, prostate size, catheter dependency, anticoagulation/antiplatelet therapy, AUA symptom score, prior BPH surgery, or prostate cancer in final pathology. Conclusion Regardless of prostate size, same day catheter removal is a safe and reliable method of post-HoLEP patient management. Patients with an ASA 3 or 4 should be counseled regarding potential risks of temporary re-catheterization. Given ongoing nationwide shortages in hospital beds and staffing, same day discharge and catheter removal may allow for wider availability of surgical treatment for BPH.Item Next generation sequencing in patients with nephrolithiasis: how does it perform compared with standard urine and stone cultures?(Sage, 2021-02-22) Nottingham, Charles U.; Assmus, Mark A.; Peters, Alexander W.; Large, Tim; Agarwal, Deepak K.; Rivera, Marcelino E.; Krambeck, Amy E.; Urology, School of MedicineBackground: Our aim was to compare microorganism detection between standard culture (Ctx) and next generation sequencing (NGS) in patients undergoing surgery for nephrolithiasis; we prospectively compared both urine and stone culture results using these two techniques. Methods: We prospectively compared microorganism detection of urine and stone cultures using Ctx versus NGS in patients undergoing surgery for nephrolithiasis. We analyzed preoperative voided urine (Voided) using both Ctx and NGS. Intraoperatively, renal stone (Stone) cultures were analyzed with Ctx and NGS. The primary outcome was concordance in microorganism detection between Voided Ctx and Stone NGS, as well as between Stone Ctx and Stone NGS. Results: We prospectively evaluated 84 patients. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of Voided Ctx predicting Stone Ctx were 66.7%, 73.7%, 54.5%, and 82.4%, respectively. Concordance of Voided Ctx microorganisms to Stone microorganisms decreased when NGS was used for the Stone compared with Ctx. The sensitivity, specificity, PPV, and NPV of Voided NGS to predict Stone Ctx microorganisms were 85.2%, 24.6%, 34.8%, and 77.8%, respectively. The concordance of Voided NGS to Stone microorganisms improved when the Stone was analyzed via NGS compared with Ctx. Conclusion: NGS has a higher detection rate of microorganisms than standard culture for both preoperative urine and stone cultures. Voided NGS was the most sensitive in predicting a positive Stone sample, but the specificity and PPV were, overall, low. Further correlation of NGS microorganism detection with patient outcomes will determine which clinical situations may benefit most from NGS versus standard culture in patients with urinary-tract stones.Item In Vivo Renal Tubule pH in Stone-Forming Human Kidneys(Mary Ann Liebert, Inc., 2020-02) Borofsky, Michael S.; Handa, Rajash K.; Evan, Andrew P.; Williams, James C., Jr.; Bledsoe, Sharon; Coe, Fredric L.; Worcester, Elaine M.; Lingeman, James E.; Urology, School of MedicineIntroduction: There is evidence that patients with a history of ileostomies, who produce acidic urine and form uric acid or calcium oxalate stones, may plug some collecting ducts with calcium phosphate (CaP) and urate crystals. This is a paradoxical finding as such minerals should not form at an acid pH. One possible explanation is the presence of acidification defects due to focal damage to inner medullary collecting duct and Bellini duct (BD) cells. We sought to further investigate this hypothesis through direct measurement of ductal pH in dilated BDs in patients with ileostomies undergoing percutaneous nephrolithotomy (PCNL) for stone removal. Methods: After obtaining institutional review board approval, we used a fiber-optic pH microsensor with a 140-μm-diameter tip to measure intraluminal pH from the bladder, saline irrigant, and dilated BDs of patients undergoing PCNL. Results: Measurements were taken from three patients meeting inclusion criteria. Measured pH of bladder urine ranged from 4.97 to 5.58 and pH of saline irrigant used during surgery ranged from 5.17 to 5.75. BD measurements were achieved in 11 different BDs. Mean intraductal BD pH was more than 1 unit higher than bulk urine (6.43 ± 0.22 vs 5.31 ± 0.22, p < 0.01). Conclusions: This is the first evidence for focal acidification defects within injured/dilated BDs of human kidneys producing highly acidic bulk phase urine. These results may help explain the paradoxical finding of CaP and urate plugs in dilated ducts of patients with stone-forming diseases characterized by highly acidic urine.Item Consulting “Dr. YouTube”: an objective evaluation of hypospadias videos on a popular video-sharing website(Elsevier, 2020-02-16) Salama, Amr; Panoch, Janet; Bandali, Elhaam; Carroll, Aaron; Wiehe, Sarah; Downs, Stephen; Cain, Mark P.; Frankel, Richard; Chan, Katherine H.; Urology, School of MedicineIntroduction: Parents who make decisions about hypospadias repair for their child may seek information from online platforms such as YouTube. Objective: The purpose of this study is to evaluate the health literacy demand of hypospadias videos on YouTube using the Patient Education Materials Assessment Tool for Audiovisual Materials (PEMAT-A/V). Study design: We performed a YouTube search using the term "hypospadias," limiting results to the first 100 videos. We excluded videos that were <1 min or >20 min and videos that were not in English or did not include subtitles. Two evaluators independently examined videos and determined PEMAT-A/V scores for understandability and actionability (i.e., ability to identify actions the viewer can take). Videos with scores >70% are understandable or actionable. The inter-rater reliability (kappa) and intraclass correlation coefficient (ICC) of PEMAT scores were calculated. Bivariate and multivariable linear regression models assessed the association of video characteristics with respective scores. Results: Of the 100 videos that were identified on YouTube, 47 (47%) were excluded leaving 53 for analysis: 14 were >20 min, 14 were <1 min, 9 had no audio or subtitles, 7 were not in English, 1 was a duplicate, 1 was unrelated to hypospadias, and 1 was deleted at the time of data analysis. Three (5.6%) were understandable (mean score 54.5%, standard deviation (SD) 14.9) and eight (15.1%) were actionable (mean score 21.8%, SD 16.6) (Extended Summary Figure). Kappa values ranged from 0.4 to 1. The ICC's were 0.55 and 0.33 for understandability and actionability, respectively. In the bivariate analysis, mean understandability scores were significantly higher for English language videos (p = 0.04), videos with animation (p = 0.002), and those produced by industry (p = 0.02). In the multivariable analysis, mean understandability scores were significantly higher for "expert testimonial" or "other" video types after adjusting for graphics type and overall tone (p = 0.04). Mean understandability scores were also significantly higher for videos with animation after adjusting for video type and overall tone (p = 0.01). Mean actionability scores were significantly higher for videos with a negative tone (p = 0.01). Discussion: The vast majority of hypospadias-related YouTube content is not appropriate for users with low health literacy although certain types of videos, such those with animation and expert testimonials, scored higher on understandability than other types. Conclusion: Due to the lack of sufficient online informational content regarding hypospadias, we plan to engage parents of sons with hypospadias in the development of high-quality patient educational materials about hypospadias.Item OTL-38-Guided Fluorescent Imaging in Renal Cell Cancer Robotic Partial Nephrectomy(Mary Ann Liebert, Inc., 2017-02-06) Bahler, Clinton D.; Maniar, Viraj; Marley, Kristen N.; Kheyfets, Steven V.; Shum, Cheuk Fan; Sundaram, Chandru P.; Urology, School of MedicineIntroduction and Objective: The folate receptor (FR) protein is upregulated in numerous epithelial malignancies while having limited expression on normal tissues. This overexpression of FR in renal-cell carcinoma (RCC) can be exploited by attaching nearly any therapeutic or imaging agent for delivery to cancer cells. In one of its first applications, platinum-resistant ovarian cancer, folate was used to deliver pegylated liposomal doxorubicin (a folate-linked vinca alkaloid) and improved progression-free survival versus standard treatment. RCCs are thought to be the second highest FR-expressing cancer. OTL-38 is a folate analogue conjugated with a fluorescent dye that emits light in the near infrared spectrum. This longer wavelength allows for deeper penetration of the fluorescent light through tissues with the potential to better image tumors beneath adipose tissue or deeper into organ parenchyma. We are currently conducting a pilot, phase 2, nonrandomized study in patients with RCC, scheduled to undergo primary, partial, or radical nephrectomy. The aim is to explore the use of OTL-38 and fluorescence imaging to observe RCC at the margins of resection in partial nephrectomy and in lymph node(s) or other metastases for radical nephrectomy. Methods: Currently two patients have participated in the trial to date with an accrual target of 20 patients. The first was a 67-year-old male with an incidental 2.2 cm right-sided renal mass, and the second was a 70-year-old male with an enlarging 2 cm renal mass. Per protocol, both patients were administered OTL-38 in the preoperative area 1 hour before the procedure. Subsequently, both procedures were performed with robotic assistance as per normal routine with the use of Firefly fluorescence to aid in observation of OTL-38 uptake. Results: Intraoperative guidance through OTL-38 demonstrated minimal to no uptake of the OTL-38 as seen by Firefly fluorescence (green color). Surprisingly, the normal renal parenchyma showed strong uptake of OTL-38 as seen by Firefly fluorescence. Both pathology reports revealed conventional clear cell RCC. Immunohistochemistry slides of the tumor revealed only mild staining for folate. In contrast, immunohistochemistry slides of the normal renal parenchyma in the surgical margin revealed a strongly positive stain for folate. Conclusions: In conclusion, our first two patients' renal tumors did not stain strongly for folate; however, the normal renal parenchyma did, which served as an intraoperative guide to confirm a negative margin. Further study of patients will reveal whether folate receptors are, in fact, predominant or not in renal cell cancer.Item Introduction of a Renal Papillary Grading System for Patients with Nephrolithiasis(Mary Ann Liebert, Inc., 2015-12-03) Borofsky, Michael Seth; Paonessa, Jessica E.; Evan, Andrew P.; Williams, James C.; Coe, Fredric L.; Worcester, Elaine M.; Lingeman, James E.; Urology, School of MedicineIntroduction: An overlooked finding at the time of renal endoscopy for patients with nephrolithiasis is the appearance of the renal papillae. Recent work has demonstrated that it is possible to distinguish specific stone-forming phenotypes by endoscopic patterns of papillary appearance alone.1-4 These variable expressions are likely to have clinical significance; yet, the ability to pursue such research efforts remains limited by the lack of a standardized system to describe these findings. Herein, we describe a novel grading system designed to standardize and simplify the description of renal papillary appearance in stone formers at the time of endoscopy. Materials and Methods: Since 1999, 342 patients have been prospectively enrolled and given consent to be part of an NIH funded project studying the pathogenesis of stone formation at a single institution (Methodist Hospital, Indiana University Health). Patients have been treated and studied using both percutaneous and retrograde ureteroscopic approaches. Digital scopes are utilized when feasible along with fluoroscopy to map the affected renal unit(s), and stones are removed and analyzed individually when possible.5 Results: Four recurring abnormal papillary features were identified based upon the collective knowledge and expertise of the primary research team. Each variable was then quantitated based on the severity in appearance. Three features believed to be associated with papillary injury include ductal plugging, pitting, and loss of papillary contour. Ductal plugging is evident as either suburothelial deposits of yellow mineral or as dilated ducts of Bellini, presumably left behind after a plug has passed. These two subfeatures are considered the same for the purposes of grading. Pitting reflects crater-like erosion of the papillary surface. Loss of contour reflects global depression of the papilla relative to the surrounding tissue. Upon papillary inspection, each papilla receives a numerical grade from 0 to 2 for each of these measured domains. The three scores are then added together to create a sum total score regarding the degree of papillary injury ranging from 0 to 6. The fourth feature, the amount of Randall's plaque, is evident as white deposits along the papillary surface. It is not known to cause papillary injury6 and, as such, is designated with an alphabetical subscore (a-c) rather than a number. Each papilla then receives a final unique score incorporating both the sum numerical and alphabetical grade. Reference examples are shown in the accompanying video. Conclusions: The creation of a standardized system to describe the papillary appearance in stone formers has considerable clinical and academic utility. On a clinical level, it could be applied as a tool to document intraoperative findings and determine changes in papillary appearance over time in recurrent stone formers. It also has the potential to distinguish high-risk patients with more pressing needs of metabolic evaluations, medical therapy, and surveillance imaging. As a research tool, it would help create a common language to describe papillary appearance and improve collaboration between researchers. It also might allow surgeons to better correlate endoscopic findings to pathological findings and clinical outcomes such as stone analysis, associated metabolic diseases, risk of progressive renal injury, and stone recurrence.Item Temporal study of renal volume losses in patients with robotic partial nephrectomies(Liebert, 2022) Patel, Rushi S; Sundaram, Chandru P; Kondo, Tsunenori; Bahler, Clinton D; Urology, School of MedicinePurpose: Robotic partial nephrectomies by their nature are associated with renal volume loss. Our goal from this study is to examine renal volume loss over time post partial nephrectomy. Materials and Methods: Fifty patients were followed for 1-year post robotic partial nephrectomy with two-layer renorrhaphy and the sliding clip technique. This was done with a preoperative computed tomography (CT) scan to assess renal mass and location. Post robotic partial nephrectomy patients were imaged at time points 3-days, 6-months, and 12-months. Results: Patient demographics were 82% male with a median (IQR) age of 57 (45-67)and all were of Japanese descent. The medians (IQR) for warm ischemia time: 18 minutes (14-22), total operative time: 181.5 minutes (169.3-218.5), and estimated blood loss: 20 mL (10-50). The tumor characteristics had a median (IQR) diameter of 2.8 cm (2.5-3.4)with a RENAL score of 7 (6-8). The renal CT volumes showed median (IQR) volume losses at 3-days: -1% (-7.1, 1.8), 6-months: -15.3% (-20.6, -11.2), and 12-months: -16.3% (-19.0, -12.8). Significance was seen at the 3-days to 6-months comparison for volume loss (p<0.0001). Mean (SD) eGFR losses were as follows: at discharge 0.5% (12.9), 1-month -6.4% (11.8), 6-months -4.6% (9.8), and 12-months -3.6% (11.9). Statistical analysis showed significance for GFR loss at the comparison between discharge to 1-month and 6-months (p=0.01, p=0.04).Conclusion: The initial volume loss seen post-surgery from resected healthy tissue was not significant and only became relevant atlonger time points suggesting that loss could be from atrophy. Volume loss over time supports the hypothesis that suture renorrhaphy is a primary cause of volume loss when warm ischemia time is <25minutes.