Endourology survey on radiation exposure and post-ureteroscopy US and CT reveals a need for clear guidelines.

BACKGROUND: Nephrolithiasis patients undergo repeated imaging increasing their radiation risk. Guidelines recommend imaging following ureteroscopic lithotripsy (URSL), but not the modality or frequency of imaging. As such, we sought to elucidate common imaging practices following URSL and current knowledge of radiation exposure among endourologists. METHODS: A web-based survey of Endourological Society members was used to evaluate knowledge and clinical practices regarding radiation exposure in post-URSL imaging. Respondents were grouped by years of experience (< 10, >= 10 years) and geographic location (USA or non-USA). An interaction term was included in the models to allow response rate to vary across experience level with geographic location and P values were derived from model main effects. RESULTS: A total of 309 respondents answered the survey out of the 1800 active members of the Endourological Society that received the survey (17.2% total response rate). 204 of the respondents were included in our analysis as fellowship trained endourologists that perform URSL with a mean of 13.3 years in practice (IQR 6.75, 20 years). Overall, routine postoperative imaging is performed by 92% of respondents: 97% in the USA and 88% outside the US (P = 0.143). 39% of respondents correctly estimated standard dose CT scan (SCT) dose, while 36% correctly estimated that of a low-dose CT scan (LCT). American urologists correctly identified the SCT radiation dose more often than non-US respondents (54% vs 32%, respectively) (P value = 0.004). Respondents with < 10 years of experience more frequently identified the correct SCT dose (52% vs. 34%, respectively), though not significantly so (P value = 0.171). 79% of respondents consider LCT quality to be similar to SCT and 50% would use LCT on obese patients. However, only 26% of respondents identified that image quality deteriorates with BMI > 30 kg/m2. CONCLUSIONS: We demonstrate a knowledge gap regarding radiation exposure during CT scans and the limitations of low-dose CT imaging. This gap is wider in non-US-based urologists and in those with over 10 years of experience. However, all urologists would benefit from improved education and clear guidelines regarding radiation exposure in nephrolithiasis patients.

Targeting Bladder Urothelial Carcinoma with pHLIP-ICG and Inhibition of Urothelial Cancer Cell Proliferation by pHLIP-amanitin.

Acidity is a useful biomarker for the targeting of metabolically active-cells in tumors. pH Low Insertion Peptides (pHLIPs) sense the pH at the surfaces of tumor cells and can facilitate intracellular delivery of cell-permeable and cell-impermeable cargo molecules. In this study we have shown the targeting of malignant lesions in human bladders by fluorescent pHLIP agents, intracellular delivery of amanitin toxin by pHLIP for the inhibition of urothelial cancer cell proliferation, and enhanced potency of pHLIP-amanitin for cancer cells with 17p loss, a mutation frequently present in urothelial cancers. Twenty-eight ex-vivo bladder specimens, from patients undergoing robotic assisted laparoscopic radical cystectomy for bladder cancer, were treated via intravesical incubation for 15-60 minutes with pHLIP conjugated to indocyanine green (ICG) or IR-800 near infrared fluorescent (NIRF) dyes at concentrations of 4-8 µM. White light cystoscopy identified 47/58 (81%) and NIRF pHLIP cystoscopy identified 57/58 (98.3%) of malignant lesions of different subtypes and stages selected for histopathological processing. pHLIP NIRF imaging improved diagnosis by 17.3% (p < 0.05). All carcinoma-in-situ cases missed by white light cystoscopy were targeted by pHLIP agents and were diagnosed by NIRF imaging. We also investigated the interactions of pHLIP-amanitin with urothelial cancer cells of different grades. pHLIP-amanitin produced concentration- and pH-dependent inhibition of the proliferation of urothelial cancer cells treated for 2 hrs at concentrations up to 4 µM. A 3-4x enhanced cytotoxicity of pHLIP-amanitin was observed for cells with a 17p loss after 2 hrs of treatment at pH6. Potentially, pHLIP technology may improve the management of urothelial cancers, including imaging of malignant lesions using pHLIP-ICG for diagnosis and surgery, and the use of pHLIP-amanitin for treatment of superficial bladder cancers via intravesical instillation.

Development of a Deep Learning Algorithm for the Histopathologic Diagnosis and Gleason Grading of Prostate Cancer Biopsies: A Pilot Study.

BACKGROUND: The pathologic diagnosis and Gleason grading of prostate cancer are time-consuming, error-prone, and subject to interobserver variability. Machine learning offers opportunities to improve the diagnosis, risk stratification, and prognostication of prostate cancer. OBJECTIVE: To develop a state-of-the-art deep learning algorithm for the histopathologic diagnosis and Gleason grading of prostate biopsy specimens. DESIGN, SETTING, AND PARTICIPANTS: A total of 85 prostate core biopsy specimens from 25 patients were digitized at 20× magnification and annotated for Gleason 3, 4, and 5 prostate adenocarcinoma by a urologic pathologist. From these virtual slides, we sampled 14803 image patches of 256×256 pixels, approximately balanced for malignancy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We trained and tested a deep residual convolutional neural network to classify each patch at two levels: (1) coarse (benign vs malignant) and (2) fine (benign vs Gleason 3 vs 4 vs 5). Model performance was evaluated using fivefold cross-validation. Randomization tests were used for hypothesis testing of model performance versus chance. RESULTS AND LIMITATIONS: The model demonstrated 91.5% accuracy (p<0.001) at coarse-level classification of image patches as benign versus malignant (0.93 sensitivity, 0.90 specificity, and 0.95 average precision). The model demonstrated 85.4% accuracy (p<0.001) at fine-level classification of image patches as benign versus Gleason 3 versus Gleason 4 versus Gleason 5 (0.83 sensitivity, 0.94 specificity, and 0.83 average precision), with the greatest number of confusions in distinguishing between Gleason 3 and 4, and between Gleason 4 and 5. Limitations include the small sample size and the need for external validation. CONCLUSIONS: In this study, a deep learning-based computer vision algorithm demonstrated excellent performance for the histopathologic diagnosis and Gleason grading of prostate cancer. PATIENT SUMMARY: We developed a deep learning algorithm that demonstrated excellent performance for the diagnosis and grading of prostate cancer.

Intravesical docetaxel for high-risk non-muscle invasive bladder cancer after Bacillus Calmette-Guérin failure.

BACKGROUND: There are limited bladder-preserving therapeutic options for patients with high-risk non-muscle invasive bladder cancer (NMIBC) after failed Bacillus Calmette-Guérin (BCG) therapy. Salvage intravesical docetaxel therapy was described in 2006 but has not been validated outside of the original institution. In this study, we presented the first external report on the oncologic outcomes of intravesical docetaxel. MATERIALS AND METHODS: We identified 13 patients with high-risk NMIBC treated with ≥1 course of intravesical BCG who received salvage intravesical docetaxel. Recurrence-free survival (RFS) was estimated using the Kaplan-Meier method. Associations of clinicopathologic features with RFS were evaluated using Cox regression. RESULTS: Median age was 75.2 years, and 46.2% of patients were male. Of the patients 92.3% had a prior diagnosis of high-grade T1 disease, 38.5% had a prior diagnosis of carcinoma in situ, and 46.2% had received ≥2 courses of BCG. Only 1 (7.7%) patient experienced docetaxel-related toxicity. Nine (69.2%) patients had a complete response at initial post-docetaxel cystoscopy. During a median follow-up of 12.0 (interquartile range 5.0-18.1) months, a total of 7 (53.8%) patients developed recurrence. Median time to recurrence was 10.1 (interquartile range 4.8-11.6) months. Estimated RFS at 6-, 12-, 18-, and 24-months was 75%, 50%, 50%, and 25%. Three (23.1%) patients ultimately underwent cystectomy. On univariable analysis, multiple courses of induction BCG were associated with decreased RFS, although this did not reach statistical significance (hazard ratio 4.69, p = 0.08). CONCLUSIONS: In this first external validation study, intravesical docetaxel was associated with excellent response rates and intermediate-term RFS among patients with high-risk NMIBC after failed BCG therapy.

p53 Expression, Programmed Death Ligand 1, and Risk Factors in Urinary Tract Small Cell Carcinoma.

Introduction: Small cell carcinoma of the urinary tract (SCCUT) is a rare finding with poor clinical course. This study sheds light on the molecular subtype and identifies risk factors in patients diagnosed with SCCUT. Methods: Immunohistochemical expression of immunotherapy target programmed death ligand 1 (PD-L1) and luminal (GATA3), basal (p63), and p53 markers are assessed in patients diagnosed with SCCUT. Univariate analysis identified risk factors. Overall survival (OS) is computed using the Kaplan-Meier method. Results: Tissue was available for 70.2% (33/47). All showed a high PD-L1 expression phenotype. p53 is seen in 93.9% (31/33), mostly as overexpression, GATA3 in 45.5% (15/33), and p63 in 57.6% (19/33). For the entire cohort (n = 47), 1-year survival was 59.6%, and the median OS was 17 months. Univariate analysis shows that chemotherapy [hazard ratio (HR) = 0.29, 95% confidence interval (CI) = 0.14-0.61, p = 0.001], radical surgery (HR = 0.37, 95% CI = 0.18-0.76, p = 0.007), and diagnosis of non-pure SCCUT (HR = 0.44, 95% CI = 0.22-0.86, p = 0.02) are favorable prognostic features. Metastasis had negative associations with survival (HR = 2.1, 95% CI = 1.1-4.2, p = 0.03). Conclusions: In this series, pure and mixed SCCUT are characterized by p53 overexpression and a high PD-L1 phenotype. Histology of non-pure SCCUT is a positive prognosticator, and radical cystectomy or chemotherapy can improve OS. These findings demonstrate that SCCUT may be eligible for PD-L1 immunotherapy.

Clinically node-positive (cN+) urothelial carcinoma of the bladder treated with chemotherapy and radical cystectomy: Clinical outcomes and development of a postoperative risk stratification model.

INTRODUCTION AND OBJECTIVE: Although node-positive (cN+) bladder cancer is considered Stage IV disease, a subset of patients is treated with chemotherapy and consolidative radical cystectomy (RC). We examined the clinical outcomes of such patients and developed a risk prediction model to facilitate risk-stratification and management. METHODS: We identified adult patients with cTany cN1-3 M0 urothelial carcinoma of the bladder treated with chemotherapy followed by RC from 2006 to 2013 in the NCDB. The associations of clinicopathologic features with overall survival (OS) were evaluated using Cox regression, and a simplified risk score was developed. RESULTS: A total of 491 patients received chemotherapy followed by RC. Median number of lymph nodes removed was 16 (interquartile range 9-25). At RC, 10% of patients were ypT0, and 35% were ypN0. Over a median follow-up of 18.7 months, 160 patients died of any cause. 1-, 5-, and 8-year OS were 69%, 34%, and 29%, respectively. On multivariable analysis, pT stage (hazard ratio [HR] 2.18; P = 0.003 for pT3, HR 2.65; P < 0.001 for pT4 vs.

Ex-vivo Imaging of Upper Tract Urothelial Carcinoma Using Novel pH Low Insertion Peptide (Variant 3), a Molecular Imaging Probe.

OBJECTIVE: To improve visualization of upper tract urothelial carcinomas. Previous studies using the novel pH low insertion peptide (pHLIP) variant 3 (Var3) conjugated to indocyanine green (ICG) have demonstrated high sensitivity and specificity for imaging of bladder urothelial carcinoma. Here, we describe a novel approach for the imaging of upper tract urothelial carcinomas using ICG-Var3 pHLIP. METHODS: Twelve ex-vivo upper urinary tract specimens were irrigated with ICG-Var 3 pHLIP for 15 minutes and then examined using a white light laparoscopic camera followed by near infrared fluorescent (NIRF) imaging using a Stryker 1588 AIM imaging system. Standard histopathologic evaluation was performed and findings were correlated with white light and ICG-Var3 NIRF imaging. One patient who underwent radical nephrectomy for renal cell carcinoma was used as a negative control. RESULTS: Nineteen lesions were identified on histopathologic evaluation in 10 patients, including 82% high-grade urothelial carcinoma and 18% low-grade urothelial carcinoma. Nineteen (100%) malignant lesions were identified using NIRF imaging, while 15 (78.9%) lesions were identified using conventional white light examination. The sensitivity of ICG-Var3 pHLIP NIRF imaging was 100% compared to 78.9% white light examination. Both modalities are 100% specific. Benign collecting systems and ureters did not show uptake of the pHLIP construct. CONCLUSION: In this feasibility study, the ICG-Var3 pHLIP imaging agent demonstrated superior diagnostic performance compared to conventional white light examination. While additional studies are required for validation and in-vivo translation, pHLIP-based imaging represents a promising tool to improve the evaluation and management of upper tract urothelial carcinoma.

Indications for stent omission after ureteroscopic lithotripsy defined: A single-institution experience with cost analysis.

Objectives: To report on our experience with the use of an evidence-based algorithm defining specific indications for stent omission (SO) after ureteroscopic lithotripsy (URSL), as stent placement has been associated with increased cost and morbidity and indications for SO in the setting of uncomplicated ureteroscopy have been proposed but remain vague. Patients and methods: Indications for SO were defined as per the attached figure, data from URSL procedures performed from January 2016 to September 2017 were collected. For procedures eligible for SO, preoperative and intraoperative factors were recorded including: stone burden, presence of preoperative stent, procedure time, access sheath use, and whether SO was performed. Morbidity data were reviewed including: postoperative events, patient telephone calls for bothersome symptoms, unplanned return visits, and admissions within 30 days. Results: In all, 250 URSL procedures were performed during the study period, and 106 (42.4%) were eligible for SO. SO was performed in 60 (24.0%) cases reflecting a 56.7% compliance with the algorithm. There were no readmissions or re-operations within 30 days for the SO group. Lower postoperative event rates were noted in the SO group (16.7% vs 34.8%, P = 0.03), unplanned return visits (8.3% vs 17.4%, P = 0.16) and 30-day readmission rates (0.0% vs 6.5%, P = 0.08) were also lower in the SO group, although they did not reach statistical significance. Analysis also demonstrated a protective effect of SO on unplanned return visits (odds ratio 0.43, 95% confidence interval 0.13-1.42, P = 0.17), although this was not statistically significant. No statistically significant associations were noted between postoperative events and stone burden, procedure time, or presence of preoperative stent. Conclusions: We provide an algorithm defining indications for SO. SO is safe in a significant portion of URSL procedures, and SO appears to decrease postoperative events when performed judiciously. Abbreviations: IQR: interquartile range; LUTS: lower urinary tract symptoms; OR, odds ratio; SO: stent omission; URSL: ureteroscopic lithotripsy; YAG: yttrium-aluminium-garnet.

The BMI Paradox and Robotic Assisted Partial Nephrectomy.

Introduction: Partial nephrectomy (PN), has become the gold standard for the surgical management of small renal masses, due to excellent oncologic control with concomitant preservation of nephron units. However, data regarding the association of obesity with perioperative outcomes following PN are mixed. Therefore, the association between obesity (using BMI) and post-operative complications (POC) rate following Robotic assisted laparoscopic PN (RPNx) was tested. Methods: Two hundred and fifty-one adult patients who underwent RPNx from 1/2011 to 5/2017 at a single institution, with at least 90 days follow-up were identified and included. No patients were excluded. Electronic medical records were reviewed to record all POC within 90 days of surgery. A piecewise generalized linear model for binary outcomes (logistic) was used to model the proportion of subjects with POC by their BMI. The slope of the line is adjusted to a BMI of 30 Kg/m2. Results: BMI is significantly associated with POC rate. POC rate decreased with increasing BMI below the inflection point of 30 Kg/m2 (0.848[0.756, 0.952]) (OR [95% CI], p = 0.005). POC rate was found to increase with increasing BMI above the BMI inflection of 30 Kg/m2 (1.102 [1.027, 1.182], p = 0.0071). Conclusions: In this cohort study, BMI showed an association with PC. It may be important to take BMI into account in surgical and clinical management considerations of RPNx, since higher rates of POC are associated with patients who are underweight, morbidly obese, and even with normal BMI. Further research is required on larger cohorts of RPNx patients to provide better description of this phenomenon and elucidate the role of BMI in development of POC.