Should I freeze my sperm?-readability and quality of health resources for sperm banking.

Background: Sperm banking refers to the collection and storage of sperm cells for future use. Despite the recommendations of major medical societies, sperm banking is not discussed sufficiently with patients at risk of future fertility. Majority of Americans utilize the internet regarding health information. The aim of this study is to assess the reading level and the quality of online health information on sperm banking. Methods: The top 50 search results from Google, Bing, and Yahoo were selected after searching for the term "sperm banking". Duplicate pages, advertisements, news and magazines, blog posts, videos, paid subscriptions, articles intended for health professionals, and non-related pages were excluded. Four validated readability and two quality assessment tools were used to score the text. Websites were divided into five categories: academic, hospital-affiliated, commercial, non-profit health advocacy, and non-categorized. Descriptive statistics, one sample t-test, and Pearson's correlation coefficient were used to analyze the data. Results: Forty-one webpages were included. The mean Flesch Reading Ease Score (FRES) for all pages was 46.9/100 and the mean reading level was 11th grade, compared to the recommended 6th grade level, across various assessment tools. Utilizing the DISCERN Instrument, quality of online health information was fair. Seven percent of pages received a "good" quality score and no pages received a score of "excellent". On average, 1.5 out of 4 criteria categorized by the JAMA Benchmark, a validated quality assessment tool, were met. The hospital-affiliated webpages received the best reading scores and commercial pages received the highest quality scores. Conclusions: Online health information on sperm banking available in English is of poor quality based on several quality assessment tools and at a reading level significantly higher than what is recommended. Further efforts are needed by providers and healthcare institutions to improve the quality of information available to patients.

A middle-aged man with hyperandrogenic state.

Hyperandrogenism secondary to testicular cancer typically arises in patients in whom Leydig cell hyperplasia or neoplasia can be identified. Additionally, benign and malignant adrenocortical tumors can also present with signs and symptoms of hyperandrogenism. We report a case of a 40-year-old gentleman who experienced several months of weight gain, worsening gynecomastia, and mood changes secondary to high testosterone and estradiol levels. Workup initially was negative for testicular malignancy and positive for a benign-appearing lesion in the adrenal gland. Despite adrenalectomy, symptoms continued to persist and ultimately a testicular cancer without Leydig cell involvement was identified.

Ureteritis cystica mimicking upper tract urothelial cancer in a patient with bladder cancer.

Ureteritis cystica is a rare condition of the upper urinary tract characterized by the presence of numerous small cystic lesions. Associated urinary tract malignancy is exceedingly rare, and ureteritis cystica is not thought to have malignant potential. We present the case of a 62-year-old male who was found to have both urothelial carcinoma of the bladder and numerous filling defects of the bilateral upper urinary tracts which were subsequently diagnosed as ureteritis cystica. To our knowledge this is the only published case of ureteritis cystica associated with bladder cancer and the clinical challenges it poses.

Chronic Kidney Disease and Kidney Cancer Surgery: New Perspectives.

PURPOSE: We sought to provide a contemporary understanding of chronic kidney disease and its relevance to kidney cancer surgery. Another purpose was to resolve points of discrepancy regarding the survival benefits of partial vs radical nephrectomy by critically evaluating the results of prospective and retrospective studies in the urological literature. MATERIALS AND METHODS: We performed a comprehensive literature search for relevant articles listed in MEDLINE® from 2002 to 2018 using the key words radical nephrectomy, partial nephrectomy, glomerular filtration rate, kidney function and chronic kidney disease. We also assessed select review articles and society guidelines about chronic kidney disease pertinent to urology and nephrology. RESULTS: Complete evaluation of the potential consequences of chronic kidney disease involves assessment of the cause, the glomerular filtration rate level and the degree of albuminuria. Chronic kidney disease is commonly defined in the urological literature solely as a glomerular filtration rate less than 60 ml/minute/1.73 m2. This ignores the significance of the cause of chronic kidney disease, and the presence and degree of albuminuria. Although this glomerular filtration rate is relevant for preoperative assessment of patients who undergo surgery of kidney tumors, recent studies suggest that a glomerular filtration rate less than 45 ml/minute/1.73 m2 represents a more discerning postoperative prognostic threshold. Reported survival benefits of partial over radical nephrectomy in retrospective studies were likely influenced by selection bias. The lack of survival benefit in the partial nephrectomy cohort in the only randomized trial of partial vs radical nephrectomy was consistent with data demonstrating that patients in each study arm were at relatively low risk for mortality due to chronic kidney disease when accounting for the chronic kidney disease etiology and the postoperative glomerular filtration rate. CONCLUSIONS: The prognostic risk of chronic kidney disease in patients with kidney cancer is increased when the preoperative glomerular filtration rate is less than 60 ml/minute/1.73 m2 or the postoperative rate is less than 45 ml/minute/1.73 m2. Additional factors, including nonsurgical causes of chronic kidney disease and the degree of albuminuria, can also dramatically alter the consequences of chronic kidney disease after kidney cancer surgery. Urologists must have a comprehensive knowledge of chronic kidney disease to assess the risks and benefits of partial vs radical nephrectomy when managing tumors with increased complexity and/or oncologic aggressiveness.

Second primary lung cancer in United States Cancer Survivors, 1992-2008.

PURPOSE: Lung cancer is common and lethal, and can occur in survivors of previous cancers. We sought to describe the incidence and mortality attributable to second primary lung cancers (SPLC) among survivors of other cancers, and to identify survivors at highest risk. METHODS: We identified adults diagnosed with a localized malignancy from non-pulmonary cancer sites from surveillance, epidemiology, and end results (SEER) data from 1992 to 2008. We explored factors associated with the incidence and death from SPLC using bivariable and multivariable models. Finally, we compared standardized incidence rates for SPLC in our cohort with the control arm of the National Lung Screening Trial (NLST), a randomized lung cancer screening trial. RESULTS: We identified 1,450,837 survivors of non-pulmonary cancers, of whom 25,472 developed SPLC at a mean (SD) follow-up of 5.7 (3.6) years. Over half (57%) of patients with SPLC died of the disease. Survivors of cancer of the hypopharynx, oropharynx, tonsil, and larynx, experienced SPLC at standardized incidence rates which greatly exceeded that observed in the control arm of the NLST (572/100,000 person-years). Additionally, survivors of bladder and esophageal cancer had rates that approached the NLST control arm rate. Increasing age and being divorced/widowed/separated were independent risk factors for SPLC in most primary cancer types. CONCLUSION: The incidence of SPLC in survivors of certain primary cancers greatly exceeds the rate observed in the control arm of the NLST. Further study could help determine if screening for lung cancer in these cancer survivors could prevent death from lung cancer.

Continuous saline bladder irrigation for two hours following transurethral resection of bladder tumors in patients with non-muscle invasive bladder cancer does not prevent recurrence or progression compared with intravesical Mitomycin-C.

BACKGROUND: Intravesical Mitomycin-C (MMC) following transurethral resection of bladder tumor (TURBT), while efficacious, is associated with side effects and poor utilization. Continuous saline bladder irrigation (CSBI) has been examined as an alternative. In this study we sought to compare the rates of recurrence and/or progression in patients with NMIBC who were treated with either MMC or CSBI after TURBT. METHODS: We retrospectively reviewed records of patients with NMIBC at our institution in 2012-2015. Perioperative use of MMC (40 mg in 20 mL), CSBI (two hours), or neither were recorded. Primary outcome was time to recurrence or progression. Descriptive statistics, chi-squared analysis, Kaplan-Meier survival analysis, and Cox multivariable regression analyses were performed. RESULTS: 205 patients met inclusion criteria. Forty-five (22.0%) patients received CSBI, 71 (34.6%) received MMC, and 89 (43.4%) received no perioperative therapy. On survival analysis, MMC was associated with improved DFS compared with CSBI (p = 0.001) and no treatment (p = 0.0009). On multivariable analysis, high risk disease was associated with increased risk of recurrence or progression (HR 2.77, 95% CI: 1.28-6.01), whereas adjuvant therapy (HR 0.35, 95% CI: 0.20-0.59) and MMC (HR 0.43, 95% CI: 0.25-0.75) were associated with decreased risk. CONCLUSIONS: Postoperative MMC was associated with improved DFS compared with CSBI and no treatment. The DFS benefit seen with CSBI in other studies may be limited to patients receiving prolonged irrigation. New intravesical agents being evaluated may consider saline as a control given our data demonstrating that short-term CSBI is not superior to TURBT alone.

Analysis of National Trends in Hospital Acquired Conditions Following Major Urologic Surgery Before and After Implementation of the Hospital Acquired Condition Reduction Program.

OBJECTIVE: To define the rates of common hospital acquired conditions (HACs) in patients undergoing major urologic surgery over a period of time encompassing the implementation of the Hospital Acquired Condition Reduction program, and to evaluate whether implementation of the HAC reimbursement penalties in 2008 was associated with a change in the rate of HACs. METHODS: Using American College of Surgeons National Surgical Quality Improvement Program data, we determined rates of HACs in patients undergoing major inpatient urologic surgery from 2005 to 2012. Rates were stratified by procedure type and approach (open vs laparoscopic and/or robotic). Multivariable logistic regression was used to determine the association between year of surgery and HACs. RESULTS: We identified 39,257 patients undergoing major urologic surgery, of whom 2300 (5.9%) had at least one hospital acquired condition. Urinary tract infection (2.6%) was the most common, followed by surgical site infection (2.5%) and venous thrombotic events (0.7%). Multivariable logistic regression analysis demonstrated that open surgical approach, diabetes, congestive heart failure, chronic obstructive pulmonary disease, weight loss, and American Society of Anesthesiology class were among the variables associated with higher likelihood of HAC. We observed a nonsignificant secular trend of decreasing rates of HAC from 7.4% to 5.8% HACs during the study period, which encompassed the implementation of the Hospital Acquired Condition Reduction program. CONCLUSION: HACs occurred at a rate of 5.9% after major urologic surgery, and are significantly affected by procedure type and patient health status. The rate of HAC appeared unaffected by National Reduction program in this cohort. Better understanding of the factors associated with HACs is critical in developing effective reduction programs.

Association between Metabolic Syndrome and Recurrence of Nonmuscle Invasive Bladder Cancer following bacillus Calmette-Guérin Treatment.

INTRODUCTION: Intravesical bacillus Calmette-Guérin (BCG) therapy is the gold standard adjuvant treatment for patients with high-grade non-muscle-invasive bladder cancer (NMIBC). Despite the association between metabolic syndrome (MetS) and bladder cancer, the association between MetS and BCG failure is unknown. The objective of this study was to characterize disease recurrence following BCG in patients with and without MetS. METHODS: We retrospectively evaluated the records of patients undergoing TURBT at our institution in 2012-2015 for NMIBC and identified those who received adjuvant BCG therapy. MetS was defined as having three of four components: diabetes mellitus, hyperlipidemia, hypertension, or body mass index (BMI)≥30kg/m2. The primary outcome was recurrence or progression. Descriptive statistics, chi-squared analysis, Kaplan-Meier survival analysis, and Cox multivariable regression analyses were performed. RESULTS: High grade was present in 83/90 (92.2%) patients. MetS was present in 27/90 (30%) patients. Median follow-up was 20 months. On Kaplan-Meier analysis, patients with MetS had worse DFS compared with patient without MetS. On multivariable analysis, BMI≥30 kg/m2 was a significant predictor of recurrence or progression (HR 2.94, 95% CI: 1.43-6.03). Presence of MetS did not significantly affect the type of BCG failure. CONCLUSIONS: The association between MetS and failure to respond to BCG therapy is multifactorial but is in part associated with obesity. Elevated BMI is strongly associated with recurrence or progression. Further studies are warranted to investigate the relationship between increased adiposity and response to BCG, especially as other novel immunotherapeutic agents are likely to enter the NMIBC space.

Effect of Malnutrition on Radical Nephroureterectomy Morbidity and Mortality: Opportunity for Preoperative Optimization.

INTRODUCTION: Nutritional status has been increasingly recognized as an important predictor of prognosis and surgical outcomes for cancer patients. We evaluated the effect of preoperative malnutrition on the development of surgical complications and mortality after radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC). MATERIALS AND METHODS: Using data from the American College of Surgeons National Surgical Quality Improvement Program, we evaluated the association of poor nutritional status with 30-day postoperative complications and overall mortality after RNU from 2005 to 2015. The preoperative variables suggestive of poor nutritional status included hypoalbuminemia (< 3.5 g/dL), weight loss within 6 months before surgery (> 10%), and a low body mass index. RESULTS: A total of 1200 patients were identified who had undergone RNU for UTUC. The overall complication rate was 20.5% (n = 246), and mortality rate was 1.75% (n = 21). On univariate analysis, patients who experienced a postoperative complication were more likely to have hypoalbuminemia (25.0% vs. 11.4%; P < .001) and weight loss (3.7% vs. 1.0%; P = .003). After controlling for baseline characteristics and comorbidities, hypoalbuminemia was found to be a significant independent predictor of postoperative complications (odds ratio, 2.09; 95% confidence interval, 1.29-3.38; P = .003). Hypoalbuminemia was also a significant independent predictor of mortality (odds ratio, 4.31; 95% confidence interval, 1.45-12.79; P = .008) on multivariable regression analysis. CONCLUSION: Our results have shown that hypoalbuminemia is a significant predictor of surgical complications and mortality after RNU for UTUC. This finding supports the importance of patients' preoperative nutritional status in this population and suggests that effective nutritional interventions in the preoperative setting could improve patient outcomes.

Overall survival in patients with metastatic renal cell carcinoma and clinical N1 disease undergoing cytoreductive nephrectomy and lymph node dissection.

BACKGROUND: Patients with metastatic renal cell carcinoma (mRCC) have limited treatment options. Cytoreductive nephrectomy (CN) in select patients has been associated with improved survival. We aim to assess the survival in patients with mRCC and cN1 disease who underwent CN with and without lymph node dissection (LND). METHODS: Data were abstracted from the National Cancer Database for patients diagnosed with mRCC and cN1 from 2003 to 2014. Using propensity matching, we compared overall survival (OS) in patients who underwent a LND. Kaplan-Meier survival analysis and multivariable Cox proportional hazards modeling were used. We performed a logistic regression to assess predictors of LND. RESULTS: We identified 1,780 patients in the matched cohort, of which 71% underwent a LND. Patients undergoing LND were younger (P = 0.01) and had similar size tumors (5cm; P = 0.31). Increased LN yield was associated with LND at an academic center (odds ratio = 1.91; 95% CI: 1.51-2.42; P<0.01). LND was associated with worse OS on KM analysis (log rank; P = 0.01). However, on multivariable analysis, we found no significant difference in OS (hazard ratio = 1.10; 95% CI: 0.94-1.29; P = 0.22). However, when adjusting for number of positive LN removed, an increase in LN yield was associated with improved OS (hazard ratio = 0.97; 95% CI: 0.95-0.99; P = 0.01). CONCLUSION: We demonstrate that patients with mRCC and cN1 disease undergoing LND did not have a survival benefit when compared with patients undergoing CN. However, lymph node yield showed an increase in survival when adjusting for the number of positive lymph nodes. Further research and validation of the ideal number of LN removed that may benefit patients is warranted.

Role of surgical approach on lymph node dissection yield and survival in patients with upper tract urothelial carcinoma.

OBJECTIVES: With increasing utilization of robot-assisted surgery in urologic oncology, robotic nephroureterectomy (RNU) is becoming the surgical modality of choice for patients with upper tract urothelial carcinoma (UTUC). The role of surgical approach on lymph node dissection (LND) and lymph node (LN) yield is unclear, and potential therapeutic effects are unknown. Here we analyze the effects of surgical approach on LN yield, performance of LND, and overall survival (OS). METHODS AND MATERIALS: Patients with UTUC who underwent nephroureterectomy from 2010 to 2013 were identified in the National Cancer Database. Outcomes of interest included rate of LND, LN yield, and OS. Logistic regression analyses were used to predict performance of LND. Negative binomial regression was used to derive incidence rate ratios for LN yield. Cox proportional hazards models were used to quantify survival outcomes. RESULTS: A total of 3,116 patients met inclusion criteria. LND was performed in 41% (314/762) of RNU, 27% (380/1385) of LNU cases, and 35% (340/969) of ONU (P<0.001). Compared with an ONU, patients who underwent a LNU had significantly lower odds of receiving a LND (OR = 0.70, 95% CI: 0.55-0.87) and had fewer LNs removed (IRR = 0.69, 95% CI: 0.60-0.80), while RNU trended toward increased LN yield (IRR = 1.14, 95% CI: 0.98-1.33). In a Cox proportional hazards model, increasing LN yield was associated with improved OS in patients with pN0 disease (HR = 0.97 per 1 unit increase in LN yield, 95% CI: 0.95-0.99). CONCLUSIONS: Compared with an ONU, RNU does not compromise performance of a LND and may be associated with improved LN yield. LNU is associated with the lowest rates of LND and LN yield. Increasing LN yield is associated with improved OS in patients with pN0 disease. Despite differential rates of LND and LN yield, surgical approach did not independently affect OS.

Trends in usage of cytoreductive partial nephrectomy and effect on overall survival in patients with metastatic renal cell carcinoma.

PURPOSE: Cytoreductive radical nephrectomy (cRN) improves survival in select patients with metastatic renal cell carcinoma (mRCC). It is unclear, however, whether cytoreductive partial nephrectomy (cPN) compromises oncologic efficacy. We evaluated trends in utilization of cPN and compared overall survival (OS) in patients who underwent cRN or cPN for mRCC. MATERIALS AND METHODS: We queried the National Cancer Database from 2006 to 2013 and identified patients who underwent cPN and cRN for mRCC. We analyzed rates of cPN over time. Logistic regression identified predictors of cPN. We matched patients based on propensity score for treatment. We used matched Kaplan-Meier survival analyses to compare OS, stratified by tumor size. We used multivariable Cox proportional hazards models to determine the effect of cPN and cRN on OS. RESULTS: A total of 10,144 patients met inclusion criteria, with 9,764 (96.2%) undergoing cRN and 381 (3.8%) undergoing cPN. Rates of cPN increased over time from 1.8% to 4.3% over the study period. Treatment at an academic/research facility, papillary and chromophobe histology, and more recent year of treatment were associated with increased odds of cPN. In a matched survival analysis, cPN was associated with improved OS compared with cRN (log rank, P = 0.001). This effect was limited to primary tumors<4cm. In a propensity-score adjusted multivariable Cox model, cPN was associated with improved OS (hazard ratio = 0.81; 95% CI: 0.71-0.93; P = 0.002). CONCLUSIONS: The use of cPN in patients with mRCC is increasing. cPN is associated with improved OS in patients with mRCC, although this effect is limited to patients with primary tumors<4cm.

Adjuvant Therapy for High Risk Localized Kidney Cancer: Emerging Evidence and Future Clinical Trials.

PURPOSE: We reviewed the literature on adjuvant therapies for patients with high risk localized kidney cancer following surgical resection. In this analysis we merge 2 recently published prospective trials with conflicting results within the context of their respective designs. In addition, we spotlight upcoming trials that use novel immunotherapy based checkpoint inhibitors and have the potential to establish a new standard of care. MATERIALS AND METHODS: We searched PubMed® for English language articles published through January 2017 using the keywords "renal cell carcinoma," "kidney cancer," "immunotherapy," "targeted therapy" and "adjuvant therapy." ClinicalTrials.gov was queried for ongoing studies. Relevant data recently presented at major urology and medical oncology meetings are also included. RESULTS: Adjuvant therapies for high risk localized kidney cancer can be grouped into the categories of 1) traditional immunotherapy, 2) inhibitors of the vascular endothelial growth factor and mTOR (mammalian target of rapamycin) pathways, 3) vaccines and antibody dependent cytotoxic agents, and 4) immune checkpoint inhibitors. Several trials of traditional immunotherapy, such as interferon-α and high dose interleukin-2, failed to demonstrate benefit as adjuvant treatment and were associated with significant adverse events. Vascular endothelial growth factor and mTOR inhibitors have less severe toxicity in metastatic disease and, therefore, are natural considerations for adjuvant trials. However, current data are conflicting. The ASSURE (Sunitinib Malate or Sorafenib Tosylate in Treating Patients with Kidney Cancer that was Removed by Surgery, NCT00326898) trial found no recurrence-free survival benefit of sorafenib or sunitinib over placebo, while S-TRAC (Clinical Trial Comparing Efficacy and Safety of Sunitinib versus Placebo for the Treatment of Patients at High Risk of Recurrent Renal Cell Cancer, NCT00375674) revealed that 1 year of sunitinib improved recurrence-free survival by 1.2 years. Vaccine based treatments and antibody dependent cytotoxic agents have had mixed results. New trials evaluating immune checkpoint inhibitors are planned, given the impressive efficacy and tolerability as second line agents in metastatic disease. Future adjuvant trials are likely to be guided by molecular signatures to treat patients most likely to benefit. CONCLUSIONS: Based on the available data, there appears to be no role for traditional immunotherapy as adjuvant treatment in patients with high risk localized kidney cancer following surgical resection. S-TRAC provides evidence that 1 year of adjuvant sunitinib in patients with higher risk locoregional disease increases the median time to recurrence. However, the data on overall survival are immature and adverse effects are common. Results from trials investigating immune checkpoint inhibitors are highly anticipated.

Why Targeting PSMA Is a Game Changer in the Management of Prostate Cancer.

Prostate-specific membrane antigen (PSMA) is a transmembrane glycoprotein that is highly expressed on prostate adenocarcinomas, exhibits only limited expression in benign and extraprostatic tissues, and thus represents an ideal target for the diagnosis and management of prostate cancer. Since its discovery over 30 y ago, significant effort has been made to develop clinical technology targeting PSMA. The last 5 y have seen an explosion of development of new agents targeting PSMA for diagnostic and therapeutic use. Imaging agents targeting PSMA have been developed for SPECT and PET platforms. PSMA PET imaging appears to outperform traditional imaging in the high-risk localized-disease state, in patients with biochemical recurrence after treatment, and in advanced disease. To date, most of the reported clinical studies of therapeutic agents have used PSMA-targeted radiometals to deliver ß-radiation to metastatic disease sites, with 177Lu being the most widely investigated therapeutic radioisotope. Studies of both antibodies and small-molecule agents have been published and have demonstrated encouraging results. Safety appears generally limited to mild transient bone marrow toxicity and xerostomia because of uptake of the small-molecule agents in the salivary glands. Radiologic responses can be dramatic, and decreases in pain have been observed. The effect on overall survival, however, has yet to be demonstrated.

Evaluation of Unplanned Hospital Readmissions After Major Urologic Inpatient Surgery in the Era of Accountable Care.

OBJECTIVE: To provide a multi-institutional analysis of clinical factors predicting unplanned hospital readmission after major inpatient urologic surgery. MATERIALS AND METHODS: The American College of Surgeons National Surgical Quality Improvement Program is a risk-adjusted data collection mechanism for analyzing clinical outcomes data including 30-day perioperative readmissions and complications. We identified 23,108 patients who underwent major inpatient urologic surgery from 2011 to 2012. Readmission rates were determined and stratified by procedure type. Multiple logistic regression was used to determine independent risk factors for 30-day unplanned hospital readmissions. RESULTS: Of a total of 23,108 patients undergoing urologic surgery, 1329 patients (5.8%) had unplanned readmissions. Upper tract reconstruction and urinary diversion without cystectomy (21/102) and with cystectomy (291/1662) had the highest rates of readmission of all procedures analyzed. Readmitted patients had a 64.2% (853/1329) and 64.4% (855/1329) rate of major and minor complications, respectively, compared with 6.7% (1459/21,779) and 15.9% (3462/21,779) for patients not readmitted (P <.02). Organ space infection (odds ratio [OR] 15.23), pulmonary embolism (OR 12.14), deep venous thrombosis (OR 10.96), and return to the operating room (OR 8.46) were the most substantial predictors of readmission. Laparoscopic-robotic procedures had significantly lower readmission rates compared with open procedures for prostatectomy, partial nephrectomy, and nephrectomy (P <.01). CONCLUSION: Readmission after inpatient urologic surgery occurs at a rate of 5.8%, with cystectomy and urinary diversion demonstrating the highest rates. Major and minor postoperative complications were the most substantial predictors of readmission. These results may guide risk reduction initiatives to prevent readmissions after major urologic surgery.

Genomic landscape and evolution of metastatic chromophobe renal cell carcinoma.

Chromophobe renal cell carcinoma (chRCC) typically shows ~7 chromosome losses (1, 2, 6, 10, 13, 17, and 21) and ~31 exonic somatic mutations, yet carries ~5%-10% metastatic incidence. Since extensive chromosomal losses can generate proteotoxic stress and compromise cellular proliferation, it is intriguing how chRCC, a tumor with extensive chromosome losses and a low number of somatic mutations, can develop lethal metastases. Genomic features distinguishing metastatic from nonmetastatic chRCC are unknown. An integrated approach, including whole-genome sequencing (WGS), targeted ultradeep cancer gene sequencing, and chromosome analyses (FACETS, OncoScan, and FISH), was performed on 79 chRCC patients including 38 metastatic (M-chRCC) cases. We demonstrate that TP53 mutations (58%), PTEN mutations (24%), and imbalanced chromosome duplication (ICD, duplication of ≥ 3 chromosomes) (25%) were enriched in M-chRCC. Reconstruction of the subclonal composition of paired primary-metastatic chRCC tumors supports the role of TP53, PTEN, and ICD in metastatic evolution. Finally, the presence of these 3 genomic features in primary tumors of both The Cancer Genome Atlas kidney chromophobe (KICH) (n = 64) and M-chRCC (n = 35) cohorts was associated with worse survival. In summary, our study provides genomic insights into the metastatic progression of chRCC and identifies TP53 mutations, PTEN mutations, and ICD as high-risk features.

A phase 2 study of TMX-101, intravesical imiquimod, for the treatment of carcinoma in situ bladder cancer.

PURPOSE: Imiquimod is a toll-like receptor agonist with proven antitumor activity as a topical treatment for skin cancer. TMX-101 (Vesimune) is a novel liquid formulation of imiquimod optimized for intravesical delivery. The agent demonstrated safety as an intravesical treatment for non-muscle-invasive bladder cancer in a phase 1 clinical trial. We report the results of a phase 2 prospective multicenter clinical trial assessing the safety and activity of TMX-101. MATERIALS AND METHODS: Patients with non-muscle-invasive bladder cancer containing carcinoma in situ were eligible for inclusion. Enrolled patients received 6 weekly intravesical administrations of 200mg/50ml TMX-101 0.4%. End points included rate of adverse events, changes in urinary cytokine levels following treatment, and clinical response at 6 weeks following final instillation, defined as negative posttreatment bladder biopsy and urine cytology results. RESULTS: A total of 12 patients were enrolled, with 10 available for efficacy analysis. Half of the patients (6/12) had received≥2 prior induction courses of bacillus Calmette-Guerin. All patients received all 6 doses of TMX-101 per protocol. Overall, 75% of patients experienced treatment-related adverse events, only 1 of which was>grade 2 (urinary tract infection). Furthermore, 2 patients demonstrated a negative cytology and biopsy result at 6 weeks following treatment. Significant increases in urinary cytokines, including IL-6 and IL-18, were seen following treatment. CONCLUSION: In this phase 2 pilot study in patients with carcinoma in situ bladder cancer, intravesical TMX-101 was safe and well tolerated with common, mild genitourinary adverse effects. Clinical activity was suggested by the increase in posttreatment urinary cytokines. Complete responders were seen. Further investigation of the agent is warranted.

Serial retrograde instillations of sustained release formulation of mitomycin C to the upper urinary tract of the Yorkshire swine using a thermosensitive polymer: Safety and feasibility.

BACKGROUND: MitoGel is a novel drug formulation intended for the treatment of upper tract urothelial cancer with proven feasibility and safety in an animal model. OBJECTIVE: To evaluate the feasibility, safety, toxicokinetics, and histologic changes associated with serial retrograde MitoGel instillations to the upper urinary tract in a swine model. DESIGN, SETTING, AND PARTICIPANTS: Overall, 27 Yorkshire swine underwent 6 once-weekly unilateral retrograde instillations of MitoGel. Doses of 14, 28, or 56-mg mitomycin C (respective concentrations of 2, 4, and 8mg/ml with 9 animals per group) were evaluated. Additionally, 6 animals received sterile water as a procedure control, and 9 received gel alone (without mitomycin C), as a vehicle control. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Blood and urine samples were collected for determination of MMC toxicokinetics and for hematology, biochemistry, coagulation, and urinalysis throughout the study. Two-thirds of the cohort were euthanized 24 hours after final instillation, and one-third was euthanized 1 month after final instillation. Necropsy was performed to evaluate the histologic effects of treatments. RESULTS AND LIMITATIONS: All animals received all 6 doses of agents per protocol. No mortality, clinical adverse events, or meaningful changes in hematology, chemistry, coagulation, or urinalysis were attributable to MitoGel, RTGel alone, or water instillations. Peak plasma levels of MMC were 2 orders of magnitude less than known toxicity thresholds. MitoGel-related dose-dependent microscopic findings were seen in the treated kidneys and ureters, but were of limited severity, lacked associated clinical adverse findings, and decreased over time. CONCLUSIONS: Serial retrograde instillations of MitoGel to the pyelocaliceal system were technically feasible, and produced no observable adverse clinical, laboratory, or histologic effects.

Immunotherapy for the Treatment of Urothelial Carcinoma.

PURPOSE: We review the biological mechanisms of action, clinical safety and efficacy of immunotherapies for urothelial carcinoma. We also describe current areas of research in immunotherapy, and highlight ongoing trials and promising and novel investigational agents. MATERIALS AND METHODS: Data were obtained by a search of PubMed®, ClinicalTrials.gov and Cochrane databases for English language articles published through February 2016. Applicable abstracts from recent Society of Urologic Oncology, European Association of Urology, American Urological Association and ASCO® meetings were used. RESULTS: Bacillus Calmette-Guérin is one of the most successful immunotherapies in cancer treatment and remains the gold standard of care for patients with high risk, nonmuscle invasive bladder cancer, with initial response rates of approximately 70%. However, with the exception of valrubicin and standard chemotherapeutics there is a paucity of available treatment options for patients with recurrence or progression to more advanced disease. Recently there has been significant interest in novel immunotherapeutic agents in the management of cases where bacillus Calmette-Guérin fails, as well as cases of more advanced cancer. These investigational therapies can generally be classified into several broad categories, including recombinant bacillus Calmette-Guérin and cell wall derived therapies, cytokines, gene therapy, cancer vaccines, immune checkpoint inhibitors, oncolytic viruses, adoptive immunotherapies and immune agonists, as well as several additional immunomodulatory agents. The majority of these agents are currently under investigation in phase I or II clinical trials. Recently investigators reported evidence that inhibition of the PD-1/PD-L1 pathway has clinical activity in patients with advanced bladder cancer. These findings, along with successful phase III trials and U.S. Food and Drug Administration approvals of other checkpoint inhibitors in melanoma, nonsmall cell lung cancer and renal cell carcinoma, ultimately led to Food and Drug Administration approval of atezolizumab for advanced disease, the first new treatment approved for advanced urothelial carcinoma in 20 years. CONCLUSIONS: While bacillus Calmette-Guérin has demonstrated significant clinical efficacy in the treatment of patients with bladder cancer, additional therapies are needed for those in whom bacillus Calmette-Guérin fails, as well as for those with advanced disease. Immunotherapy for urothelial carcinoma remains a promising and active area of research, and numerous agents, particularly the monoclonal antibodies targeting checkpoint inhibition pathways, are showing encouraging signs of clinical activity.