Cystoscopy and Systematic Bladder Tissue Sampling in Predicting pT0 Bladder Cancer: A Prospective Trial.

PURPOSE: Concern for discordance between clinical staging and final pathology drives current management of patients deemed appropriate candidates for radical cystectomy. Therefore, we set out to prospectively investigate reliability and shortcomings of cystoscopic evaluation in radical cystectomy candidates. MATERIALS AND METHODS: Patients undergoing radical cystectomy for urothelial carcinoma were enrolled in a prospective single-arm study to evaluate reliability of Systematic Endoscopic Evaluation in predicting pT0 urothelial carcinoma (NCT02968732). Systematic Endoscopic Evaluation consisted of cystoscopy and tissue sampling at the time of radical cystectomy. Systematic Endoscopic Evaluation results were compared to radical cystectomy pathology. The primary end point was the negative predictive value of Systematic Endoscopic Evaluation findings in predicting radical cystectomy pathology. RESULTS: A total of 61 patients underwent Systematic Endoscopic Evaluation and radical cystectomy. Indications included muscle invasive bladder cancer in 42 (68.9%) and high risk nonmuscle invasive bladder cancer in 19 (31.1%). In all, 38 (62.3%, 90.5% of patients with muscle invasive bladder cancer) received neoadjuvant chemotherapy. On Systematic Endoscopic Evaluation, 31 (50.8%) patients demonstrated no visual nor biopsy-based evidence of disease (seeT0), yet 16/31 (51.6%) harbored residual disease (>pT0), including 8 (8/31, 25.8%) with residual ≥pT2 disease upon radical cystectomy. The negative predictive value of Systematic Endoscopic Evaluation predicting a pT0 bladder was 48.4% (CI 30.2-66.9), which was below our prespecified hypothesis. Therefore, the trial was stopped for futility. CONCLUSIONS: Approximately 1 of 4 patients with seeT0 at the time of radical cystectomy harbored residual muscle invasive bladder cancer. These prospective data definitively confirm major limitations of endoscopic assessment for pT0 bladder cancer. Future work should focus on novel imaging and biomarker strategies to optimize evaluations before radical cystectomy for improved decision making regarding bladder preservation.

Clinical implications of molecular subtyping in bladder cancer.

PURPOSE OF REVIEW: The purpose of this review is to examine and evaluate similarities and differences in bladder cancer expression subtypes and to understand the clinical implications of the molecular subtyping. RECENT FINDINGS: Four independent classification systems have been described, and there are broad similarities among the subtyping callers. Two major subtypes have been identified, that is, luminal and basal, with underlying subcategories based on various distinct characteristics. Luminal tumors generally bear a better prognosis and increased survival than basal tumors, although there is subtle variation in prognosis among the different subtypes within the luminal and basal classifications. Clinical subtyping is now commercially available, although there are limitations to its generalizability and application. SUMMARY: Expression subtyping is a new method to personalize bladder cancer management. However, there is probably not sufficient evidence to incorporate use into current standards-of-care. Validation cohorts with clinically meaningful outcomes may further establish the clinical relevance of molecular subtyping of bladder cancer. Additionally, genetic alterations in bladder cancer may 'color' the interpretation of individual tumors beyond the expression subtype to truly personalize care for bladder cancer.

Perioperative Outcomes Following Partial Nephrectomy Performed on Patients Remaining on Antiplatelet Therapy.

PURPOSE: We evaluated the risk of bleeding complications in patients undergoing partial nephrectomy in whom perioperative antiplatelet therapy was continued, as antiplatelet therapy is increasingly used and hemorrhage is a significant concern in partial nephrectomy. MATERIALS AND METHODS: In this 2-center retrospective analysis 1,097 patients underwent partial nephrectomy between 2000 and 2014. The cohort was split into 3 groups of perioperative continuation of antiplatelet therapy (group 1-67), antiplatelet therapy stopped preoperatively (group 2-254) and no chronic antiplatelet therapy (group 3-776). Bleeding complications were defined as any transfusion, or any hospital readmission or secondary procedure performed for hemorrhage. Multivariable analysis was performed to elucidate independent risk factors for bleeding complications. RESULTS: Patients in group 1 were older (median age 66 years vs 64 and 57 years in groups 2/3, p <0.0001), and had greater comorbidity (median ASA classification score 3 vs 2 and 2, p <0.0001). Group 1 had a higher rate of bleeding complications (20.9% vs 7.1% and 6.4%, p <0.0001) and transfusions (16.4% vs 5.9% and 5.4%, p=0.002). Multivariable analysis revealed continued antiplatelet therapy was an independent predictor of bleeding complications (OR 2.19, 95% CI 1.06-4.51, p=0.03). These findings appear attributable to intraoperative clopidogrel use. On multivariable analysis the use of aspirin alone was not associated with bleeding complications (OR 1.64, 95% CI 0.72-3.75, p=0.24). CONCLUSIONS: The risk of bleeding complications due to antiplatelet therapy use at partial nephrectomy may be due to clopidogrel. The need to continue perioperative aspirin alone does not appear to be a contraindication to the safe performance of partial nephrectomy.

Genomic Copy Number Alterations in Renal Cell Carcinoma with Sarcomatoid Features.

PURPOSE: Sarcomatoid changes in renal cell carcinoma are associated with a poor prognosis. The identification of genetic alterations that drive this aggressive phenotype could aid in the development of more effective targeted therapies. In this study we aimed to pinpoint unique copy number alterations in sarcomatoid renal cell carcinoma compared to classical renal cell carcinoma subtypes. MATERIALS AND METHODS: Genomic copy number analysis was performed using single nucleotide polymorphism based microarrays on tissue extracted from the tumors of 81 patients who underwent renal mass excision, including 17 with sarcomatoid renal cell carcinoma. RESULTS: Sarcomatoid renal cell carcinoma showed a significantly higher number of copy number alterations than clear cell, papillary and chromophobe renal cell carcinoma (mean 18.0 vs 5.8, 6.5 and 7.2, respectively, p <0.0001). Copy number losses of chromosome arms 9q, 15q, 18p/q and 22q, and gains of 1q and 8q occurred in a significantly higher proportion of sarcomatoid renal cell carcinomas than in the other 3 histologies. Patients with sarcomatoid renal cell carcinoma demonstrated significantly worse overall survival compared to those without that condition on Kaplan-Meier analysis (p = 0.0001). Patients with 9 or more copy number alterations also demonstrated significantly worse overall survival than those with fewer than 9 copy number alterations (p = 0.004). CONCLUSIONS: Sarcomatoid changes in renal cell carcinoma are associated with a high rate of chromosomal imbalances with losses of 9q, 15q, 18p/q and 22q, and gains of 1q and 8q occurring at significantly higher frequencies in comparison to nonsarcomatoid renal cell carcinoma. Identifying candidate driver genes or tumor suppressor loci in these chromosomal regions may help identify targets for future therapies.

Surgical Apgar Score predicts an increased risk of major complications and death after renal mass excision.

PURPOSE: Tailoring perioperative management to minimize the postoperative complication rates depends on reliable prognostication of patients most at risk. The Surgical Apgar Score is an objective measure of the operative course validated to predict major complications and death after general/vascular surgery. We assessed the ability of the Surgical Apgar Score to identify patients most at risk for postoperative morbidity and mortality after renal mass excision. MATERIALS AND METHODS: Data for 886 patients undergoing renal mass excision via radical or partial nephrectomy from 2010 to 2013 were extracted from a prospectively collected database. The Surgical Apgar Score was calculated using electronic anesthesia records. Major postoperative complications, readmission and reoperation within 30 days of surgery as well as 90-day mortality were examined. RESULTS: Overall 13.2% of patients experienced major postoperative complications at 30 days. Clavien grade I, II, III, IV and V complications were experienced by 1.7%, 2.9%, 5.8%, 1.9% and 0.9%, respectively. The 90-day all cause mortality rate was 1.4%. The Surgical Apgar Score was significantly lower in patients experiencing major complications (mean 7.3 vs 7.8, p=0.004) and death (6.3 vs 7.7, p=0.03). Patients with a Surgical Apgar Score of 4 or less were 3.7 times more likely to experience a major complication (p=0.01) and 24 times more likely to die within 90 days of surgery (p=0.0007) compared to patients with a Surgical Apgar Score greater than 8. CONCLUSIONS: The Surgical Apgar Score is an easily collected metric that can identify patients at higher risk for major complications and death after renal mass excision. A prospective trial to help further delineate the optimal use of this tool in an adjusted perioperative management approach with patients undergoing renal mass excision is warranted.

Role of Gut Microbiome in Neoadjuvant Chemotherapy Response in Urothelial Carcinoma: A Multi-institutional Prospective Cohort Evaluation.

Neoadjuvant chemotherapy (NAC) is linked with clinical advantages in urothelial carcinoma for patients with muscle-invasive bladder cancer (MIBC). Despite comprehensive research into the influence of tumor mutation expression profiles and clinicopathologic factors on chemotherapy response, the role of the gut microbiome (GM) in bladder cancer chemotherapy response remains poorly understood. This study examines the variance in the GM of patients with bladder cancer compared with healthy adults, and investigates GM compositional differences between patients who respond to chemotherapy versus those who exhibit residual disease.Our study reveals distinct clustering, effectively separating the bladder cancer and healthy cohorts. However, no significant differences were observed between chemotherapy responders and nonresponders within community subgroups. Machine learning models based on responder status outperformed clinical variables in predicting complete response (AUC 0.88 vs. AUC 0.50), although no single microbial species emerged as a fully reliable biomarker.The evaluation of short chain fatty acid (SCFA) concentration in blood and stool revealed no correlation with responder status. Still, SCFA analysis showed a higher abundance of Akkermansia (rs = 0.51, P = 0.017) and Clostridia (rs = 0.52, P = 0.018), which correlated with increased levels of detectable fecal isobutyric acid. Higher levels of fecal Lactobacillus (rs = 0.49, P = 0.02) and Enterobacteriaceae (rs = 0.52, P < 0.03) correlated with increased fecal propionic acid.In conclusion, our study constitutes the first large-scale, multicenter assessment of GM composition, suggesting the potential for a complex microbial signature to predict patients more likely to respond to NAC based on multiple taxa. SIGNIFICANCE: Our study highlights results that link the composition of the GM to the efficacy of NAC in MIBC. We discovered that patients with higher levels of Bacteroides experienced a worse response to NAC. This microbial signature shows promise as a superior predictor of treatment response over traditional clinical variables. Although preliminary, our findings advocate for larger, more detailed studies to validate these associations.

Urine Biopsy as Dynamic Biomarker to Enhance Clinical Staging of Bladder Cancer in Radical Cystectomy Candidates.

PURPOSE: There is significant interest in identifying complete responders to neoadjuvant chemotherapy (NAC) before radical cystectomy (RC) to potentially avoid removal of a pathologically benign bladder. However, clinical restaging after NAC is highly inaccurate. The objective of this study was to develop a next-generation sequencing-based molecular assay using urine to enhance clinical staging of patients with bladder cancer. METHODS: Urine samples from 20 and 44 patients with bladder cancer undergoing RC were prospectively collected for retrospective analysis for molecular correlate analysis from two clinical trials, respectively. The first cohort was used to benchmark the assay, and the second was used to determine the performance characteristics of the test as it correlates to responder status as measured by pathologic examination. RESULTS: First, to benchmark the assay, known mutations identified in the tissue (MT) of patients from the Accelerated Methotrexate, Vinblastine, Doxorubicin, Cisplatin trial (ClinicalTrials.gov identifier: NCT01611662, n = 16) and a cohort from University of California-San Francisco (n = 4) were cross referenced against mutation profiles from urine (MU). We then determined the correlation between MU persistence and residual disease in pre-RC urine samples from a second prospective clinical trial (The pT0 trial; ClinicalTrials.gov identifier: NCT02968732). Residual MU status correlated strongly with residual disease status (pT0 trial; n = 44; P = .0092) when MU from urine supernatant and urine pellet were assessed separately and analyzed in tandem. The sensitivity, specificity, PPV, and NPV were 91%, 50%, 86%, and 63% respectively, with an overall accuracy of 82% for this second cohort. CONCLUSION: MU are representative of MT and thus can be used to enhance clinical staging of urothelial carcinoma. Urine biopsy may be used as a reliable tool that can be further developed to identify complete response to NAC in anticipation of safe RC avoidance.

Characterization of Changes in Penile Microbiome Following Pediatric Circumcision.

BACKGROUND: While microbiome and host regulation contribute independently to many disease states, it is unclear how circumcision in pediatric population influences subsequent changes in penile microbiome. OBJECTIVE: Our study aims to analyze jointly paired taxonomic profiles and assess pathways implicated in inflammation, barrier protection, and energy metabolism. DESIGN, SETTING, AND PARTICIPANTS: We analyzed 11 paired samples, periurethral collection, before and after circumcision, to generate microbiome and mycobiome profiling. Sample preparation of 16S ribosomal RNA and internal transcribed spacer sequencing was adapted from the methods developed by the National Institutes of Health Human Microbiome Project. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We obtained the predictive functional attributes of the microbial communities between samples using Silva-Tax4Fun and the Greengenes-Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) approach. The predictive functioning of the microbial communities was determined by linearly combining the normalized taxonomic abundances into the precomputed association matrix of Kyoto Encyclopedia of Genes and Genomes orthology reference profiles. RESULTS AND LIMITATIONS: Several notable microbiome and mycobiome compositional differences were observed between pre- and postcircumcision patients. Pairwise comparisons across taxa revealed a significant decrease (p < 0.05, false discovery rate corrected) of microbiome organisms (Clostridiales, Bacteroidales, and Campylobacterales) and mycobiome (Saccharomycetales and Pleosporales) following circumcision. A total of 14 pathways were found to differ in abundance between the pre- and postcircumcision groups (p < 0.005, false discovery rate <0.1 and linear discriminant analysis score >3; five enriched and nine depleted). The pathways reduced after circumcision were mostly involved with amino acid and glucose metabolism, while pathways prior to circumcision were enriched in genetic information processing and transcription processes. As expected, enrichment in methyl-accepting chemotaxis protein, an integral membrane protein involved in directed motility of microbes to chemical cues and environment, occurred prior to circumcision, while the filamentous hemagglutinin pathway (a strong immunogenic protein) was depleted after circumcision CONCLUSIONS: Our results offer greater insight into the host-microbiota relationship of penile circumcision and may serve to lay the groundwork for future studies focused on drivers of inflammation, infection, and oncogenesis. PATIENT SUMMARY: Our study showed a significant reduction in bacteria and fungi after circumcision, particularly anaerobic bacteria, which are known to be potential inducers of inflammation and cancer. This is the first study of its kind showing the changes in microbiome after circumcision, and some of the changes that occur in healthy infants after circumcision that may explain the differences in cancer and inflammatory disorders in adulthood.

Role of Gut Microbiome in Neoadjuvant Chemotherapy Response in Urothelial Carcinoma: A Multi-Institutional Prospective Cohort Evaluation.

Treatment with neoadjuvant chemotherapy (NAC) in muscle invasive bladder cancer (MIBC) is associated with clinical benefit in urothelial carcinoma. While extensive research evaluating role of tumor mutational expression profiles and clinicopathologic factors into chemoresponse has been published, the role of gut microbiome (GM) in bladder cancer in chemoresponse has not been thoroughly evaluated. A working knowledge of the microbiome and its effect on all forms of cancer therapy in BC is critical. Here we examine gut microbiome of bladder cancer patients undergoing NAC. Overall, there was no significant difference in alpha and beta diversity by responder status. However, analysis of fecal microbiome samples showed that a higher abundance of Bacteroides within both institutional cohorts during NAC was associated with residual disease at the time of radical cystectomy regardless of chemotherapy regimen. Group community analysis revealed presence of favorable microbial subtypes in complete responders. Finally, fecal microbial composition outperformed clinical variables in prediction of complete response (AUC 0.88 vs AUC 0.50), however, no single microbial species could be regarded as a fully consistent biomarker. Microbiome-based community signature as compared to single microbial species is more likely to be associated as the link between bacterial composition and NAC response.

Human Gut Mycobiome and Fungal Community Interaction: The Unknown Musketeer in the Chemotherapy Response Status in Bladder Cancer.

Background: Until recently, the properties of microbiome and mycobiome in humans and its relevance to disease have largely been unexplored. While the interest of microbiome and malignancy over the past few years have burgeoned with advent of new technologies, no research describing the composition of mycobiome in bladder cancer has been done. Deciphering of the metagenome and its aggregate genetic information can be used to understand the functional properties and relationships between the bacteria, fungi, and cancer. Objective: The aim of this project is to characterize the compositional range of the normal versus bladder cancer mycobiome of the gut. Design setting and participants: An internal transcribed spacer (ITS) survey of 52 fecal samples was performed to evaluate the gut mycobiome differences between noncancer controls and bladder cancer patients. Outcome measurements and statistical analysis: Our study evaluated the differences in mycobiome among patients with bladder cancer, versus matched controls. Our secondary analysis evaluated compositional differences in the gut as a function of response status with neoadjuvant chemotherapy. Data demultiplexing and classification were performed using the QIIME v.1.1.1.1 platform. The Ion Torrent-generated fungal ITS sequence data were processed using QIIME (v.1.9.1), and the reads were demultiplexed, quality filtered, and clustered into operation taxonomic units using default parameters. Alpha and beta diversity were computed and plotted in Phyloseq, principal coordinate analysis was performed on Bray-Curtis dissimilarity indices, and a one-way permutational multivariate analysis of variance was used to test for significant differences between cohorts. Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) was applied to infer functional categories associated with taxonomic composition. Results and limitations: We found distinctive mycobiome differences between control group (n = 32) and bladder cancer (n = 29) gut flora, and identified an increasing abundance of Tremellales, Hypocreales, and Dothideales. Significant differences in alpha and beta diversity were present between the groups (control vs bladder; p = 0.002), noting distinct compositions within each cohort. A subgroup analysis by sex and neoadjuvant chemotherapy status did not show any further differences in mycobiome composition and diversity. Our results indicate that the gut mycobiome may modulate tumor response to preoperative chemotherapy in bladder cancer patients. We propose that patients with a "favorable" mycobiome composition (eg, high diversity, and low abundance of Agaricomycetes and Saccharomycetes) may have enhanced systemic immune response to chemotherapy through antigen presentation. Conclusions: Our study is the first to characterize the enteric mycobiome in patients with bladder cancer and describe complex ecological network alterations, indicating complex bacteria-fungi interactions, particularly highlighted among patients with complete neoadjuvant chemotherapy response. Patient summary: Our study has demonstrated that the composition of stool mycobiome (fungal inhabitants of the gastrointestinal tract) in patients with bladder cancer is different from that in noncancer individuals. Furthermore, when evaluating how patients respond to chemotherapy given prior to their surgery, our study noted significant differences between patients who responded and those who did not.

Bladder preservation: Translating discovery for clinical impact in urothelial cancer.

Muscle-invasive bladder cancer can be treated with either radical cystectomy or bladder preservation approaches, and there is a need for reliable biomarkers to guide the optimal choice of therapy. The recent elucidation of the genomic landscape and biological drivers of bladder cancer has enabled the identification of tumor molecular features that may be helpful in driving clinical decision-making. Here, we summarize recent efforts to develop molecular biomarkers that could be leveraged to guide therapeutic decisions, post-treatment monitoring, and the optimal use of bladder preservation approaches for the effective treatment of muscle-invasive bladder cancer.

Differential Effects of Clinically Relevant N- versus C-Terminal Truncating CDKN1A Mutations on Cisplatin Sensitivity in Bladder Cancer.

Muscle-invasive bladder cancer (MIBC) frequently harbors mutations in the CDKN1A gene, which encodes the tumor suppressor protein p21, with the majority of alterations truncating the peptide. The effect of these mutations is poorly understood. We hypothesized that after DNA-damaging events, cells deficient in p21 would be unable to halt the cell cycle and efficiently repair DNA damage, thus proceeding down the apoptotic pathway. We used synthetic CRISPR guide RNAs to ablate the whole peptide (sg12, targeting the 12th amino acid) or the C-terminal proliferating cell nuclear antigen (PCNA)-binding domain (sg109) to mimic different p21-truncating mutations compared with a negative control (sgGFP) in bladder cancer cell lines. Loss of detectable p21 and a stable truncated p21 peptide were identified in sg12 and sg109 single-cell clones, respectively. We found that p21-deficient cells (sg12) were sensitized to cisplatin, while cells harboring distally truncated p21 (sg12 clones) demonstrated enhanced cisplatin resistance. p21-deficient sg12 clones demonstrated less repair of DNA-platinum adducts and increased γ-H2AX foci after cisplatin exposure, suggesting there was persistent DNA damage after p21 loss. p21-deficient sg12 clones were also unable to prevent the activation of CDK1 after DNA damage, and therefore, continued through the cell cycle, resulting in replication fork collapse, potentially explaining the observed cisplatin sensitization. sg109 clones were neither unable to sequester PCNA nor localize p21 to the nucleus after DNA damage, potentially explaining the chemoresistant phenotype. Our findings suggest that different CDKN1A truncations have different and perhaps disparate biology, and that there may be a duality of effect on cisplatin sensitivity depending on mutation context. IMPLICATIONS: Some truncating CDKN1A mutations generate a retained peptide that may have neomorphic functions and affect cisplatin sensitivity in patients with bladder cancer.

Synthesis, characterization, and biological activity of a triphenylphosphonium-containing imidazolium salt against select bladder cancer cell lines.

Imidazolium salts have shown great promise as anticancer materials. A new imidazolium salt (TPP1), with a triphenylphosphonium substituent, has been synthesized and evaluated for in vitro and in vivo cytotoxicity against bladder cancer. TPP1 was determined to have a GI50 ranging from 200 to 250 µM over a period of 1 h and the ability to effectively inhibit bladder cancer. TPP1 induces apoptosis, and it appears to act as a direct mitochondrial toxin. TPP1 was applied intravesically to a bladder cancer mouse model based on the carcinogen N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN). Cancer selectivity of TPP1 was demonstrated, as BBN-induced tumors exhibited apoptosis but normal adjacent urothelium did not. These results suggest that TPP1 may be a promising intravesical agent for the treatment of bladder cancer.

Urine Biopsy-Liquid Gold for Molecular Detection and Surveillance of Bladder Cancer.

With recent advancements in a non-invasive approach to cancer diagnosis and surveillance, the term "liquid biopsy" has gained traction but is currently limited by technological challenges in identifying and isolating circulating tumor cells (CTCs), proteins, cell-free DNA (cfDNA), or other nucleic acids. Tumor tissue biopsy, especially in genitourinary (GU) system is sometimes inadequate and requires invasive surgical options, especially for upper tract urothelial cancer. Urine can prove to be "liquid gold" since it may be a more abundant source of tumor-derived material without the background noise; however, urine DNA (uDNA) may be associated with low mutant allele fraction (MAF). Molecular detection of mutations in uDNA requires a sensitive and accurate method of analysis that allows a high depth of sequencing while minimizing artifacts. Several sequencing approaches to address this hurdle using enhanced library preparation techniques such as Tagged amplicon deep sequencing (TAm-Seq), Safe-SeqS, FAST-SeqS, and CAPP-Seq approaches have been developed. Urine biopsy utilizing next-generation sequencing (NGS) can prove useful at all stages of urologic malignancy care, where urine can be collected to aid in clinical decision making through the identification of commonly known mutations, and potentially reduce or avoid all forms of invasive procedures.

ERCC2 Helicase Domain Mutations Confer Nucleotide Excision Repair Deficiency and Drive Cisplatin Sensitivity in Muscle-Invasive Bladder Cancer.

PURPOSE: DNA-damaging agents comprise the backbone of systemic treatment for many tumor types; however, few reliable predictive biomarkers are available to guide use of these agents. In muscle-invasive bladder cancer (MIBC), cisplatin-based chemotherapy improves survival, yet response varies widely among patients. Here, we sought to define the role of the nucleotide excision repair (NER) gene ERCC2 as a biomarker predictive of response to cisplatin in MIBC. EXPERIMENTAL DESIGN: Somatic missense mutations in ERCC2 are associated with improved response to cisplatin-based chemotherapy; however, clinically identified ERCC2 mutations are distributed throughout the gene, and the impact of individual ERCC2 variants on NER capacity and cisplatin sensitivity is unknown. We developed a microscopy-based NER assay to profile ERCC2 mutations observed retrospectively in prior studies and prospectively within the context of an institution-wide tumor profiling initiative. In addition, we created the first ERCC2-deficient bladder cancer preclinical model for studying the impact of ERCC2 loss of function. RESULTS: We used our functional assay to test the NER capacity of clinically observed ERCC2 mutations and found that most ERCC2 helicase domain mutations cannot support NER. Furthermore, we show that introducing an ERCC2 mutation into a bladder cancer cell line abrogates NER activity and is sufficient to drive cisplatin sensitivity in an orthotopic xenograft model. CONCLUSIONS: Our data support a direct role for ERCC2 mutations in driving cisplatin response, define the functional landscape of ERCC2 mutations in bladder cancer, and provide an opportunity to apply combined genomic and functional approaches to prospectively guide therapy decisions in bladder cancer.See related commentary by Grivas, p. 907.

WBC Associates with Readmission Following Cystectomy.

Background: Radical cystectomy is associated with perioperative complication rates exceeding 50% in some series. Readmission rates are increasingly used as a surgical quality metric. White blood cell count is a crude surrogate for physiologic processes which may reflect postoperative complications leading to readmission. Objective: We assessed the association between final white blood cell count at discharge and risk of readmission following radical cystectomy. Methods: Records on 477 patients undergoing radical cystectomy from 2006-2013 were reviewed. Final white blood cell count was defined as the last documented value during index admission. Univariate analysis was performed using Fisher's exact, Wilcoxon rank sum test, and Spearman's coefficient tests where appropriate. Multivariable logistic regression models were used to test the associations between final white blood cell count and readmission. Results: 34% of patients were readmitted within 90 days of surgery. Amongst this cohort, a cutoff final white blood cell count of 9000/mm3 was identified, with a significantly higher proportion of patients with values >9000/mm3 experiencing readmission than those with values≤9000/mm3 (42% vs 28%, p = 0.004). Other perioperative variables associated with an increased readmission rate included initial hospital length of stay≤10 days, and receipt of a continent diversion. Following adjustment, final white blood cell count >9000/mm3 was associated with increased risk of readmission (OR 2.09, 95% CI 1.23-3.53, p = 0.006). Conclusions: Final white blood cell count is associated with hospital readmission following radical cystectomy. This metric may provide important guidance in discharge algorithms.

Circulating biomarkers to guide systemic therapy for urothelial carcinoma.

There are very few biomarkers used to diagnose bladder cancer and no clinically approved biomarkers for prediction or prognostication of this disease. All currently available biomarkers are based on urine tests, and thus, they may not be applicable to patients with extravesical tumors. Biopsy of metastatic sites requires an invasive procedure, whereas serum-based markers, which can be easily obtained and serially measured, thus have obvious merit. These deficiencies may be overcome with advances in genome sequencing, identification of circulating tumor cells, and RNA-, protein-, and DNA-based biomarkers. Here, progress in circulating biomarkers in both superficial and invasive bladder cancer is described.

Is anatomic complexity associated with renal tumor growth kinetics under active surveillance?

INTRODUCTION: Linear growth rate (LGR) is the most commonly employed trigger for definitive intervention in patients with renal masses managed with an initial period of active surveillance (AS). Using our institutional cohort, we explored the association between tumor anatomic complexity at presentation and LGR in patients managed with AS. METHODS AND MATERIALS: Enhancing renal masses managed expectantly for at least 6 months were included for analysis. The association between Nephrometry Score and LGR was assessed using generalized estimating equations, adjusting for the age, Charlson score, race, sex, and initial tumor size. RESULTS: Overall, 346 patients (401 masses) met the inclusion criteria (18% ≥ cT1b), with a median follow-up of 37 months (range: 6-169). Of these, 44% patients showed progression to definitive intervention with a median duration of 27 months (range: 6-130). On comparing patients managed expectantly to those requiring intervention, no difference was seen in median tumor size at presentation (2.2 vs. 2.2 cm), whereas significant differences in median age (74 vs. 65 y, P < 0.001), Charlson comorbidity score (3 vs. 2, P<0.001), and average LGR (0.23 vs. 0.49 cm/y, P < 0.001) were observed between groups. Following adjustment, for each 1-point increase in Nephrometry Score sum, the average tumor LGR increased by 0.037 cm/y (P = 0.002). Of the entire cohort, 6 patients (1.7%) showed progression to metastatic disease. CONCLUSIONS: The demonstrated association between anatomic tumor complexity at presentation and renal masses of LGR of clinical stage 1 under AS may afford a clinically useful cue to tailor individual patient radiographic surveillance schedules and warrants further evaluation.

Lymphopenia is an independent predictor of inferior outcome in papillary renal cell carcinoma.

PURPOSE: Lymphopenia as a likely index of poor systemic immunity is an independent predictor of inferior outcome in patients with clear cell renal cell carcinoma (RCC). We sought to evaluate the prognostic relevance of preoperative absolute lymphocyte count (ALC) in a cohort of patients with papillary RCC (PRCC). MATERIALS AND METHODS: A prospectively maintained, renal cancer database was analyzed. Patients with preoperative ALC, within 3 months before surgery, were eligible for the study. Those with multifocal or bilateral renal tumors were excluded. Correlations between ALC and age, gender, smoking, Charlson comorbidity index, pathologic T category, PRCC subtype, and TNM stage were evaluated. Differences in overall survival (OS) and cancer-specific survival by ALC status were assessed using the log-rank test and cumulative incident estimators, respectively. Cox proportional hazards model was used for multivariable analyses. RESULTS: A total of 192 patients met the inclusion criteria. As a continuous variable, preoperative ALC was associated with higher TNM stage (P = 0.001) and older age (P = 0.01). As a dichotomous variable, lymphopenia (<1,300 cells/µl) was associated with higher TNM stage (P = 0.003). On multivariable analyses, controlling for covariates, after a median follow-up of 37.3 months, lymphopenia was associated with inferior OS (hazard ratio = 2.3 [95% CI: 1.2-4.3], P = 0.011) and trended to significance for cancer-specific survival (P = 0.071). Among patients with nonmetastatic disease and lymphopenia, OS at 37.5 months was shorter compared with those with normal ALC (83% vs. 93%, P = 0.0006). CONCLUSIONS: In patients with PRCC, lymphopenia is associated with lower survival independent of TNM stage, age, and histology. ALC may provide an additional preoperative prognostic factor.

Is extended pharmacologic venous thromboembolism prophylaxis uniformly safe after radical cystectomy?

OBJECTIVE: To quantitate the risk of clinically significant renal function deterioration after radical cystectomy (RC), which could result in supratherapeutic levels of low-molecular-weight heparin (LMWH) and increased risk of bleeding events with the use of extended pharmacologic venous thromboembolism prophylaxis (EPVTEP) after hospital discharge. METHODS: Patients undergoing RC between 2006 and 2011 were identified from the institutional registry. Estimated glomerular filtration rate (eGFR) was calculated and categorized as preoperative, discharge, and nadir. Perioperative eGFR trends in patients who would have been candidates for EPVTEP were evaluated. RESULTS: Three hundred four patients with eGFR >30 mL/min/1.73 m(2) at the time of hospital discharge were included in the analysis as potentially eligible for EPVTEP. Large portion of patients (43%) exhibited decline in eGFR after discharge. Importantly, 13.0% of patients (n = 40), who would have qualified for EPVTEP at discharge, experienced nadir GFR below the 30-mL/min/1.73 m(2) threshold value at which LMWH would have become supratherapeutic. The odds ratio for developing a GFR <30 mL/min/1.73 m(2) was 9.1 (95% confidence interval, 4.3-19.3; P <.001), comparing those with a discharge GFR ≥60 mL/min/1.73 m(2) with those with a discharge GFR <60 mL/min/1.73 m(2). CONCLUSION: More than 10% experienced an eGFR, which would have rendered LMWH supratherapeutic and potentially would have placed the patient at risk for clinically significant bleeding. Although postoperative venous thromboembolic event after RC is a recognized concern, a better understanding of the risks of EPVTEP is needed before this strategy is universally adopted in patients undergoing RC.