Kalen Rimar

Prostate cancer diagnosis is associated with an increased risk of erectile dysfunction after prostate biopsy.

There have been several studies that have suggested there may be a relationship between prostate biopsy and erectile function and LUTS. Previous studies have suggested a specific association between the type of local anaesthesia administered and/or the number of biopsies performed. Other studies have suggested an exacerbation of LUTS after prostate biopsy. The present study identifies a positive cancer diagnosis as a novel characteristic that may explain a relationship between biopsy and worsening erectile function.

A Carcinogen-induced mouse model recapitulates the molecular alterations of human muscle invasive bladder cancer

The N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) mouse model is an attractive model system of muscle-invasive bladder cancer (MIBC) as it recapitulates the histology of human tumors in a background with intact immune system. However, it was unknown whether this carcinogen-induced model also mimicked human MIBC at the molecular and mutational level. In our study, we analyzed gene expression and mutational landscape of the BBN model by next-generation sequencing followed by a bioinformatic comparison to human MIBC using data from The Cancer Genome Atlas and other repositories. BBN tumors showed overexpression of markers of basal cancer subtype, and had a high mutation burden with frequent Trp53 (80%), Kmt2d (70%), and Kmt2c (90%) mutations by exome sequencing, similar to human MIBC. Many variants corresponded to human cancer hotspot mutations, supporting their role as driver mutations. We extracted two novel mutational signatures from the BBN mouse genomes. The integrated analysis of mutation frequencies and signatures highlighted the contribution of aberrations to chromatin regulators and genetic instability in the BBN tumors. Together, our study revealed several similarities between human MIBC and the BBN mouse model, providing a strong rationale for its use in molecular and drug discovery studies.

APOBEC-mediated mutagenesis in urothelial carcinoma is associated with improved survival, mutations in DNA damage response genes, and immune response

APOBEC enzymes are responsible for a mutation signature (TCW>T/G) implicated in a wide variety of tumors. We explore the APOBEC mutational signature in bladder cancer and the relationship with specific mutations, molecular subtype, gene expression, and survival using sequencing data from The Cancer Genome Atlas (n = 395), Beijing Genomics Institute (n = 99), and Cancer Cell Line Encyclopedia. Tumors were split into “APOBEC-high” and “APOBEC-low” based on APOBEC enrichment. Patients with APOBEC-high tumors have better overall survival compared to those with APOBEC-low tumors (38.2 vs. 18.5 months, p = 0.005). APOBEC-high tumors are more likely to have mutations in DNA damage response genes (TP53, ATR, BRCA2) and chromatin regulatory genes (ARID1A, MLL, MLL3), while APOBEC-low tumors are more likely to have mutations in FGFR3 and KRAS. APOBEC3A and APOBEC3B expression correlates with mutation burden, regardless of bladder tumor molecular subtype. APOBEC mutagenesis is associated with increased expression of immune signatures, including interferon signaling, and expression of APOBEC3B is increased after stimulation of APOBEC-high bladder cancer cell lines with IFNγ. In summary, APOBEC-high tumors are more likely to have mutations in DNA damage response and chromatin regulatory genes, potentially providing more substrate for APOBEC enzymes, leading to a hypermutational phenotype and the subsequent enhanced immune response.

The emerging role of homologous recombination repair and PARP inhibitors in genitourinary malignancies

As cells age and are exposed to genotoxic stress, preservation of the genomic code requires multiple DNA repair pathways to remove single‐strand or double‐strand breaks. Loss of function somatic genomic aberrations or germline deficiency in genes involved in DNA repair can result in acute cell death or, after a latency period, cellular transformation. Therapeutic exploitation of DNA repair by inhibition of poly (adenosine diphosphate [ADP]) ribose polymerases (PARP), a family of enzymes involved in the repair of single‐strand and in some cases double‐strand breaks, has become a novel cancer treatment. Although the application of PARP inhibitors (PARPis) initially focused on tumors with BRCA1 or BRCA2 deficiencies, synthetic susceptibilities to PARPis have been expanded due to the identification of tumors with mutations pathways involved in DNA damage repair, in particular those that repair double‐strand breaks using homologous recombination (HR). There is an increasing appreciation that genitourinary (GU) malignancies, including bladder cancer and especially prostate cancer, contain subsets of patients with germline and somatic alterations in HR genes that may reflect an increased response to PARPis. In this review, the authors describe the mechanisms and rationale of the use of PARPis in patients with GU cancers, summarize previously reported preclinical and clinical trials, and identify ongoing trials to determine how PARPis and strategies targeted at HR repair can have widespread application in patients with GU cancers. Cancer 2017;123:1912–1924.

Radiofrequency Ablation-Assisted Zero-Ischemia Robotic Laparoscopic Partial Nephrectomy: Oncologic and Functional Outcomes in 49 Patients

Introduction and Objectives. Robotic partial nephrectomy with peritumoral radiofrequency ablation (RFA-RPN) is a novel clampless technique. We describe oncologic and functional outcomes in a prospective cohort. Methods. From May, 2007, to December, 2009, 49 consecutive patients with renal masses <7 cm underwent RFA-RPN. During this period, only the RFA-RPN technique was utilized for all cases of partial nephrectomy. Pre- and postoperative data were analyzed and compared to 36 consecutive patients who underwent LPN. Results. In total, 49 tumors were treated in the RFA-RPN group and 36 tumors in the comparison group. Mean operative time was longer in the RFA-RPN group (370 min versus 293 min, p < 0.001). There were no significant differences in mean EBL (231 cc versus 250 cc, p = 0.42), transfusion rate (8.2% versus 11.1%, p = 0.7), or hospital stay (3.9 versus 4.4 days, p = 0.2). Two patients in the RFA-RPN (4.1%) and 1 (2.7%) patient in the comparison group had a positive surgical margin (p = 0.75). 17 (34.7%) patients had a postoperative urine leak in the RFA-RPN group versus 2 (5.6%) patients in the comparison group (p = 0.001). Mean follow-up was 54 months versus 68.4 months in the comparison group. There was no significant difference between the two groups regarding change in GFR (p = 0.67). There were 3 recurrences (6.1%) in the RFA-RPN group and 0 recurrences in the RPN group (p = 0.23). There were 3 deaths (6.1%) in the RFA-RPN group (one cancer specific) and 4 deaths (11.1%) in the RPN group (non-cancer specific) over the follow-up period (p = 0.44). Conclusions. Our data suggests that this technique is associated with a similar degree of renal preservation but higher rates of postoperative urine leak and possibly higher rates of recurrence.

Vasovasostomy Techniques for Microsurgery Specialists

Every year, roughly 500,000 vasectomies are performed in the USA, and it is estimated that up to 6% of these men will eventually request a reversal [1, 2]. Surgical technique has evolved since Dr. William Quinby performed the first vasovasostomy in 1919 [3], and microsurgical repair with the aid of stenting or loupe magnification has largely been replaced by microsurgical approaches. The improved visualization and stabilization the operating microscope provides are well suited for re-approximating a delicate, 0.3 mm diameter structure like the vas deferens. This chapter provides a brief history of vasal repair, an overview of the authors’ preferred technique for microsurgical vasovasostomy, and evidence-based recommendations for preoperative and postoperative care.

MP32-10 VARIATIONS IN THE PATIENT EXPERIENCE AT AN ACADEMIC UROLOGY DEPARTMENT: HOW SURVEY RESULTS DRIVE LIKELIHOOD TO RECOMMEND METRICS

p1⁄40.04, respectively). Men >70 were more likely to visit the emergency department (OR 4.7, p1⁄40.004). CONCLUSIONS: Men with uncomplicated BPH receiving value-based surgical care were more likely to avoid certain negative outcomes. While these data validate our a priori hypothesis, we continue to measure clinical outcomes using near real time data extraction and analysis. Iterative evaluation of processes and outcomes are crucial in implementing value-based care models. A limitation is lack of IPSS data. Further studies may elucidate whether these findings apply in other settings.

PD62-08 CHANGES IN LEAN MUSCLE MASS ASSOCIATED WITH NEOADJUVANT CHEMOTHERAPY IN PATIENTS WITH MUSCLE INVASIVE BLADDER CANCER

evaluated (RECIST criteria): CR was observed in 2 pts (6%), PR in 18 (60%); PD in 1 (3%) and SD in 9 (30%) regarding primary bladder tumor. In 12 pts with enlarged lymph-nodes, the response to NGC was CR in 1, PR in 10 and SD in 1. Patients receiving neoadjuvant GC had a greater chance of achieving a pathologically lower stage compared to the untreated population: organ-confined cancer in 53,3% (16/30) vs. 33% (p < 0.001). Lymph-node metastasis resulted in 25% patients after GC (n1⁄410) vs 45.5% of untreated patients (n1⁄420; p < 0.001). Considering patients resulted CR and PR after NGC (n1⁄420), 70% had down-staging on pathologic report after RC. Complication rates were higher in NGC group (4 thromboembolisms; 2 sepsis; 12 hematologic complications); all complications were not related to surgery. Pathological TRG after NGC was not correlated to clinical regression grade. The OS (mean follow-up 30 months) of patients who received NGC resulted of 66.6% compared with 56% of patients undergoing cystectomy alone (p<0,001). Fifty percent of patients in NGC group were alive without cancer vs 40,1% in cystectomy alone group (p<0,001). CONCLUSIONS: Neoadjuvant chemotherapy for muscle-invasive bladder cancer increases the rate of down-staging and cancer specific survival. NGC is associated with an increased risk of complications that may be prevented using tailored strategies. Pathological regression grades after NGC are not correlated to RECIST criteria based on CT.

MP44-12 APOBEC-MEDIATED MUTAGENESIS IS ASSOCIATED WITH EXPRESSION OF IMMUNE-RELATED GENES AND OVERALL SURVIVAL IN BLADDER CANCER

INTRODUCTION AND OBJECTIVES: The APOBEC family of enzymes is responsible for a mutation signature characterized by a TcW->T/G mutation. APOBEC-mediated mutagenesis is implicated in a wide variety of tumors, including bladder cancer. However, less is known about regulation and function of the APOBEC genes and their subsequent mutation signature. In this study, we explore the APOBEC mutational signature in bladder cancer and the relationship with mutation burden, molecular classification, gene expression, and survival. METHODS: The Cancer Genome Atlas (TCGA) bladder urothelial carcinoma data was downloaded from cBioPortal (http://cbioportal.org) and the Broad Institute (http://gdac.broadinstitute.org). APOBEC enrichment score was calculated as previously described (Nat Genet 2013;45:970). Tumors with >2-fold enrichment with a Benjamini-Hochberg corrected p-value <0.05 were considered high in APOBEC enrichment. Statistical analysis was performed with R. Functional annotations were performed with DAVID (http:// david.ncifcrf.gov). RESULTS: Expression of APOBEC3A and APOBEC3B are associated with the mutational burden in bladder cancer (r1⁄40.18, p<0.001; r1⁄40.334, p<0.001). High APOBEC enrichment score is associated with improved overall survival (Figure 1A). APOBEC enrichment does not vary between TCGA molecular subtypes 1-4 (Figure 1B). Of the top mutated genes in bladder cancer, patients with high APOBEC enrichment are more likely to have mutations in TP53, ERBB2, KMT2C and PIK3CA, but not ARID1A, CSMD3, RB1, KMT2D, KDM6A, or STAG2. Genes with expression positively associated with APOBEC enrichment (including PD-1, CTLA-4, TIM-3, and TIGIT) are involved in IFN-gamma signaling, antigen processing and presentation, and regulation of the immune response, while genes negatively associated with APOBEC enrichment are involved in translational initiation and ribosome assembly. CONCLUSIONS: APOBEC enzymes are a major source of mutation in bladder cancer. Both luminal and basal subtypes of bladder cancer have similar APOBEC mutational signatures. This signature is associated with overall survival as well as expression of immune-related genes. Further study of regulation of APOBEC enzymes may provide further insight into the mutational landscape and potential therapeutics for bladder cancer.