Alexander P. Glaser

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.

The Impact of Prostate Biopsy on Urinary Symptoms, Erectile Function, and Anxiety

Transrectal ultrasound-guided prostate needle biopsy (PB) is considered the gold standard for the diagnosis of prostate cancer. Recently, lower urinary tract symptoms and erectile dysfunction have been reported following PB. We reviewed the literature on PB and these symptoms and summarized known findings between these conditions and other variables, such as periprostatic nerve block, saturation biopsy, serial biopsies, and psychological factors associated with PB and cancer. A PubMed search was performed using keywords “prostate biopsy,” “complications,” “erectile dysfunction,” “lower urinary tract symptoms,” “anxiety,” and “quality of life.” Eleven key papers are discussed and personal experience is drawn upon. Based upon available evidence, PB appears to be associated with short-term exacerbation of urinary symptoms in some men, as well as associated with anxiety and temporary erectile dysfunction, without a distinct relationship to periprostatic nerve block or the number of cores biopsied. Additional studies are warranted to determine the definitive etiology of these symptoms and to determine if interventions could reduce patient morbidity. In the interim, patients should be educated and counseled about these risks before undergoing PB.

Urinary Tract Infection and Bacteriuria in Pregnancy

Bacteriuria during pregnancy may be classified as asymptomatic bacteriuria, infections of the lower urinary tract (cystitis), or infections of the upper urinary tract (pyelonephritis). Lower tract bacteriuria is associated with an increased risk of developing pyelonephritis in pregnancy, which is itself associated with adverse maternal and fetal outcomes. Pregnant women should be screened for the presence of bacteriuria early in pregnancy. All bacteriuria in pregnancy should be treated, and antimicrobial choice in pregnancy should reflect safety for both the mother and the fetus. After treatment of bacteriuria, patients should be followed closely due to risk of recurrent bacteriuria.

The evolving genomic landscape of urothelial carcinoma

Survival of patients with urothelial carcinoma (including bladder cancer and upper tract urothelial carcinoma) is limited by our current approaches to staging, surgery, and chemotherapy. Large-scale, next-generation sequencing collaborations, such as The Cancer Genome Atlas, have already identified drivers and vulnerabilities of urothelial carcinoma. This disease has a high degree of mutational heterogeneity and a high frequency of somatic mutations compared with other solid tumours, potentially resulting in an increased neoantigen burden. Mutational heterogeneity is mediated by multiple factors including the apolipoprotein B mRNA editing enzyme catalytic polypeptide family of enzymes, smoking exposure, viral integrations, and intragene and intergene fusion proteins. The mutational landscape of urothelial carcinoma, including specific mutations in pathways and driver genes, such as FGFR3, ERBB2, PIK3CA, TP53, and STAG2, affects tumour aggressiveness and response to therapy. The next generation of therapies for urothelial carcinoma will be based on patient-specific targetable mutations found in individual tumours. This personalized-medicine approach to urothelial carcinoma has already resulted in unique clinical trial design and has the potential to improve patient outcomes and survival.

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.

Perioperative effects of caudal and transversus abdominis plane (TAP) blocks for children undergoing urologic robot-assisted laparoscopic surgery

INTRODUCTION Regional anesthesia is often used in combination with general anesthesia for pediatric surgery, however, it is unknown if adjunctive regional blocks are beneficial to children undergoing urologic laparoscopic or robot-assisted laparoscopic (RAL) procedures. OBJECTIVE To compare perioperative outcomes in children with adjunctive caudal blocks, transversus abdominis plane (TAP) blocks, or no regional anesthesia for common RAL surgical procedures in pediatric urology. STUDY DESIGN Inclusion in this retrospective study was limited to children who underwent RAL renal or ureteral/bladder procedures and received a standardized regimen of scheduled intravenous ketorolac and oral acetaminophen for acute postoperative pain control, with opioids as needed (PRN). Perioperative outcomes were compared between patients with an adjunctive caudal block (n = 25), bilateral TAP blocks (n = 44), or no regional anesthesia (n = 51). RESULTS Children with a preoperative caudal block received less intraoperative opioids than children with TAP blocks or no regional anesthesia (p < 0.001). This difference was observed both for renal procedures (p < 0.01) and ureteral/bladder procedures (p = 0.01). Patients with caudal blocks were also the least likely to require postoperative antiemetics (p = 0.03). There were no significant differences between groups in postoperative opioid use, maximum pain scores within 6 and 24 hours postoperatively, or length of hospital stay (LOS). No complications attributable to regional blocks were identified by chart review. DISCUSSION Use of adjunctive caudal blocks for pediatric RAL renal or ureteral/bladder surgical procedures may reduce need for alternate analgesic and/or anesthetic agents intraoperatively, as well as decrease postoperative nausea and vomiting. These findings may be related, since nausea and vomiting are common side effects of opioids and inhalational anesthetics. Consideration of the potential impact of caudal blocks on general anesthetic requirements is timely in light of concerns regarding the risk of anesthetic neurotoxicity in young patients. There was no evidence of improved postoperative pain control or shorter LOS for children who received regional anesthesia. It is unknown if regional blocks would have a greater impact in the absence of scheduled pain medications, which all patients in our study received. Limitations of this study include its retrospective nature and moderate sample size. Future randomized controlled trials are necessary to provide a more definitive understanding of regional anesthesias role in minimizing pediatric surgical and anesthetic morbidity. CONCLUSION Administration of caudal blocks should be considered for children of suitable age undergoing RAL surgery involving either the upper or lower urinary tract.

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.

Automated Extraction of Grade, Stage, and Quality Information From Transurethral Resection of Bladder Tumor Pathology Reports Using Natural Language Processing

PURPOSE Bladder cancer is initially diagnosed and staged with a transurethral resection of bladder tumor (TURBT). Patient survival is dependent on appropriate sampling of layers of the bladder, but pathology reports are dictated as free text, making large-scale data extraction for quality improvement challenging. We sought to automate extraction of stage, grade, and quality information from TURBT pathology reports using natural language processing (NLP). METHODS Patients undergoing TURBT were retrospectively identified using the Northwestern Enterprise Data Warehouse. An NLP algorithm was then created to extract information from free-text pathology reports and was iteratively improved using a training set of manually reviewed TURBTs. NLP accuracy was then validated using another set of manually reviewed TURBTs, and reliability was calculated using Cohens κ. RESULTS Of 3,042 TURBTs identified from 2006 to 2016, 39% were classified as benign, 35% as Ta, 11% as T1, 4% as T2, and 10% as isolated carcinoma in situ. Of 500 randomly selected manually reviewed TURBTs, NLP correctly staged 88% of specimens (κ = 0.82; 95% CI, 0.78 to 0.86). Of 272 manually reviewed T1 tumors, NLP correctly categorized grade in 100% of tumors (κ = 1), correctly categorized if muscularis propria was reported by the pathologist in 98% of tumors (κ = 0.81; 95% CI, 0.62 to 0.99), and correctly categorized if muscularis propria was present or absent in the resection specimen in 82% of tumors (κ = 0.62; 95% CI, 0.55 to 0.73). Discrepancy analysis revealed pathologist notes and deeper resection specimens as frequent reasons for NLP misclassifications. CONCLUSION We developed an NLP algorithm that demonstrates a high degree of reliability in extracting stage, grade, and presence of muscularis propria from TURBT pathology reports. Future iterations can continue to improve performance, but automated extraction of oncologic information is promising in improving quality and assisting physicians in delivery of care.

Abstract B29: A carcinogen-induced mouse model recapitulates the molecular alterations of human muscle-invasive bladder cancer

Bladder cancer is the fourth most common cancer in men and fifth most common malignancy in the United States. Survival of patients with muscle-invasive or metastatic bladder cancer is poor, with only 35% survival at 5 years. Developing innovative anticancer drugs relies on the availability of model systems that closely recapitulate the corresponding human disease at both the histologic and molecular levels. One of the major limitations in the field of bladder cancer research is the limited availability of such models. The N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) mouse model is an attractive model system of muscle-invasive bladder cancer (MIBC) since it recapitulates the complex 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 the mutational landscape of the BBN model by whole-exome sequencing followed by a bioinformatic comparison to human MIBC using genomic data from The Cancer Genome Atlas and other repositories. Similar to human MIBC, BBN tumors had a high mutation burden. Next, we extracted mouse-specific mutational signatures that correspond to different genetic instability processes operating in BBN tumors. Interestingly, one of these de novo extracted signatures aligned to a human mutational signature previously associated to DNA-repair deficiencies in human bladder cancers. We further analyzed the most commonly mutated genes and their intratumor mutation frequencies with the aim of identifying potential driver mutations. Our analyses converged on three genes that seem crucial in the process of tumorigenesis in both mouse and human bladder cancers: the tumor suppressor Trp53 as well as the genes Kmt2c and Kmt2d. These encode for methyltransferases involved in the methylation of histone H3K4 and play a key role in the epigenetic regulation of enhancer activity. Also, many of the putative driver mutations found in the BBN genomes corresponded to human cancer hotspot mutations, supporting their role as driver mutations. Together, our study revealed several similarities between human MIBC and the BBN mouse model. Our results highlighted the contribution of aberrations to chromatin regulators and genetic instability in both human and BBN bladder tumors, thus providing a strong rationale for the use of this mouse model in molecular and drug discovery studies. Citation Format: Damiano Fantini, Alexander P. Glaser, Rimar J. Kalen, Wang Yiduo, Yanni Yu, Joshua J. Meeks. A carcinogen-induced mouse model recapitulates the molecular alterations of human muscle-invasive bladder cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr B29.

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.