Comparing confirmatory biopsy outcomes between MRI-targeted biopsy and standard systematic biopsy among men being enrolled in prostate cancer active surveillance.

OBJECTIVES: To evaluate the ability of magnetic resonance imaging (MRI)-targeted biopsy combined with systematic biopsy (MRI-biopsy) to reduce negative biopsies and detect clinically significant prostate cancer compared to systematic biopsy (SB) alone in the confirmatory biopsy setting using matched cohorts. PATIENTS AND METHODS: Patients were identified from an active surveillance database who had a previously positive transrectal ultrasonography-guided SB followed by a confirmatory biopsy at a single institution between 2006 and 2019. Patients were divided into two cohorts based on confirmatory biopsy technique: SB alone or MRI-biopsy (which included MRI-targeted and systematic biopsies). Cohorts were then matched on age, prostate-specific antigen (PSA) level, number of positive cores on initial biopsy and initial biopsy Gleason grade group (GG). Logistic regression was performed to identify associations with confirmatory biopsy upgrading. RESULTS: After matching, 514 patients were identified (257 per cohort). PSA, prostate volume and PSA density prior to initial biopsy, in addition to total number of initial biopsy positive cores and GG, were similar between the matched cohorts. After confirmatory biopsy, 118/257 patients (45.9%) in the MRI-biopsy cohort were upgraded compared to 46/257 patients (17.9%) in the SB cohort (P < 0.001). The rate of negative confirmatory biopsy was 32/257 (12.5%) compared to 97/257 (37.7%) in the MRI-biopsy and SB cohorts, respectively (P < 0.001). Confirmatory MRI-biopsy was associated with greater odds of confirmatory biopsy upgrade from GG 1 to ≥GG 2 compared to SB alone (odds ratio 3.62, 95% confidence interval 1.97-6.63; P < 0.001). CONCLUSION: The addition of MRI-targeted biopsies to SB in the confirmatory biopsy setting among men with previously detected prostate cancer resulted in fewer negative confirmatory biopsies and detection of more clinically significant prostate cancer compared to SB alone.

Utility of routine urinalysis and urine culture testing in an ambulatory urology clinic: a quality improvement initiative in a Veterans healthcare facility.

INTRODUCTION: Urinalysis (UA) and urine culture (UCx) are commonly performed tests in the urology clinic. Many of these urine studies are performed prior to the patient visit may not always be indicated, thus contributing to unintended consequences such as antibiotic use and costs without enhancing patient care. Our objective was to perform a quality improvement initiative aimed to assess the utility of routine UA/UCx. MATERIALS AND METHODS: The practice pattern at our site's Veteran Affairs (VA) urology clinic prior to 2014 was to obtain routine UA/UCx on most clinic visits prior to patient evaluation. Starting in 2014, we designed an intervention whereby our nurse practitioner triaged all new patient referrals and selectively ordered UA/UCx. We performed multivariable logistic regression to assess for predictors of obtaining UA or UCx. RESULTS: A total of 1308 patients were seen in January-March 2013 and 1456 in June-August 2014 and were included in this analysis. Fewer patients in 2014 received UA (59.8% versus 70.0%, p < 0.001) and UCx (49.6% versus 64.2%, p < 0.001). There was a decreased odds of obtaining UA in 2014 (OR 0.52, p < 0.001) as well as a decreased odds of obtaining UCx in 2014 (OR0.38, p < 0.001) on multivariable logistic regression. The results of UA/UCx only rarely resulted in change of management in either cohort (3%). Selective ordering resulted in an estimated cost savings of $4915.08/month in UCx costs alone. CONCLUSIONS: Our quality improvement initiatives reduced rates of UA/UCx testing when providers assess patients prior to ordering these tests. The implication of this initiative is significant cost savings for the healthcare system.

Clinical use of patient decision-making aids for stone patients.

INTRODUCTION: Patient decision-making aids (PDMAs) help patients make informed healthcare decisions and improve patient satisfaction. The utility of PDMAs for patients considering treatments for urolithiasis has not yet been published. We report our experience using PDMAs developed at our institution in the outpatient clinical setting in patients considering a variety of treatment options for stones. MATERIALS AND METHODS: Patients with radiographically confirmed urolithiasis were given PDMAs regarding treatment options for their stone(s) based on their clinical profile. We assessed patients' satisfaction, involvedness, and feeling of making a more informed decision with utilization of the PDMAs using a Likert Scale Questionnaire. Information was also collected regarding previous stone passage, history and type of surgical intervention for urolithiasis, and level of education. RESULTS: Patients (n = 43; 18 males, 23 females and two unknown) 53 +/- 14years old were included. Patients reported that they understood the advantages and disadvantages outlined in the PDMAs (97%), that the PDMAs helped them make a more informed decision (83%) and felt more involved in the decision making process (88%). Patients reported that the aids were presented in a balanced manner and used up-to-date scientific information (100%, 84% respectively). Finally, a majority of the patients prefer an expert's opinion when making a treatment decision (98%) with 73% of patients preferring to form their own opinion based on available information. Previous stone surgery was associated with patients feeling more involved with the decision making process (p = 0.0465). CONCLUSIONS: PDMAs have a promising role in shared decision-making in the setting of treatment options for nephrolithiasis.

Motoneurons are essential for vascular pathfinding.

The neural and vascular systems share common guidance cues that have direct and independent signaling effects on nerves and endothelial cells. Here, we show that zebrafish Netrin 1a directs Dcc-mediated axon guidance of motoneurons and that this neural guidance function is essential for lymphangiogenesis. Specifically, Netrin 1a secreted by the muscle pioneers at the horizontal myoseptum (HMS) is required for the sprouting of dcc-expressing rostral primary motoneuron (RoP) axons and neighboring axons along the HMS, adjacent to the future trajectory of the parachordal chain (PAC). These axons are required for the formation of the PAC and, subsequently, the thoracic duct. The failure to form the PAC in netrin 1a or dcc morphants is phenocopied by laser ablation of motoneurons and is rescued both by cellular transplants and overexpression of dcc mRNA. These results provide a definitive example of the requirement of axons in endothelial guidance leading to the parallel patterning of nerves and vessels in vivo.

Efficacy of Surgery on the Primary Tumour in Patients with Metastatic Bladder Cancer: A Comprehensive Review.

BACKGROUND: The benefit of surgery of the primary tumor in metastatic bladder cancer is unknown. OBJECTIVE: Perform a comprehensive contemporary literature review on the benefit of surgery of the primary tumor in metastatic bladder cancer. METHODS: Ovid MEDLINE, Ovid EMBASE, and Cochrane Library from January 1, 1990 to April 20, 2020 were queried for relevant articles published in English. Each article was evaluated by at least two content experts prior to inclusion which were blinded to the other's evaluation. A third content expert was used when there was not a unanimous decision. Additional articles were added at the discretion of the authors. RESULTS: Long-term survival is possible in patients with initially unresectable and/or limited metastatic disease. Multi-modal therapy with chemotherapy and surgery have the most favorable outcomes when compared to single treatment modalities in selected populations. Patients who demonstrate a robust response to pre-surgical therapy are likely to benefit the most from consolidative surgery. Patients with distant metastatic disease may benefit from consolidative surgery; however, this benefit may only be seen in those with metastatic disease limited to one site. CONCLUSIONS: Surgery of the primary tumor in metastatic bladder cancer either in the setting of surgery alone, consolidative therapy or coupled with adjuvant therapy may be beneficial in well selected patients and should generally be limited to those who have a response to primary chemotherapy. Randomized clinical control trials are needed to further our understanding of the role of surgery in metastatic bladder cancer.

Lentiviral interferon: A novel method for gene therapy in bladder cancer.

Interferon alpha (IFNα) gene therapy is emerging as a new treatment option for patients with non-muscle invasive bladder cancer (NMIBC). Adenoviral vectors expressing IFNα have shown clinical efficacy treating bacillus Calmette-Guerin (BCG)-unresponsive bladder cancer (BLCA). However, transient transgene expression and adenoviral immunogenicity may limit therapeutic activity. Lentiviral vectors can achieve stable transgene expression and are less immunogenic. In this study, we evaluated lentiviral vectors expressing murine IFNα (LV-IFNα) and demonstrate IFNα expression by transduced murine BLCA cell lines, bladder urothelium, and within the urine following intravesical instillation. Murine BLCA cell lines (MB49 and UPPL1541) were sensitive to IFN-mediated cell death after LV-IFNα, whereas BBN975 was inherently resistant. Upregulation of interleukin-6 (IL-6) predicted sensitivity to IFN-mediated cell death mediated by caspase signaling, which when inhibited abrogated IFN-mediated cell killing. Intravesical therapy with LV-IFNα/Syn3 in a syngeneic BLCA model significantly improved survival, and molecular analysis of treated tumors revealed upregulation of apoptotic and immune-cell-mediated death pathways. In particular, biomarker discovery analysis identified three clinically actionable targets, PD-L1, epidermal growth factor receptor (EGFR), and ALDHA1A, in murine tumors treated with LV-IFNα/Syn3. Our findings warrant the comparison of adenoviral and LV-IFNα and the study of novel combination strategies with IFNα gene therapy for the BLCA treatment.

Radical cystectomy in women: Impact of the robot-assisted versus open approach on surgical outcomes.

OBJECTIVES: To perform a comparison of complications following open versus robot-assisted radical cystectomy (RC) among women who undergo the procedure. Studies comparing robotic to open RC have been mixed without a clear delineation of which patients benefit the most from one modality vs. the other, leading to continued debate. PATIENTS AND METHODS: This was a retrospective study of women who underwent either open or robotic RC at the MD Anderson Cancer Center from 1/2014 to 6/2018. Co-morbidities, pathologic data, and complications were assessed with descriptive statistics, along with uni- and multivariable logistic regression. RESULTS: 122 women underwent either open (n = 76) or robotic (n = 46) RC. Open RC was associated with greater intraoperative blood loss (median EBL 775 ml vs. 300 ml, P < 0.001). In both uni- and multivariable analyses, open RC was associated with a greater odds of intraoperative transfusion compared to robotic RC (odds ratio 6.49, 95% CI 2.85-14.78, P < 0.001). Women undergoing open RC were also at greater odds of receiving 4 or more units of packed red blood cells (odds ratio 5.46 (1.75-17.02), P = 0.003). Robotic RC conferred a higher median lymph node yield (27 vs. 20 nodes, P, <0.001) and operative times (median 513 min vs. 391.5 min, P < 0.001). There were no differences in margin positivity, length of stay, or readmission rates at 30 and 90 days. CONCLUSIONS: Robotic RC was associated with a significantly lower risk of transfusion and EBL, and a higher median lymph node yield and operative time. Unique anatomic considerations may in part be responsible for these findings.

TCF21 Promotes Luminal-Like Differentiation and Suppresses Metastasis in Bladder Cancer.

Little is known regarding the subclone evolution process in advanced bladder cancer, particularly with respect to the genomic alterations that lead to the development of metastatic lesions. In this project, we identify gene expression signatures associated with metastatic bladder cancer through mRNA expression profiling of RNA isolated from 33 primary bladder cancer and corresponding lymph node (LN) metastasis samples. Gene expression profiling (GEP) was performed on RNA isolated using the Illumina DASL platform. We identified the developmental transcription factor TCF21 as being significantly higher in primary bladder cancer compared with LN metastasis samples. To elucidate its function in bladder cancer, loss- and gain-of-function experiments were conducted in bladder cancer cell lines with high and low expression of TCF21, respectively. We also performed GEP in bladder cancer cell lines following TCF21 overexpression. We identified 2,390 genes differentially expressed in primary bladder cancer and corresponding LN metastasis pairs at an FDR cutoff of 0.1 and a fold change of 1. Among those significantly altered, expression of TCF21 was higher in the primary tumor compared with LN metastasis. We validated this finding with qPCR and IHC on patient samples. Moreover, TCF21 expression was higher in luminal cell lines and knockdown of TCF21 increased invasion, tumor cell dissemination, and metastasis. In contrast, overexpression of TCF21 in highly metastatic basal bladder cancer cell lines decreased their invasive and metastatic potential. IMPLICATIONS: TCF21 is differentially overexpressed in primary bladder cancer compared with matched LN metastasis, with in vitro and in vivo studies demonstrating a metastasis suppressor function of this transcription factor.

The netrin receptor UNC5B promotes angiogenesis in specific vascular beds.

There is emerging evidence that the canonical neural guidance factor netrin can also direct the growth of blood vessels. We deleted the gene encoding UNC5B, a receptor for the netrin family of guidance molecules, specifically within the embryonic endothelium of mice. The result is a profound structural and functional deficiency in the arterioles of the placental labyrinth, which leads first to flow reversal in the umbilical artery and ultimately to embryonic death. As this is the only detectable site of vascular abnormality in the mutant embryos, and because the phenotype cannot be rescued by a wild-type trophectoderm, we propose that UNC5B-mediated signaling is a specific and autonomous component of fetal-placental angiogenesis. Disruption of UNC5B represents a unique example of a mutation that acts solely within the fetal-placental vasculature and one that faithfully recapitulates the structural and physiological characteristics of clinical uteroplacental insufficiency. This pro-angiogenic, but spatially restricted requirement for UNC5B is not unique to murine development, as the knock-down of the Unc5b ortholog in zebrafish similarly results in the specific and highly penetrant absence of the parachordal vessel, the precursor to the lymphatic system.