Faculty Bibliography

BACKGROUND:Dickkopf-related protein 1 (DKK1) is a Wingless-related integrate site (Wnt) signaling modulator that is upregulated in prostate cancers (PCa) with low androgen receptor expression. DKN-01, an IgG4 that neutralizes DKK1, delays PCa growth in pre-clinical DKK1-expressing models. These data provided the rationale for a clinical trial testing DKN-01 in patients with metastatic castration-resistant PCa (mCRPC). METHODS:(combination) for men with mCRPC who progressed on ≥1 AR signaling inhibitors. DKK1 status was determined by RNA in-situ expression. The primary endpoint of the phase 1 dose escalation cohorts was the determination of the recommended phase 2 dose (RP2D). The primary endpoint of the phase 2 expansion cohorts was objective response rate by iRECIST criteria in patients treated with the combination. RESULTS:18 pts were enrolled into the study-10 patients in the monotherapy cohorts and 8 patients in the combination cohorts. No DLTs were observed and DKN-01 600 mg was determined as the RP2D. A best overall response of stable disease occurred in two out of seven (29%) evaluable patients in the monotherapy cohort. In the combination cohort, five out of seven (71%) evaluable patients had a partial response (PR). A median rPFS of 5.7 months was observed in the combination cohort. In the combination cohort, the median tumoral DKK1 expression H-score was 0.75 and the rPFS observed was similar between patients with DKK1 H-score ≥1 versus H-score = 0. CONCLUSION/CONCLUSIONS:DKN-01 600 mg was well tolerated. DKK1 blockade has modest anti-tumor activity as a monotherapy for mCRPC. Anti-tumor activity was observed in the combination cohorts, but the response duration was limited. DKK1 expression in the majority of mCRPC is low and did not clearly correlate with anti-tumor activity of DKN-01 plus docetaxel.

OBJECTIVE:To evaluate the incidence of gender-affirming phalloplasty and complications in a large population-based dataset. METHODS:Retrospective cohort study was done using the California Department of Health Care Access and Information datasets which include patient-level data from all licensed hospitals, emergency departments, and ambulatory surgery facilities in California. Adult patients 18 years or older undergoing gender-affirming phalloplasty in California from January 1, 2009 to December 31, 2019 were included. We examined phalloplasty-related complications using International Classification of Disease diagnosis and procedure codes and Current Procedural Terminology codes. Unique record linkage number identifiers were used to follow patients longitudinally. Statistical analysis included Kaplan-Meier survival analysis and Cox proportional hazards analysis. RESULTS:We identified 766 patients who underwent gender-affirming phalloplasty in 23 facilities. Of 475 patients with record linkage numbers, 253 (55.3%) had subsequent re-presentations to the inpatient, emergency department, and ambulatory surgery settings related to phalloplasty complications. Survival analysis indicated that 50% of patients re-presented by 1 year post-phalloplasty. Asian/Pacific Islander patients had lower risk of complications, and California residents had higher risk of complications. CONCLUSIONS:This population-based study confirms that gender-affirming phalloplasty has a high complication rate, and demonstrates for the first time an association with high rates of return to hospitals, emergency departments, and ambulatory centers. These findings provide additional higher-level evidence that may aid patient counseling, shared surgical decision making, and institutional and government policy.

OBJECTIVE:To determine how a patient's demographics, including insurance type, race/ethnicity, gender, and age, may impact the choice of medication prescribed for overactive bladder. METHODS:We queried the AUA Quality Registry for adults between 2014 and 2020 with a diagnosis of overactive bladder for >1 year, excluding neurogenic causes. Variables included age, race/ethnicity, gender, insurance type, medication first prescribed, year of prescription, provider metropolitan status, and provider practice type. Primary outcome was which factors were associated with increased odds of beta-3 prescription as first medication choice. RESULTS:We found 1,453,566 patients with overactive bladder, 641,122 (44.1%) with complete data. Of these, 112,021 (17.5%) were prescribed medication. On multivariate analysis, patients with Medicaid, Medicare, and other/self-pay insurance were less likely to receive a beta-3 versus an anticholinergic compared to private or military insurance. Compared to white patients, Asian, Black, and other races were less likely to receive a beta-3, as were patients outside of metropolitan areas. Age >50, prescriptions after 2014, and non-academic settings were associated with increased odds of beta-3 prescription. There was no difference between genders. CONCLUSIONS:Many nonclinical factors, including insurance type and race, may affect which medication is first prescribed for overactive bladder. This is useful for practicing urologists and may help lower barriers to beta-3 prescription through policy change and advocacy.

OBJECTIVES/OBJECTIVE:To determine whether intravenous indigo carmine provides a visualization advantage compared to saline in the evaluation of ureteral patency in a randomized, controlled clinical trial. METHODS:Patients undergoing urological or gynecological surgical procedures in which the patency of the ureter was to be assessed received a saline injection and were randomized to receive 2.5 mL or 5.0 mL of indigo carmine. Blinded video assessments were conducted by independent reviewers using a conspicuity scale ranked 1 (poorest) to 5 (best), and subjects with scores ≥ 3 and at least a +1-point difference from saline were considered responders. Time to visualization was recorded for indigo carmine. A responder analysis evaluated whether indigo carmine showed improved visualization. RESULTS:There were 96 ureters evaluated with the 5.0 mL dose of indigo carmine, 92 with the 2.5 mL dose, and 180 with saline. Most ureters were scored a 4 or higher on the conspicuity scale following indigo carmine; both doses were significantly better than saline (p<0.0001). Overall, 92.3% of patients were rated as a responder for either ureter. The median time to visualization of blue color was not significantly different (6.0 minutes in the 5.0 mL group and 5.9 minutes in the 2.5 mL group). There were no adverse events related to indigo carmine use. CONCLUSIONS:Both dose levels of indigo carmine were significantly better than saline as a visualization aid for ureter patency.

OBJECTIVE:To evaluate the efficacy of a multimodal intervention in reducing CT pulmonary angiography (CTPA) overutilization in the evaluation of suspected pulmonary embolism in the emergency department (ED). METHODS:Previous mixed-methods analysis of barriers to guideline-concordant CTPA ordering results was used to develop a provider-focused behavioral intervention consisting of a clinical decision support tool and an audit and feedback system at a multisite, tertiary academic network. The primary outcome (guideline concordance) and secondary outcomes (yield and CTPA and D-dimer order rates) were compared using a pre- and postintervention design. ED encounters for adult patients from July 5, 2017, to January 3, 2019, were included. Fisher's exact tests and statistical process control charts were used to compare the pre- and postintervention groups for each outcome. RESULTS:Of the 201,912 ED patient visits evaluated, 3,587 included CTPA. Guideline concordance increased significantly after the intervention, from 66.9% to 77.5% (P < .001). CTPA order rate and D-dimer order rate also increased significantly, from 17.1 to 18.4 per 1,000 patients (P = .035) and 30.6 to 37.3 per 1,000 patients (P < .001), respectively. Percent yield showed no significant change (12.3% pre- versus 10.8% postintervention; P = .173). Statistical process control analysis showed sustained special-cause variation in the postintervention period for guideline concordance and D-dimer order rates, temporary special-cause variation for CTPA order rates, and no special-cause variation for percent yield. CONCLUSION/CONCLUSIONS:Our success in increasing guideline concordance demonstrates the efficacy of a mixed-methods, human-centered approach to behavior change. Given that neither of the secondary outcomes improved, our results may demonstrate potential limitations to the guidelines directing the ordering of CTPA studies and D-dimer ordering.

INTRODUCTION/BACKGROUND:Somatic mutations in the Wnt signaling gene Adenomatous Polyposis Coli (APC) promote metastatic prostate cancer (PCa) progression. Less is known regarding the impact of germline APC mutations on PCa outcomes. We sought to investigate the prevalence of aggressive variant PCa (AVPC) and treatment-emergent neuroendocrine PCa (t-NEPC) in patients with the germline APC I1307K variant, an alteration found in 7% of Ashkenazi Jewish men. MATERIALS AND METHODS/METHODS:We report a retrospective cohort study comparing patients with PCa and either APC I1307K germline mutation, APC somatic mutations, or unselected patients. Proportions of patients with AVPC among all the cases were estimated along with 95% Clopper-Pearson exact confidence intervals (CI). Odds ratios with 95% CI were provided for the prevalence of t-NEPC and AVPC in patients with germline APC I1307K compared to patients with frameshift alterations in APC. RESULTS:From 2016-2022, 18 patients with PCa at 3 institutions with the germline APC (I1307K) mutation were identified. Clinically-defined AVPC was found in 8 of the 15 cases with metastatic disease (53%; 95% CI: 26%-79%). Combined somatic alterations in two or more of RB1, TP53 or PTEN (molecularly-defined AVPC) were found in 5/18 cases (28%; 95% CI: 10%-54%). When compared to 20 patients with APC somatic frameshift mutations, patients with the germline APC I1307K variant had a significantly increased risk of AVPC (OR 7.2; 95% CI 1.27, 40.68). CONCLUSION/CONCLUSIONS:PCa that develops in the presence of the germline APC I1307K mutation appear to be enriched for clinically-defined and molecularly-defined AVPC and in particular, for t-NEPC.

OBJECTIVE:To investigate predictors of surgical success for patients undergoing robotic ureteral reconstruction (RUR) for ureteropelvic junction obstruction, proximal and middle ureteral stricture disease. METHODS:We retrospectively reviewed our multi-institutional Collaborative of Reconstructive Robotic Ureteral Surgery (CORRUS) database to identify all consecutive patients undergoing RUR for UPJO, proximal and/or middle ureteral stricture disease between 04/2012-12/2020. The specific reconstruction technique was determined by the primary surgeon based on clinical history and intraoperative findings. Patients were grouped according to whether they were surgical successful. Preoperative variables between both groups were compared using chi-square tests. All independent variables with associations of p<0.2 then underwent a binary logistic regression analysis to determine predictive variables of success for RUR (p≤0.05 was considered statistically significant). RESULTS:Overall, 338 patients met inclusion criteria. Surgical success rates of RUR are shown in Table 1. Univariate analysis (Table 2) showed that there were a lower proportion of patients with diabetes (8.9% versus 25.7%, p<0.01) and a higher proportion of patients who underwent ureteral rest (74.3% versus 48.6%, p<0.01) in the surgical success group. Multivariate logistic regression analysis (Table 3) further revealed the odds of surgical success in patients without diabetes was 3.08 times (CI 1.26-7.54, p=0.01) the odds of success for patients with diabetes. The odds of surgical success in patients who underwent preoperative ureteral rest were 2.8 times (CI 1.35-5.83, p=0.01) the odds of success for patients who did not undergo preoperative ureteral rest. CONCLUSION/CONCLUSIONS:Surgical success of RUR for management of UPJO, proximal and middle ureteral strictures may be influenced by factors including preoperative ureteral rest and presence of diabetes.

INTRODUCTION/BACKGROUND:Bladder outlet obstruction (BOO) in women includes functional and anatomic etiologies. Primary bladder neck obstruction (PBNO), Fowler's syndrome (FS), and dysfunctional voiding (DV) are some examples of functional obstructions, whereas pelvic organ prolapse (POP), periurethral masses, and intragenic causes are some of the anatomic causes. METHODS:This literature review describes the etiologies of female BOO, unique aspects of the workup and diagnosis, and the data for the standard surgical treatments and newer surgical techniques to treat women. Urethral stenosis and sling-related obstruction are treated in the other articles of this series. Where possible the focus is the efficacy and outcomes. RESULTS:Treatment of PBNO using a transurethral incision of the bladder neck and injection of botulinum toxin in the bladder neck decreases the BOO. After the failure of conservative approaches, sacral neuromodulation (SNM) is effective for FS, while DV may benefit from SNM or botulinum toxin injections. Concerning POP, most surgeries have been reported to significantly improve a pre-existent BOO but the level of evidence is low. Benign urethral and periurethral masses may provoke BOO, and surgical excision usually resolves this condition. CONCLUSION/CONCLUSIONS:Although most surgical treatments of BOO for functional and benign anatomical etiologies in women seem to be effective, data are scarce even for more common conditions like POP. Further studies are required to give better advice on the choice of surgical technique for these patients.