Oral phosphodiesterase type 5 inhibitors and priapism: A VigiBase analysis.

PURPOSE: To explore the differences of priapism events among a diverse cohort taking erectogenic medicines (i.e., phosphodiesterase type 5 inhibitors [PDE5i] and intracavernousal drugs). METHODS: We queried the World Health Organization global database of individual case safety reports (VigiBase) for records of the adverse drug reactions (ADR) with sildenafil, tadalafil, avanafil, vardenafil, papaverine, and alprostadil. Disproportionality analyses (case/non-case approach) were performed to assess the reporting odds ratio (ROR) of priapism reporting in PDE5i consumers compared to intracavernousal drug recipients. RESULTS: From a total of 133 819 ADR events for erectogenic medications, 632 were priapism (PDE5is: n = 550, 0.41%; intracavernousal drugs: n = 82, 9.92%). Priapism disproportionality signals from intracavernousal drugs were 25 times stronger than PDE5is (ROR = 34.7; confidence interval [CI] 95%: 27.12-43.94 vs. ROR = 1.38; 95% CI: 1.24-1.54). For all PDE5i agents, the 12-17 years age group had the highest ROR (9.49, 95% CI: 3.76-19.93) followed by 2-11 years (4.31, 95% CI: 1.57-9.4). Disproportionality signals for consumers under 18 for both all PDE5is as a whole (ROR = 4.57, 95% CI: 2.48-7.73) and sildenafil (ROR = 4.89, 95% CI: 2.51-8.62) were stronger than individuals 18 or older (ROR = 1.06, 95% CI: 0.93-1.21 and ROR = 1.08, 95% CI: 0.91-1.26, respectively). CONCLUSIONS: PDE5i use shows disproportionate priapism signals which are higher in young patients.

Do patients with Peyronie's disease perceive penile curvature in adults and children differently than the general population?

BACKGROUND: As perception of penile curvature varies widely, we sought to understand how adults perceive curvature and how these opinions compare with those of patients with curvature, specifically Peyronie's disease (PD). AIM: To investigate the perspectives of curvature correction from adults with and without PD, as well as differences within demographics. METHODS: A cross-sectional survey was administered to adult patients and nonpatient companions in general urology clinics at 3 institutions across the United States. Men, women, and nonbinary participants were recruited. Patients were grouped as having PD vs andrology conditions without PD vs general urology conditions plus companions. The survey consisted of unlabeled 2-dimensional images of penis models with varying degrees of curvature. Participants selected images that they would want surgically corrected for themselves and their children. Univariable and multivariable analyses were performed to identify demographic variables associated with willingness to correct. OUTCOMES: Our main outcome was to detect differences in threshold to correct curvature between those with and without PD. RESULTS: Participants were grouped as follows: PD (n = 141), andrology (n = 132), and general (n = 302) . Respectively, 12.8%, 18.9%, and 19.9% chose not to surgically correct any degree of curvature (P = .17). For those who chose surgical correction, the mean threshold for correction was 49.7°, 51.0°, and 51.0° (P = .48); for their children, the decision not to correct any degree of curvature was 21.3%, 25.4%, and 29.3% (P = .34), which was significantly higher than correction for themselves (P < .001). The mean threshold for their children's correction was 47.7°, 53.3°, and 49.4° for the PD, andrology, and general groups (P = .53), with thresholds no different vs themselves (P = .93). On multivariable analysis, no differences were seen in demographics within the PD and andrology groups. In the general group, participants aged 45 to 54 years and those who identified as LGBTQ (lesbian, gay, bisexual, transgender, queer) had a higher threshold for correction as compared with their counterparts when factoring other demographic variables (63.2° vs 48.8°, P = .001; 62.1° vs 50.4°, P = .05). CLINICAL IMPLICATIONS: With changing times and viewpoints, this study stresses the importance of shared decision making and balancing risks and benefits to correction of penile curvature. STRENGTHS AND LIMITATIONS: Strengths include the broad population surveyed. Limitations include the use of artificial models. CONCLUSION: No significant differences were seen in the decision to surgically correct curvature between participants with and without PD, with participants being less likely to choose surgical correction for their children.

Adverse reactions of PDE5 inhibitors: An analysis of the World Health Organization pharmacovigilance database.

BACKGROUND: Despite their efficacy and general safety, rare but devastating adverse drug reactions have been associated with phosphodiesterase type 5 inhibitors. OBJECTIVES: To determine the safety profile of oral phosphodiesterase type 5 inhibitors with a particular focus on priapism and malignant melanoma. MATERIALS AND METHODS: In this case-non-case study, we queried the individual case safety reports for phosphodiesterase type 5 inhibitors within the World Health Organization global database of individual case safety reports (VigiBase) between 1983 and 2021. We included all individual case safety reports for sildenafil, tadalafil, vardenafil, and avanafil in men. For comparison, we also extracted the safety data from the Food and Drug Administration trials for these drugs. We assessed the safety profile of phosphodiesterase type 5 inhibitors by disproportionality analysis by measuring reporting odds ratio for their most commonly reported adverse drug reactions, once for all phosphodiesterase type 5 inhibitor reports and once for reports of oral phosphodiesterase type 5 inhibitor use in adult men (≥18 years old) with sexual dysfunction. RESULTS: A total of 94,713 individual case safety reports for phosphodiesterase type 5 inhibitors were extracted. A total of 31,827 individual case safety reports were identified relating to adult men taking oral sildenafil, tadalafil, vardenafil, or avanafil for sexual dysfunction. The most common adverse drug reactions included poor drug efficacy (42.5%), headache (10.4% vs. 8.5%-27.6% [Food and Drug Administration]), abnormal vision (8.4% vs. ≤4.6% [Food and Drug Administration]), flushing (5.2% vs. 5.1%-16.5% [Food and Drug Administration]), and dyspepsia (4.2% vs. 3.4%-11.1% [Food and Drug Administration]). Priapism showed significant signals for sildenafil (reporting odds ratio = 13.81, 95% confidence interval: 11.75-16.24), tadalafil (reporting odds ratio = 14.54, 95% confidence interval: 11.56-18.06), and vardenafil (reporting odds ratio = 14.12, 95% confidence interval: 8.36-22.35). Comparing with other medications in VigiBase, sildenafil (reporting odds ratio = 8.73, 95% confidence interval: 7.63-9.99) and tadalafil (reporting odds ratio = 4.25, 95% confidence interval: 3.19-5.55) had significantly higher reporting odds ratios for malignant melanoma. CONCLUSION: Phosphodiesterase type 5 inhibitors show significant signals correlating with priapism among a large international cohort. Further clinical study is needed to elucidate whether this is from proper or inappropriate use or other confounding conditions, as analysis of pharmacovigilance data does not allow for quantifying the clinical risk. Also, there appears to be a relationship between phosphodiesterase type 5 inhibitor use and malignant melanoma, which warrants additional study to better understand causation.

Cushioning the blow: role of perirenal fat in renal trauma injury severity.

OBJECTIVES: To explore the association between perirenal fat thickness (PFT) and renal trauma grade. We hypothesise this association is related to a shock-absorbing effect of adiposity around the kidney. PATIENTS AND METHODS: We identified all patients with renal trauma who arrived at the emergency department of a single trauma centre between 2014 and 2020. Radiology images were reviewed to measure the PFT around the uninjured kidney due to disrupted PFT around the traumatised kidney. Patients with no available images or penetrating trauma mechanism were excluded. Logistic regression was used to assess the relation between PFT and high-grade renal trauma (HGRT; defined as American Association for the Surgery of Trauma Renal Grade IV-V), adjusting for age, sex, and Injury Severity Scale (ISS). RESULTS: A total of 150 patients with renal trauma were included. The median (interquartile range) age was 38.5 (26-52) years and 106 (70.7%) were males. The PFT ranged between 2.1 and 50.1 mm, and 31 (20.7%) had HGRT. Interestingly, PFT only mildly correlated with body mass index (BMI; Pearson correlation coefficient 0.42, P < 0.001). Those with HGRT had significantly lower PFT compared to those without HGRT (median 9.5 vs 11.9 mm, P = 0.047). In the multivariable analysis adjusting for age, sex, and ISS, increasing PFT was associated with decreased odds (odds ratio 0.91, 95% confidence interval 0.84-0.98; P = 0.015) of HGRT. CONCLUSION: Increasing PFT is associated with lower risk of HGRT following blunt injury. These results support a protective cushion role of adiposity in renal trauma. Notably, PFT was not strongly correlated with BMI, underscoring limitations of BMI in measuring adiposity.

Role for Conservative Management in Grade V Renal Trauma.

PURPOSE: We assessed the use of conservative management for American Association for the Surgery of Trauma grade V renal trauma in the National Trauma Databank. MATERIALS AND METHODS: We used data of grade V renal trauma patients in the 2017-2019 National Trauma Databank. Conservative management was defined by the absence of surgical or procedural intervention except for ureteral stent or percutaneous drain placement. We initially analyzed patients who survived to final hospital discharge and reported the percent utilization of conservative management. We then repeated our analysis in the overall grade V population and in all those who did not die in the emergency department. RESULTS: Of 1,474 who survived to discharge, 557 (37.8%) patients were managed conservatively. In the adjusted analysis, penetrating trauma mechanism (OR 0.13, 95% CI 0.09-0.19, P < .001) and receiving transfusion (OR 0.22, 95% CI 0.17-0.29, P < .001) were associated with decreased odds of receiving conservative management. Overall, there were 1,919 patients with grade V injury, of whom 731 (38.1%) were managed conservatively. Mortality rate was 22.8% in those managed conservatively vs 23.8% in those who had intervention. After excluding 110 patients who died in the emergency department, there were 1,809 patients, of whom 625 (34.6%) were managed conservatively. Mortality rate was 22.6% in the operatively managed group and 10.9% in the conservatively managed group. CONCLUSIONS: A substantial portion of grade V renal trauma cases were managed successfully without intervention in the National Trauma Databank. Further research is needed to identify radiological phenotypes suitable for nonoperative management and to overcome possible renal trauma grade misclassification.

Posterior urethral stenosis: a comparative review of the guidelines.

PURPOSE: We aimed to provide a thorough comparative review of the available guidelines on the diagnosis, management, and follow-up for patients with posterior urethral stenosis by the American Urologic Association (2016), Société Internationale d'Urologie (2010), and European Urologic Association (2022). METHODS: The AUA, SIU, and EAU guidelines were evaluated for recommendations on the diagnosis, evaluation, and treatment of posterior urethral stenosis. We also included the EAU and AUA urologic trauma guidelines for the trauma-related stenosis. The level or strength of recommendations is included in case of disparity between the guidelines. RESULTS: The three guidelines align considerably in recommendations provided for the diagnosis, management, and follow-up of patients with posterior urethral stenosis. SIU and EAU emphasize the role of repeat endoscopic treatment in guidelines compared to AUA. CONCLUSION: The preferred method to repair bulbo-membranous stricture/stenosis following radiation therapy remains an area of active interest, focusing on continence preservation. Additionally, there may be a role for advanced endoscopic treatments with or without adjunct therapies to manage even obliterated stenoses.

Alcohol Intoxication Is Associated With Bladder Injury and Bladder Surgical Repair in Patients Sustaining Motor Vehicle Collisions.

PURPOSE: Alcohol intoxication is a known risk factor for motor vehicle collisions. We hypothesize ethanol intoxication increases the risk of bladder injury and surgical repair, especially at higher blood alcohol content levels. MATERIALS AND METHODS: We identified all patients involved in motor vehicle collisions from the National Trauma Data Bank from 2017-2019. Patients were categorized into an intoxication and intoxication negative group. Variables collected included age, sex, blood alcohol content level, driver status, seat belt restraint use, nonalcoholic intoxication, pelvic fracture, and Injury Severity Scale. Primary outcome measures of bladder injury and bladder surgical repair were assessed and interaction with pelvic fracture and restraint use were measured. RESULTS: We identified 594,484 patients and 97,831 (16.5%) had a positive alcohol screen. Patients in the intoxication group were more likely to be intoxicated with other substances (32.8% vs 14.6%, P < .001), have a bladder injury (1% vs 0.4%, P < .001) and receive bladder surgical repair (0.7% vs 0.15%, P < .001). Injury Severity Scale and pelvic fracture were statistically significant predictors of bladder injury. In adjusted analysis, higher blood alcohol content was associated with both outcomes. Above the legal limit, alcohol intoxication was more predictive of bladder surgical repair than pelvic fracture. The association of alcohol intoxication with both outcomes did not differ by pelvic fracture, but strengthened with seat belt use at higher intoxication levels. CONCLUSIONS: Alcohol intoxication is independently associated with increased risk of bladder injury and subsequent bladder surgical repair following motor vehicle collisions. Trauma providers should have a high index of suspicion for bladder injuries in alcohol intoxicated patients, particularly those using seat belt restraints.

COVID-19 Misinformation and Social Network Crowdfunding: Cross-sectional Study of Alternative Treatments and Antivaccine Mandates.

BACKGROUND: Crowdfunding is increasingly used to offset the financial burdens of illness and health care. In the era of the COVID-19 pandemic and associated infodemic, the role of crowdfunding to support controversial COVID-19 stances is unknown. OBJECTIVE: We sought to examine COVID-19-related crowdfunding focusing on the funding of alternative treatments not endorsed by major medical entities, including campaigns with an explicit antivaccine, antimask, or antihealth care stances. METHODS: We performed a cross-sectional analysis of GoFundMe campaigns for individuals requesting donations for COVID-19 relief. Campaigns were identified by key word and manual review to categorize campaigns into "Traditional treatments," "Alternative treatments," "Business-related," "Mandate," "First Response," and "General." For each campaign, we extracted basic narrative, engagement, and financial variables. Among those that were manually reviewed, the additional variables of "mandate type," "mandate stance," and presence of COVID-19 misinformation within the campaign narrative were also included. COVID-19 misinformation was defined as "false or misleading statements," where cited evidence could be provided to refute the claim. Descriptive statistics were used to characterize the study cohort. RESULTS: A total of 30,368 campaigns met the criteria for final analysis. After manual review, we identified 53 campaigns (0.17%) seeking funding for alternative medical treatment for COVID-19, including popularized treatments such as ivermectin (n=14, 26%), hydroxychloroquine (n=6, 11%), and vitamin D (n=4, 7.5%). Moreover, 23 (43%) of the 53 campaigns seeking support for alternative treatments contained COVID-19 misinformation. There were 80 campaigns that opposed mandating masks or vaccination, 48 (60%) of which contained COVID-19 misinformation. Alternative treatment campaigns had a lower median amount raised (US $1135) compared to traditional (US $2828) treatments (P<.001) and a lower median percentile of target achieved (11.9% vs 31.1%; P=.003). Campaigns for alternative treatments raised substantially lower amounts (US $115,000 vs US $52,715,000, respectively) and lower proportions of fundraising goals (2.1% vs 12.5%) for alternative versus conventional campaigns. The median goal for campaigns was significantly higher (US $25,000 vs US $10,000) for campaigns opposing mask or vaccine mandates relative to those in support of upholding mandates (P=.04). Campaigns seeking funding to lift mandates on health care workers reached US $622 (0.15%) out of a US $410,000 goal. CONCLUSIONS: A small minority of web-based crowdfunding campaigns for COVID-19 were directed at unproven COVID-19 treatments and support for campaigns aimed against masking or vaccine mandates. Approximately half (71/133, 53%) of these campaigns contained verifiably false or misleading information and had limited fundraising success. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1001/jamainternmed.2019.3330.

Incidence of venous thromboembolism in benign urologic reconstructive cases.

PURPOSE: To evaluate the rate of perioperative venous thromboembolism (VTE) among patients undergoing common benign urologic reconstructive cases. We hypothesize that this rate will be lower than previously described. METHODS: We utilized the American College of Surgeons National Surgical Quality Improvement Project database from 2015 to 2019 to evaluate 30-day perioperative risk of VTE. Patients ≥ 18 years old undergoing benign urologic reconstructive cases were selected using Current Procedural Terminology (CPT) codes. Demographic, comorbidity, and operative variables were captured. The primary outcome was VTE within the 30-day postoperative period. RESULTS: We identified 8467 patients who met inclusion criteria. The majority of patients were male (> 95%) with an average age of 65 and BMI of 29.6. There were 23 VTE events (0.27%) within the 30-day perioperative period. Fourteen (14/59) procedures had a perioperative VTE. Many of the traditional factors for VTE including operative time and obesity significantly increased risk of VTE in univariate analysis. In multivariate analysis, only BMI (OR 1.09; 95% CI 1.01-1.12) and inpatient status (OR 4.42; 95% CI 1.9-10.2) were correlated with increased perioperative VTE. CONCLUSION: The rate of VTE among patients undergoing benign urologic reconstructive cases is low. Providers should continue to have high index of suspicion particularly for inpatients with high BMI in addition to other known risk factors for VTE.

Hematospermia is rarely associated with urologic malignancy: Analysis of United States claims data.

BACKGROUND: Hematospermia is an alarming symptom and can cause significant patient distress, but work-up is often negative. OBJECTIVE: To characterize the clinical evaluation of hematospermia and its association with the diagnosis of urologic malignancy. MATERIALS AND METHODS: Using MarketScan insurance claims database, we identified adult males 18-64 years old diagnosed with hematospermia from 2010 to 2018. Benign hematospermia was defined as the absence of hematuria and elevated prostate-specific antigen. Patients with urologic cancer prior to diagnosis of hematospermia were excluded. We identified those who were diagnosed with a urologic malignancy. RESULTS: The annual average incidence rate of hematospermia was 56.6 per 100,000 (95% confidence interval 55.4-57.8 per 100,000) in 2010 and increased to 73.6 per 100,000 (95% confidence interval 71.7-75.4 per 100,000) in 2018. A total of 56,157 patients presented with benign hematospermia. Most (57.5%) underwent at least one test, with the most common being urinalysis (51.7%), followed by prostate-specific antigen testing (11.9%). All other tests were performed in less than 3% of patients. Forty-seven patients were diagnosed with a urologic cancer, including 28 with prostate cancer (0.05%), nine with testicular cancer (0.016%), six with prostate carcinoma in situ (0.01%), and four with bladder cancer (0.007%). Stratified by age, there was only one cancer diagnosis (testicular) in 15,106 patients under 40 years (0.01%) and 46 cancer diagnoses in 40,611 patients 40 years old or above (0.11%). The median age of patients diagnosed with cancer was 56 years (interquartile range 52-61). DISCUSSION AND CONCLUSION: A small minority of patients with benign hematospermia were later diagnosed with urologic cancer in a large nationally representative sample. After excluding hematuria with urinalysis, physicians should conservatively manage and reassure patients with hematospermia, especially those under 40 years of age.

Foley Catheter Balloon Rupture and Risk of Free Fragment Formation.

OBJECTIVES: To assess the volume of foley catheter balloon rupture and the incidence of free fragment formation. MATERIALS AND METHODS: Forty Latex and 30 Silicone catheters of common sizes (14-20 French) were inflated with sterile water in an aqueous environment without positive pressure. Catheters producing fragments, fragment size, and maximum instilled volume prior to rupture ("burst volume") were recorded. A subset of catheters was inflated to recommended balloon volume and the balloon was needle punctured. RESULTS: Of the 40 latex catheters, 32 (80%) produced a free fragment during spontaneous rupture. Fragments ranged from 2.1 to 3.2 cm with an average size of 2.74 ± 0.33 cm. Latex catheters had average burst volume of 83 mL, 90 mL, 112 mL,120 mL, and 422 mL for 14 Fr, 16 Fr, 18 Fr, 16 Fr 3-way, and 20 Fr 30 cc, respectively. Of the 30 silicone catheters, spontaneous rupture produced no fragments. Average burst volume for silicone catheters was 57 mL, 45 mL, and 55 mL for 14 Fr, 16 Fr, and 18 Fr, respectively. No catheter balloons produced fragments when needle punctures at recommended balloon volumes. CONCLUSION: Latex catheter balloons tolerate higher fill volumes but have a high likelihood of releasing fragments. Silicone catheters burst at lower volumes, but do not release fragments. At normal fill volumes, needle puncture is safe, and cystoscopy is likely unnecessary.

Comparative review of the guidelines for anterior urethral stricture.

PURPOSE: We aimed to provide a detailed comparison between the American Urologic Association (AUA), Société Internationale d'Urologie (SIU), and the European Association of Urology (EAU) guidelines on the evaluation, management, and follow-up of the patients with anterior urethral stricture disease (USD). METHODS: The urethral stricture guidelines from SUI, AUA, and EAU were collected and evaluated regarding the recommendations on diagnosis, evaluation, and treatment of anterior USD. The strength of evidence for each statement was included and discussed when guidelines differed. RESULTS: While the guidelines remarkably align in terms of the diagnostic workup and follow-up, there is discordance in the management of anterior urethral strictures, specifically for the use of endoscopic treatment and stenting. Further, the EAU offers more comprehensive recommendations regarding urethroplasty techniques and patient follow-up. The EAU guidelines are the most recent and first to offer guidance for USD in transgender people and women. CONCLUSION: Reconstructive urology is a rapidly adapting field, and best practices change accordingly. Guideline statements have become more inclusive and expansive but will require further research to improve the level of evidence and continue to provide patients and providers with the best treatment plans.

Trends in Publication of Oncologic Abstracts Presented at the American Urological Association Annual Meeting: 1997-2017.

INTRODUCTION: Our primary aim was to characterize eventual publication of presented American Urological Association (AUA) Annual Meeting oncology abstracts from 1997 to 2017. We hypothesized that the percentage of abstracts presented at the AUA Annual Meeting that became published peer-reviewed manuscripts increased over time. METHODS: AUA Annual Meeting abstracts in "oncology" categories from 1997 to 2017 were identified. A random sample of 100 abstracts per year were assessed for publication. An abstract was considered "published" if 1) first and last author of the abstract were included on publication, 2) abstract and publication shared 1 conclusion, and 3) publication occurred from 1 year prior to the AUA Annual Meeting up to 10 years after. The search was conducted on PubMed® utilizing the MEDLINE® database. RESULTS: Over the 20-year observation period, 2,100 abstracts were reviewed and 56.3% were published. The number of journals in which manuscripts were published increased from 1997 to 2017 (R2=0.58, p <0.001), although here wasn't an increased publication rate for AUA Annual Meeting abstracts. Median time to publication was 1.1 years (IQR: 0.6-2.2). Median impact factor (IF) of publications was 3.3 (IQR 2.4-4.7). There was a decrease in median IF with longer interval to publication, from 3.6 within 1 year to 2.8 at more than 3 years (p=0.0003). Publications from multi-institutional abstracts had a higher mean IF (3.7 vs 3.1, p <0.0001). CONCLUSIONS: The majority of oncology abstracts presented at the AUA Annual Meeting are published. Despite growth in the number of journals and rise in IF among top urology journals, the rate of publication and IF were stable over time.

YAP facilitates melanoma migration through regulation of actin-related protein 2/3 complex subunit 5 (ARPC5).

Yes-associated protein 1 (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are transcriptional coactivators that have been implicated in driving metastasis and progression in many cancers, mainly through their transcriptional regulation of downstream targets. Although YAP and TAZ have shown redundancy in many contexts, it is still unknown whether or not this is true in melanoma. Here, we show that while both YAP and TAZ are expressed in a panel of melanoma cell lines, depletion of YAP results in decreased cell numbers, focal adhesions, and the ability to invade matrigel. Using non-biased RNA-sequencing analysis, we find that melanoma cells depleted of YAP, TAZ, or YAP/TAZ exhibit drastically different transcriptomes. We further uncover the ARP2/3 subunit ARPC5 as a specific target of YAP but not TAZ and that ARPC5 is essential for YAP-dependent maintenance of melanoma cell focal adhesion numbers. Our findings suggest that in melanoma, YAP drives melanoma progression, survival, and invasion.

A Legal Database Review of Circumcision Related Litigation in the United States.

OBJECTIVE: To characterize circumcision-related litigation in the United States (US) and factors predictive of lawsuit outcome. Circumcision is a common urologic procedure with medical and ethical nuances. METHODS: We reviewed the Nexis Uni legal database for state and federal cases using the term "circumcision" in combination with "medical malpractice" or "negligence" or "medical error" or "complication" or "malpractice" or "tort". Litigation primarily related to circumcision from 1939 to 2021 were reviewed for medical and legal details. RESULTS: We identified 77 unique cases. Most cases were processed in state (87%) or appellate (59%) court systems with negligent surgical performance as the most common lawsuit reason (49%). Of reported specialties, urology was the highest proportion represented among named physicians (29%) and most patients were minors at time of circumcision (64%) and lawsuit (59%). Common complications included aesthetic dissatisfaction (20%), pain (19%), impaired sexual function (17%) and surgical trauma/injury (16%). Most verdicts favored physicians (59%), but when against physicians, the median indemnity was $175,000. Lawsuits due to negligent informed consent were significantly more likely to result in verdict favoring the physician compared to those due to negligent surgical performance. CONCLUSIONS: Circumcision-related litigation in the US is rare and trial verdicts favor physicians, particularly in federal court cases or when parties allege negligent informed consent. Cases that favored plaintiffs successfully alleged negligent surgical technique. We recommend physicians performing circumcisions receive proper training, clearly communicate potential complications, and ensure appropriate indications for adult patients to reduce malpractice risk.

5-Alpha reductase inhibitor related litigation: A legal database review.

BACKGROUND: 5α-reductase inhibitors are commonly prescribed medications with multiple side effects used in the treatment of male pattern hair loss and benign prostatic hyperplasia. These side effects including "post-finasteride syndrome" may result in lawsuits. OBJECTIVES: To characterize lawsuits involving the adverse side effects of 5α-reductase inhibitor to better understand drivers of litigation and outcomes. METHODS: Legal cases were queried from Nexis Uni using the search terms "5-alpha reductase inhibitor" as well as specific agents "finasteride," "dutasteride" in combination with "malpractice," "negligence," "damage," "loss," "side effect," and "complication." Secondary review was performed with publicly available data on "In Re: Propecia." Relevant cases were reviewed and pertinent characteristics were extracted and summarized using descriptive statistics. RESULTS: Our search yielded 156 unique legal cases in the Nexis Uni database from April 2003 to May 2021. Only 18 of these cases met the inclusion criteria. Adverse events experienced by patients included medication side effects (n = 12, 66.7%), delayed cancer diagnosis (n = 3, 16.7%), and lack of symptom improvement (n = 3, 16.7%). The identity of the plaintiffs were most commonly patients themselves (n = 15, 83.3%). Defendants include pharmaceutical companies (n = 6, 33.3%), a combination of parties (n = 5, 27.8%), and physicians (n = 5, 27.8%) alone. The allegations included sexual side effects such as erectile dysfunction (n = 6, 33.3%) and decreased libido (n = 4, 22.2%). These prescriptions were made for benign prostatic hyperplasia (n = 9, 50%), male pattern hair loss (n = 7, 38.9%), and feminizing hormone therapy (n = 2, 11.1%). Several of these cases involved the same plaintiffs in related cases. No verdicts were against physicians. We noted a largely settled lawsuit involving more than 1000 plaintiffs with limited data on harms alleged and a $4.3 million settled amount. Of the total cases that resulted in a verdict, 9/18 were within the last 3 years. DISCUSSION: The most common complications experienced by patients in our legal review were those involving sexual dysfunction with erectile dysfunction and decreased libido. The growing number of cases in the later years of our review suggests litigation may continue to increase in the coming future. Our review did not identify any individual cases that resulted in a monetary payout beyond a $4.3 million settlement outside of court. CONCLUSION: 5α-reductase inhibitor was alleged to have sexual, mental, and physical side effects, resulting in legal litigation. Despite this, no judgment against a physician or pharmaceutical company was identified. We do note and discuss a large number of lawsuits settled out of court. Given the increase in the number of lawsuits resulting in verdicts over the last 3 years, we suspect that the frequency of litigation around 5α-reductase inhibitors will continue for the foreseeable future.

Targeting Pan-ETS Factors Inhibits Melanoma Progression.

The failure of once promising target-specific therapeutic strategies often arises from redundancies in gene expression pathways. Even with new melanoma treatments, many patients are not responsive or develop resistance, leading to disease progression in terms of growth and metastasis. We previously discovered that the transcription factors ETS1 and PAX3 drive melanoma growth and metastasis by promoting the expression of the MET receptor. Here, we find that there are multiple ETS family members expressed in melanoma and that these factors have redundant functions. The small molecule YK-4-279, initially developed to target the ETS gene-containing translocation product EWS-FLI1, significantly inhibited cellular growth, invasion, and ETS factor function in melanoma cell lines and a clinically relevant transgenic mouse model, BrafCA;Tyr-CreERT2;Ptenf/f. One of the antitumor effects of YK-4-279 in melanoma is achieved via interference of multiple ETS family members with PAX3 and the expression of the PAX3-ETS downstream gene MET. Expression of exogenous MET provided partial rescue of the effects of YK-4-279, further supporting that MET loss is a significant contributor to the antitumor effects of the drug. This is the first study identifying multiple overlapping functions of the ETS family promoting melanoma. In addition, targeting all factors, rather than individual members, demonstrated impactful deleterious consequences in melanoma progression. Given that multiple ETS factors are known to have oncogenic functions in other malignancies, these findings have a high therapeutic impact. SIGNIFICANCE: These findings identify YK-4-279 as a promising therapeutic agent against melanoma by targeting multiple ETS family members and blocking their ability to act as transcription factors.

The Efficiency of Verteporfin as a Therapeutic Option in Pre-Clinical Models of Melanoma.

Yes Associated Protein 1 (YAP) and Transcriptional coactivator with PDZ-Binding Motif (TAZ) have gained notoriety for their ability to drive tumor initiation and progression in a wide variety of cancers, including melanoma. YAP and TAZ act as drivers of melanoma through its interaction with the TEAD family of transcription factors. Verteporfin is a benzoporphyrin derivative that is used clinically for photodynamic treatment of macular degeneration. Recently it has emerged as a potential inhibitor of YAP/TAZ-TEAD interaction independent of light activation. In this study we determine if verteporfin has clinical potential by testing this compound on human melanoma cell cultures and in a clinically significant mouse model, BrafCA; Tyr-CreERT2; Ptenf/f, which parallels human melanoma in terms of disease progression, genetics, and histopathology. In culture, Verteporfin treatment induces a rapid drop in YAP and TAZ protein levels and cell numbers. In the transgenic model, utilizing drug levels that correspond to previously determined safe doses in human patients and with a dosing regimen calculated in this study, Verteporfin did not inhibit melanoma initiation or progression in comparison to mock treated controls. Taken together, our study suggests that although Verteporfin induces YAP/TAZ degradation in melanoma cell lines, Verteporfin was not effective as a YAP/TAZ-TEAD specific inhibitor of melanoma in our studies that aimed to mimic conditions found in clinic in terms of treatment regimen and disease model.

PAX3 and FOXD3 Promote CXCR4 Expression in Melanoma.

Metastatic melanoma is an aggressive and deadly disease. The chemokine receptor CXCR4 is active in melanoma metastasis, although the mechanism for the promotion and maintenance of CXCR4 expression in these cells is mostly unknown. Here, we find melanoma cells express two CXCR4 isoforms, the common version and a variant that is normally restricted to cells during development or to mature blood cells. CXCR4 expression is driven through a highly conserved intronic enhancer element by the transcription factors PAX3 and FOXD3. Inhibition of these transcription factors slows melanoma cell growth, migration, and motility, as well as reduces CXCR4 expression. Overexpression of these transcription factors drives the production of increased CXCR4 levels. Loss of PAX3 and FOXD3 transcription factor activity results in a reduction in cell motility, migration, and chemotaxis, all of which are rescued by CXCR4 overexpression. Here, we discover a molecular pathway wherein PAX3 and FOXD3 promote CXCR4 gene expression in melanoma.