Nephrotoxicity of immune checkpoint inhibitor therapy: a pharmacovigilance study.

BACKGROUND: Immune checkpoint inhibitor (ICI) therapy has demonstrated impressive clinical benefits across cancers. However, adverse drug reactions (ADRs) occur in every organ system, often due to autoimmune syndromes. We sought to investigate the association between ICI therapy and nephrotoxicity using a pharmacovigilance database, hypothesizing that inflammatory nephrotoxic syndromes would be reported more frequently in association with ICIs. METHODS: We analyzed VigiBase, the World Health Organization pharmacovigilance database, to identify renal ADRs (rADRs), such as nephritis, nephropathy and vascular disorders, reported in association with ICI therapy. We performed a disproportionality analysis to explore if rADRs were reported at a different rate with one of the ICI drugs compared with rADRs in the entire database, using an empirical Bayes estimator as a significance screen and defining the effect size with a reporting odds ratio (ROR). RESULTS: We found 2341 rADR for all examined ICI drugs, with a disproportionality signal solely for nephritis [ROR = 3.67, 95% confidence interval (CI) 3.34-4.04]. Examining the different drugs separately, pembrolizumab, nivolumab and ipilimumab + nivolumab combination therapy had significantly higher reporting odds of nephritis than the other ICI drugs (ROR = 4.54, 95% CI 3.81-5.4; ROR = 3.94, 95% CI 3.40-4.56; ROR 3.59, 95% CI 2.71-4.76, respectively). CONCLUSIONS: Using a pharmacovigilance method, we found increased odds of nephritis when examining rADRs associated with ICI therapy. Pembrolizumab, nivolumab and a combination of ipilimumab + nivolumab showed the highest odds. Clinicians should consider these findings and be aware of the increased risk of nephritis, especially in patients treated with pembrolizumab, when administering ICI therapy.

Surgical Complications Requiring Intervention in Open versus Minimally Invasive Radical Prostatectomy.

INTRODUCTION: Injuries to surrounding structures during radical prostatectomy (RP) are rare but serious complications. However, it remains unknown if injuries to intestines, rectum, or vascular structures occur at different rates depending on the surgical approach. METHODS: We compared the frequency of these outcomes in open RP (ORP) and minimally invasive RP (MIS-RP) using the national American College of Surgeons National Surgical Quality Improvement Program database (2012-2017). Along with important metrics of clinical and surgical outcomes, patients were identified as undergoing surgical repair of small or large bowel, vascular structures, or hernias based on Current Procedural Terminology codes. RESULTS: In our propensity matched analysis, a total of 13,044 patients were captured. Bowel injury occurred more frequently in ORP than in MIS-RP (0.89 vs. 0.26%, p < 0.01). By intestinal segment, rectal and large bowel injuries were more common in ORP than MIS-RP (0.41 vs. 0.11% and 0.31 vs. 0.05%, both p < 0.01). However, there was no statistically significant difference between the groups for small bowel injury (0.17 vs. 0.11%, p = 0.39). Vascular injury was more common in MIS-RP (0.18 vs. 0.08%, p = 0.08). Hernias requiring repair were only identified in the MIS-RP group (0.12%). CONCLUSION: When considering surgical approach, rectal and large bowel injuries were more common in ORP, while vascular injuries and hernia repair were more common in MIS-RP. Our findings can be used in counseling patients and identifying risk factors and strategies to reduce these complications.

Access denied: The relationship between patient insurance status and access to high-volume hospitals.

BACKGROUND: Underinsured patients face significant barriers in accessing high-quality care. Evidence of whether access to high-volume surgical care is mediated by disparities in health insurance coverage remains wanting. METHODS: The authors used the National Cancer Data Base to identify all adult patients who had a confirmed diagnosis of breast, prostate, lung, or colorectal cancer during 2004 through 2016. The odds of receiving surgical care at a high-volume hospital were estimated according to the type of insurance using multivariable logistic regression analyses for each malignancy. Then, the interactions between study period and insurance status were assessed. RESULTS: In total, 1,279,738 patients were included in the study. Of these, patients with breast cancer who were insured by Medicare (odds ratio [OR], 0.75; P < .001), Medicaid (OR, 0.55; P < .001), or uninsured (OR, 0.50; P < .001); patients with prostate cancer who were insured by Medicare (OR, 0.87; P = .003), Medicaid (OR, 0.58; P = .001), or uninsured (OR, 0.36; P < .001); and patients with lung cancer who were insured by Medicare (OR, 0.84; P = .020), Medicaid (OR, 0.74; P = .001), or uninsured (OR, 0.48; P < .001) were less likely to receive surgical care at high-volume hospitals compared with patients who had private insurance. For patients with colorectal cancer, the effect of insurance differed by study period, and improved since 2011. For those on Medicaid, the odds of receiving care at a high-volume hospital were 0.51 during 2004 through 2007 and 0.99 during 2014 through 2016 (P for interaction = .001); for uninsured patients, the odds were 0.45 during 2004 through 2007 and 1.19 during 2014 through 2016 (P for interaction < .001) compared with patients who had private insurance. CONCLUSIONS: Uninsured, Medicare-insured, and Medicaid-insured patients are less likely to receive surgical care at high-volume hospitals. For uninsured and Medicaid-insured patients with colorectal cancer, the odds of receiving care at high-volume hospitals have improved since implementation of the Patient Protection and Affordable Care Act of 2010.

Systematic Review of Time to Definitive Treatment for Intermediate Risk and High Risk Prostate Cancer: Are Delays Associated with Worse Outcomes?

PURPOSE: Prostate cancer is most commonly an indolent disease, especially when detected at a localized stage. Unlike other tumors that may benefit from timely receipt of definitive therapy, it is generally accepted that treatment delays for localized prostate cancer are acceptable, especially for low risk prostate cancer. Since treatment delay for intermediate risk and high risk disease is more controversial, we sought to determine if delays for these disease states negatively impacted oncological outcomes. MATERIALS AND METHODS: We conducted a systematic review of the literature with searches of Medline, EMBASE and the Cochrane Database of Systematic Reviews from inception to June 30, 2020. General study characteristics as well as study population and delay information were collected. The outcomes of interest extracted included biochemical recurrence, pathological features (positive surgical margins, upgrading, extracapsular extension, and other pathological features), cancer specific survival and overall survival. RESULTS: After identifying 1,793 unique references, 24 manuscripts met criteria for data extraction, 15 of which were published after 2013. Based on our review, delays up to 3 months are safe for all localized prostate cancer and are not associated with worse oncological outcomes. Some studies identified worse oncological outcomes as a result of delays beyond 6 to 9 months. However, these studies are counterbalanced by others finding no statistically significant association with delays up to 12 months. Studies that did find worse outcomes as a result of delays identified a higher risk of biochemical recurrence and worse pathological outcomes but not worse cancer specific or overall survival. CONCLUSIONS: Definitive treatment for intermediate risk and high risk prostate cancer can be delayed up to 3 months without any oncological consequences. Some evidence suggests that there is a higher risk of biochemical recurrence and worse pathological outcomes associated with delays beyond 6 to 9 months. To date, there are no reports of worse cancer specific survival or overall survival as a result of delayed treatment for intermediate risk and high risk prostate cancer.

Association of the hospital readmission reduction program with readmission and mortality outcomes after coronary artery bypass graft surgery.

The Affordable Care Act established the Hospital Readmissions Reduction Program (HRRP) to reduce payments to hospitals with excessive readmissions in an effort to link payment to the quality of hospital care. Prior studies demonstrating an association of HRRP implementation with increased mortality after heart failure discharges have prompted concern for potential unintended adverse consequences of the HRRP. We examined the impact of these policies on coronary artery bypass graft (CABG) surgery outcomes using the Nationwide Readmissions Database and found that, in line with previously observed readmission trends for CABG, readmission rates continued to decline in the era of the HRRP, but that this did not come at the expense of increased mortality. These results suggest that inclusion of surgical procedures, such as CABG in the HRRP might be an effective cost-reducing measure that does not adversely affect quality of hospital care.

Clinical applications of artificial intelligence in urologic oncology.

PURPOSE OF REVIEW: This review aims to shed light on recent applications of artificial intelligence in urologic oncology. RECENT FINDINGS: Artificial intelligence algorithms harness the wealth of patient data to assist in diagnosing, staging, treating, and monitoring genitourinary malignancies. Successful applications of artificial intelligence in urologic oncology include interpreting diagnostic imaging, pathology, and genomic annotations. Many of these algorithms, however, lack external validity and can only provide predictions based on one type of dataset. SUMMARY: Future applications of artificial intelligence will need to incorporate several forms of data in order to truly make headway in urologic oncology. Researchers must actively ensure future artificial intelligence developments encompass the entire prospective patient population.

Cost-effectiveness comparison of ureteral calculi treated with ureteroscopic laser lithotripsy versus shockwave lithotripsy.

PURPOSE: To evaluate the cost-effectiveness of shockwave lithotripsy (SWL) versus ureteroscopic lithotripsy (URS) for patients with ureteral stones less than 1.5 cm in diameter. METHODS: Patient age, stone diameter, stone location, and stone-free status were recorded for patients treated with SWL or URS for ureteral stones under 1.5 cm over a 1 year period. Institutional charges were obtained from in-house billing. A decision analysis model was constructed to compare the cost-effectiveness of SWL and URS using our results and success rates for modeling. Three separate models were created to reflect differing practice patterns. RESULTS: A total of 113 patients were included-51 underwent SWL and 62 underwent URS as primary treatment. Single procedure stone-free rates for SWL and URS were 47.1 and 88.7 %, respectively (p < 0.002). Decision analysis modeling demonstrated cost-effectiveness of SWL when SWL single procedure stone-free rates (SFR) were greater than or equal to 60-64 % or when URS single procedure SFRs were less than or equal to 57-76 %, depending on practice patterns. CONCLUSIONS: This retrospective study revealed superior SFR for ureteral stones less than 1.5 cm treated with URS compared to SWL. Our decision analysis model demonstrated that when SFR for SWL is less than 60-64 % or is greater than 57-76 % for URS, SWL is not a cost-effective treatment option. Based on these findings, careful stratification and selection of stone patients may enable surgeons to increase the cost-effectiveness of SWL.

Biomarkers for Wilms Tumor: A Systematic Review.

PURPOSE: Wilms tumor is the most common childhood renal malignancy and the fourth most common childhood cancer. Many biomarkers have been studied but there has been no comprehensive summary. We systematically reviewed the literature on biomarkers in Wilms tumor to quantify the prognostic implications of the presence of individual tumor markers. MATERIALS AND METHODS: We searched for English language studies from 1980 to 2015 performed in patients younger than 18 years with Wilms tumor and prognostic data. The protocol was conducted per PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Two reviewers abstracted data in duplicate using a standard evaluation form. We performed descriptive statistics, then calculated relative risks and 95% confidence intervals for markers appearing in multiple level II or III studies. RESULTS: A total of 40 studies were included examining 32 biomarkers in 7,381 patients with Wilms tumor. Studies had a median of 61 patients, 24 biomarker positive patients per series and a median followup of 68.4 months. Median percentages of patients with stages 1, 2, 3, 4 and 5 tumors were 28.5%, 26.4%, 24.5%, 14.1% and 1.7%, respectively, and 10.2% had anaplasia. The strongest negative prognostic association was loss of heterozygosity at 11p15, with a risk of recurrence of 5.00, although loss of heterozygosity at 1p and gain of function at 1q were also strongly linked to increased recurrence (2.93 and 2.86, respectively). CONCLUSIONS: Several tumor markers are associated with an increased risk of recurrence or a decreased risk of overall survival in patients with Wilms tumor. These data suggest targets for development of diagnostic tests and potential therapies.

Outcomes for Arthroplasties in Military Health: A Retrospective Analysis of Direct Versus Purchased Care.

INTRODUCTION: The Department of Defense is reforming the military health system where surgeries are increasingly referred from military treatment facilities (MTFs) with direct care to higher-volume civilian hospitals under purchased care. This shift may have implications on the quality and cost of care for TRICARE beneficiaries. This study examined the impact of care source and surgical volume on perioperative outcomes and cost of total hip arthroplasties (THAs) and total knee arthroplasties (TKAs). MATERIALS AND METHODS: We examined TRICARE claims for patients who underwent THA or TKA between 2006 and 2019. The 30-day readmissions, complications, and costs between direct and purchased care were evaluated using the logistic regression model for surgical outcomes and generalized linear models for cost. RESULTS: We included 71,785 TKA and THA procedures. 11,013 (15.3%) were performed in direct care. They had higher odds of readmissions (odds ratio, OR 1.29 [95% CI, 1.12-1.50]; P < 0.001) but fewer complications (OR 0.83 [95% CI, 0.75-0.93]; P = 0.002). Within direct care, lower-volume facilities had more complications (OR 1.27 [95% CI, 1.01-1.61]; P = 0.05). Costs for index surgeries were significantly higher at MTFs $26,022 (95% CI, $23,393-$28,948) vs. $20,207 ($19,339-$21,113). Simulating transfer of care to very high-volume MTFs, estimated cost savings were $4,370/patient and $20,229,819 (95% CI, $17,406,971-$25,713,571) in total. CONCLUSIONS: This study found that MTFs are associated with lower odds of complications, higher odds of readmission, and higher costs for THA and TKA compared to purchased care facilities. These findings mean that care in the direct setting is adequate and consolidating care at higher-volume MTFs may reduce health care costs.

Are work relative value units correlated with operative duration of common surgical procedures?

OBJECTIVES: Work relative value units (wRVUs) quantify physician workload. In theory, higher wRVU assignments for procedures recognize an increase in complexity and time required to complete the procedure. The fairness of wRVU assignment is debated across specialties, with some surgeons arguing that reimbursement may be unfairly low for longer, more complex cases. For this reason, we sought to assess the correlation of wRVUs with operative time in commonly performed surgeries. STUDY DESIGN: We analyzed the National Surgical Quality Improvement Program database, selecting the 15 most performed surgical procedures across specialties in a 90-day global period, using Current Procedural Terminology codes. METHODS: Calculation and comparison of mean operative time and mean wRVUs were performed for each of the 15 procedures. Cases with missing values for wRVUs or operative time and cases with an operative time of less than 15 minutes were excluded. The Spearman correlation coefficient was calculated to evaluate the strength of correlation between operative duration and wRVUs. RESULTS: A total of 1,994,394 patients met criteria for analysis. The lowest mean wRVU was 7.78 (95% CI, 7.77-7.78) for inguinal hernia repair; the highest was 43.50 (95% CI, 43.37-43.60) for pancreatectomy. The shortest mean operative time was 51.0 (95% CI, 50.8-51.1) minutes for appendectomy; the longest was for pancreatectomy at 324.6 (95% CI, 323.2-326.0) minutes. The Spearman correlation coefficient was 0.81. CONCLUSIONS: In our analysis, we found a strong correlation between operative duration and wRVU assignment. Thus, the reimbursement of physicians depending on wRVUs is fair for the most commonly performed surgical procedures across specialties.

Immune checkpoint inhibitor monotherapy is associated with less cardiac toxicity than combination therapy.

BACKGROUND: Treatment options for many cancers include immune checkpoint inhibitor (ICI) monotherapy and combination therapy with impressive clinical benefit across cancers. We sought to define the comparative cardiac risks of ICI combination and monotherapy. METHODS: We used VigiBase, the World Health Organization pharmacovigilance database, to identify cardiac ADRs (cADRs), such as carditis, heart failure, arrhythmia, myocardial infarction, and valvular dysfunction, related to ICI therapy. To explore possible relationships, we used the reporting odds ratio (ROR) as a proxy of relative risk. A lower bound of a 95% confidence interval of ROR &gt; 1 reflects a disproportionality signal that more ADRs are observed than expected due to chance. RESULTS: We found 2278 cADR for ICI monotherapy and 353 for ICI combination therapy. Combination therapy was associated with significantly higher odds of carditis (ROR 6.9, 95% CI: 5.6-8.3) versus ICI monotherapy (ROR 5.0, 95% CI: 4.6-5.4). Carditis in ICI combination therapy was fatal in 23.4% of reported ADRs, compared to 15.8% for ICI monotherapy (P = 0.058). CONCLUSIONS: Using validated pharmacovigilance methodology, we found increased odds of carditis for all ICI therapies, with the highest odds for combination therapy. Given the substantial risk of severe ADR and death, clinicians should consider these findings when prescribing checkpoint inhibitors.

Professional Burnout, Career Choice Regret, and Unmet Needs for Well-Being Among Urology Residents.

OBJECTIVE: To measure burnout and career choice regret from the American Urological Association Census, a national sample of urology residents, and to identify unmet needs for well-being. METHODS: This is a cross-sectional study describing U.S. urology residents' responses to the 22-item Maslach Burnout Inventory and questions about career and specialty choice regret from the 2019 AUA Census. Respondents reported and prioritized unmet needs for resident well-being. RESULTS: Among 415 respondents (31% response), the prevalence of professional burnout was 47%. Burnout symptoms were significantly higher among second-year residents (65%) compared to other training levels (P = .02). Seventeen and 9% of respondents reported regretting their overall career and specialty choices, respectively. Among the 53% of respondents who had ever reconsidered career and specialty choice, a majority (54%) experienced this most frequently during the second year of residency, significantly more than other training levels (P = .04). Regarding unmet needs, 62% of respondents prioritized the ability to attend personal health appointments; the majority experienced difficulty attending such appointments during work hours, more so among women than men (70% vs 53%, P < .01). CONCLUSION: In the largest study of urology resident burnout to date, 47% of residents, including 65% of second-year residents, met criteria for professional burnout. One in 6 residents reported career choice regret. Targeting interventions to early-career residents and enabling access to medical and mental health care should be priorities for reform.

Trends in Surgical Volume in the Military Health System-A Potential Threat to Mission Readiness.

INTRODUCTION: The Military Health System (MHS) is tasked with a dual mission both to provide medical services for covered patients and to ensure that its active duty medical personnel maintain readiness for deployment. Knowledge, skills, and attitudes (KSA) is a metric evaluating the transferrable skills incorporated into a given surgery or medical procedure that are most relevant for surgeons deployed to a theatre of war. Procedures carrying a high KSA value are those utilizing skills with high relevance for maintaining deployment readiness. Given ongoing concerns regarding surgical volumes at MTFs and the potential adverse impact on military surgeon mission readiness were high-value surgeries to be lost to the civilian sector, we evaluated trends in the setting of high-value surgeries for beneficiaries within the MHS. METHODS: We retrospectively analyzed inpatient admissions data from MTFs and TRICARE claims data from civilian hospitals, 2005-2019, to identify TRICARE-covered patients covered under "purchased care" (referred to civilian facilities) or receiving "direct care" (undergoing treatment at MTFs) and undergoing seven high-value/high-KSA surgeries: colectomy, pancreatectomy, hepatectomy, open carotid endarterectomy, abdominal aortic aneurysm (AAA) repair, esophagectomy, and coronary artery bypass grafting (CABG). Overall and procedure-specific counts were captured, MTFs were categorized into quartiles by volume, and independence between trends was tested with a Cochran-Armitage test, hypothesizing that the proportion of cases referred for purchased care was increasing. RESULTS: We captured 292,411 cases, including 7,653 pancreatectomies, 4,177 hepatectomies, 3,815 esophagectomies, 112,684 colectomies, 92,161 CABGs, 26,893 AAA repairs, and 45,028 carotid endarterectomies. The majority of cases included were referred for purchased care (90.3%), with the proportion of cases referred increasing over the study period (P < .01). By procedure, all cases except AAA repairs were increasingly referred for treatment over the study period (all P < .01, except esophagectomy P = .04). On examining volume, we found that even the highest-volume-quartile MTFs performed a median of less than one esophagectomy, hepatectomy, or pancreatectomy per month. The only included procedure performed once a month or more at the majority of MTFs was CABG. CONCLUSION: On examining volume and referral trends for high-value surgeries within the MHS, we found low surgical volumes at the vast majority of included MTFs and an increasing proportion of cases referred to civilian hospitals over the last 15 years. Our findings illustrate missed opportunities for maintaining the mission readiness of military surgical personnel. Prioritizing the recapture of lost surgical volume may improve the surgical teams' mission readiness.

Gender-based Differences in Career Plans, Salary Expectations, and Business Preparedness Among Urology Residents.

OBJECTIVE: To characterize gender-related differences between the values and salary expectations of US urology residents. METHODS: We analyzed 2016-2018 American Urological Association Census data regarding residents' demographics, motivations, and concerns. To explore gendered differences, we queried Census items related to demographics, values, and preparedness for the business of practice. Descriptive statistics and test of hypotheses were used for analysis. RESULTS: A total of 705 residents responded of whom 196 (28%) were female. More than half of residents (54%) reported educational debt >$150,000. Factors influencing choice of practice setting included lifestyle (87%), compensation (82%), and location (78%) and was not significantly different between males and females. There were also no differences regarding planned practice setting. However, women had significantly lower first year salary expectations; 53% expected to make <$300,000, compared with only 32% of men (P <.001). Finally, significantly more women reported feeling unprepared to handle the business of urology practice, including salary negotiation, (74% vs 53%, P <.001). CONCLUSION: Among a nationally representative sample of urology residents, women had significantly lower salary expectations and expressed significantly more discomfort with the business aspects of medicine, including contract negotiation, than their male counterparts. These observational findings may contribute to and potentially perpetuate the urology wage gap.

Cardiovascular toxicities associated with abiraterone compared to enzalutamide-A pharmacovigilance study.

BACKGROUND: Androgen deprivation therapy (ADT) is standard-of-care for advanced prostate cancer. Studies have generally found increased cardiovascular risks associated with ADT, but the comparative risk of newer agents is under-characterized. We defined the cardiac risks of abiraterone and enzalutamide, using gonadotropic releasing hormone (GnRH) agonists to establish baseline ADT risk. METHODS: We used VigiBase, the World Health Organization pharmacovigilance database, to identify cardiac adverse drug reactions (ADRs) in a cohort taking GnRH agonists, abiraterone, or enzalutamide therapy for prostate cancer, comparing them to all other patients. To examine the relationship, we used an empirical Bayes estimator to screen for significance, then calculated the reporting odds ratio (ROR), a surrogate measure of association. A lower bound of a 95% confidence interval (CI) of ROR > 1 reflects a disproportionality signal that more ADRs are observed than expected due to chance. FINDINGS: We identified 2,433 cardiac ADRs, with higher odds for abiraterone compared to all other VigiBase drugs for overall cardiac events (ROR 1•59, 95% CI 1•48-1•71), myocardial infarction (1•35, 1•16-1•58), arrythmia (2•04, 1•82-2•30), and heart failure (3•02, 2•60-3•51), but found no signal for enzalutamide. Patients on GnRH agonists also had increased risk of cardiac events (ROR 1•21, 95% CI 1•12-1•30), myocardial infarction (1•80, 1•61-2•03) and heart failure (2•06, 1•76-2•41). INTERPRETATION: We found higher reported odds of cardiac events for abiraterone but not enzalutamide. Our data may suggest that patients with significant cardiac comorbidities may be better-suited for therapy with enzalutamide over abiraterone. FUNDING: None.