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.

Lessons from Pharmacovigilance: Pulmonary Immune-Related Adverse Events After Immune Checkpoint Inhibitor Therapy.

PURPOSE: To characterize pulmonary toxicities associated with the use of novel immune checkpoint inhibitors METHODS: Adverse event reports from immune checkpoint inhibitors targeting PD-1/L1 and CTLA-4 were captured from the W.H.O pharmacovigilance database (VigiBase) up until Dec. 31st 2019 and were analyzed to evaluate for measures of association between the use of immune checkpoint inhibitors and pulmonary toxicities. Disproportionality analysis using both frequentist and Bayesian approaches were used to detect signals between pulmonary immune-related adverse events and the use of these agents. RESULTS: A total of 9202 adverse pulmonary immune checkpoint inhibitor-related events were captured up until 2019. Adverse pulmonary events were compromised of 1305 airway, 18 alveolar, 5491 interstitial, 898 pleural, 560 vascular and 939 non-specific pulmonary events. We found a common association between all immune checkpoint inhibitors studied and pneumonitis, interstitial lung disease, pulmonary embolism and respiratory failure. We also noted other associations between immune checkpoint inhibitors, however not as uniformly across agents. Most of these immune-related adverse drug reactions were noted to be severe and accounted for a significant source of mortality in the reported cases. CONCLUSION: Immune checkpoint inhibitors are associated with a spectrum of inflammatory pulmonary toxicities. The breadth of pulmonary complications and prevalence may be underappreciated with the use of these agents.

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.

Minimally invasive cancer surgery is associated with a lower risk of venous thromboembolic events.

BACKGROUND: Venous thromboembolism (VTE) is a significant source of postoperative morbidity and mortality in patients undergoing common oncologic procedures. We sought to estimate the effect of surgical approach on the risk of developing a VTE. METHODS: IBM Watson Health Marketscan Database was used to conduct this retrospective study. In total, 12 938 patients who underwent either a radical prostatectomy, partial colectomy, or hysterectomy via a minimally invasive or open approach. We used a propensity-weighted logistic regression analysis to assess the independent effect of surgical approach on VTE. The primary outcome of interest was the 90-day rate of VTE after surgery. RESULTS: Patients undergoing minimally invasive surgery across all three surgical procedures were noted to have a lower odds of developing a VTE: (radical prostatectomy, odds ratio [OR]: 0.667, 95% confidence interval [CI]: 0.500-0.891; P = .006 |partial colectomy: OR, 0.620, 95% CI: 0.477-0.805; P < .001| hysterectomy: OR, 0.549 95% CI: 0.353-0.854; P = .008). CONCLUSION: We found that a minimally invasive approach was associated with significantly lower odds of VTE compared with undergoing the same open procedure. This study highlights how surgical approach may be an independent risk factor for development of VTE and may elucidate potential risk mitigation strategy.

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.

High Survivorship and Few Complications With Cementless Total Wrist Arthroplasty at a Mean Followup of 9 Years.

BACKGROUND: Total wrist arthroplasty (TWA) has been described as traditionally being performed with fixation in the radius and carpus with cement. The TWA implant used in our series has been associated with promising results in studies with up to 6 years followup; however, studies evaluating survivorship, pain, and function with this implant are limited. QUESTION/PURPOSE: (1) To report ROM and pain scores after wrist reconstruction with cementless fourth-generation TWA at a mean followup of 9 years (range, 4.8-14.7 years). (2) To report complications of a cementless fourth-generation TWA and the cumulative probability of not undergoing a revision at a mean followup of 9 years. METHODS: This is a retrospective case series of 69 patients who were treated for pancarpal wrist arthritis between 2002 and 2014. Of those, 31 had inflammatory arthritis (rheumatoid arthritis [n = 29], juvenile rheumatoid arthritis [n = 1], and psoriatic arthritis [n = 1]); all of these patients received TWA with the cementless implant studied in this investigation. Another 38 patients had osteoarthritis or posttraumatic arthritis; in this subgroup, 28 patients were 65 years or younger, and all underwent wrist fusion (none were offered TWA). Ten patients with osteoarthritis were older than 65 years and all were offered TWA; of those, eight underwent TWA, and two declined the procedure and instead preferred and underwent total wrist arthrodesis. The mean age of the 39 patients who had TWA was 56 ± 8.9 years (range, 31-78 years) at the time of surgery; 36 were women and three were men. The patients who underwent TWA were seen at a minimum of 4 years (mean, 9 years; range, 4-15 years), and all had been examined in 2016 as part of this study except for one patient who died 9 years after surgery. The dominant wrist was involved in 60% (25) of the patients. All patients were immobilized for 4 weeks postoperatively and then underwent hand therapy for 4 to 6 weeks. Pain and ROM were gathered before surgery as part of clinical care, and were measured again at latest followup; at latest followup, radiographs were analyzed (by the senior author) for evidence of loosening, defined as any implant migration compared with any previous radiograph with evidence of periimplant osteolysis and bone resorption. Subjective pain score was assessed by a verbal pain scale (0-10) and ROM was measured with a goniometer. Complications were determined by chart review and final examination. Kaplan Meier survival analysis was performed to estimate the cumulative probability of not undergoing a revision. RESULTS: The mean preoperative active ROM was 34o ± 18° flexion and 36° ± 18° extension. Postoperatively, the mean active ROM was 37° ± 14° flexion and 29° ± 13° extension. The mean difference between the preoperative pain score (8.6 ± 1.2) and postoperative pain score (0.4 ± 0.8) was 8.1 ± 1.9 (p < 0.001). Implant loosening occurred in three (7.7%) patients. No other complications occurred in this series. Kaplan-Meier survivorship analysis estimated the cumulative probability of remaining free from revision as 78% (95% CI, 62%-91%) at 15 years. CONCLUSION: Cementless fourth-generation TWA improves pain while generally preserving the preoperative arc of motion. The cumulative probability of remaining free from revision at 14.7 years after the index procedure is 77.7% (95% CI, 62.0%-91.4%). Future studies should compare alternative approaches for patients with endstage wrist arthritis; such evaluations-which might compare TWA implants, or TWAs with arthrodesis-will almost certainly need to be multicenter, as the problem is relatively uncommon. LEVEL OF EVIDENCE: Level IV, therapeutic study.

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.