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Background A nivolumab monotherapy flat-dosing regimen of 480 mg every 4 weeks (Q4W) has been approved in several markets, including the United States, Canada, and European Union, as an alternative dosing regimen for several indications. Approvals of this Q4W regimen were based on population pharmacokinetic (PK) analyses, established flat exposure–response relationships, and clinical safety. The objective of this study was to compare the PK exposure of 480 mg Q4W with 3 mg/kg every 2 weeks (Q2W) and 240 mg Q2W using modeling and simulation, and to evaluate clinical safety of the Q4W regimen. Patients and methods Nivolumab PK exposure for the 480 mg Q4W schedule was simulated for 3817 patients across multiple tumor types and compared with those for the 3 mg/kg Q2W and 240 mg Q2W schedules. The safety profile of the Q4W schedule was assessed by analysis of clinical data from 61 patients who transitioned to nivolumab 480 mg Q4W from 3 mg/kg Q2W during four phase III clinical trials. Results Compared with 3 mg/kg Q2W, nivolumab 480 mg Q4W produced similar time-averaged concentration, approximately 16% lower trough concentration, and 45% higher peak concentration at steady state. The peak concentration for 480 mg Q4W was significantly lower than that of 10 mg/kg Q2W, a dose previously shown to have an acceptable tolerability and safety profile. Treatment-related adverse events (TRAEs) that started after transitioning from 3 mg/kg Q2W to 480 mg Q4W were reported in 14.8% of patients, with 1.6% of patients reporting grades 3–4 TRAEs. Pooled safety data for these patients are consistent with those for the 3 mg/kg Q2W schedules, and no new safety signals were identified. Conclusions The time-averaged steady-state exposure and safety profile of nivolumab 480 mg Q4W are consistent with that of 3 mg/kg Q2W across multiple tumor types. Nivolumab 480 mg Q4W represents a new dosing schedule option, and in addition to 240 mg Q2W, provides convenience and flexibility for patient care. Clinical trial numbers NCT01721772, NCT01668784, NCT01673867, NCT01642004 [ABSTRACT FROM AUTHOR]

On December 14, 2022, the FDA approved revisions to the United States Prescribing Information (USPI) for capecitabine that revised existing indications and dosage regimens, added new indications and their recommended dosage regimens, revised safety information, updated the description of the risk of capecitabine in patients with dihydropyrimidine dehydrogenase deficiency, and edited other sections of the USPI to conform with FDA's current labeling guidance. These supplements were reviewed and approved under Project Renewal, a public health initiative established by the FDA's Oncology Center of Excellence that aims to update the prescribing information of certain older oncology drugs to ensure information is clinically meaningful and scientifically up to date. This article summarizes the FDA approach that supported revisions to the capecitabine USPI within the context of Project Renewal., (©2024 American Association for Cancer Research.)

FDA Oncology Center's @Falleh_Fallah and colleagues discuss loss of equipoise and other trial conduct challenges in an era of breakthrough therapies - via @JCO_ASCO.

Background: This pooled analysis of patient-level data from trials evaluated the clinical outcomes of patients with metastatic renal cell carcinoma with or without cytoreductive nephrectomy before a combination of immune checkpoint inhibitor and antiangiogenic therapy., Methods: Data from 5 trials of immune checkpoint inhibitors plus antiangiogenic therapy were pooled. Only patients with stage 4 disease at initial diagnosis were included to ensure that nephrectomy was performed for cytoreductive purposes and not to previously treat an earlier stage of disease. The effect of cytoreductive nephrectomy before immune checkpoint inhibitor therapy on outcomes was evaluated using the Kaplan-Meier method and a Cox proportional hazards regression model, adjusted for age, sex, risk group, performance status, and the presence of sarcomatoid differentiation., Results: A total of 981 patients were included. The estimated median progression-free survival with and without nephrectomy was 15 and 11 months, respectively; the adjusted hazard ratio was 0.71 (95% confidence interval = 0.59 to 0.85). The estimated median overall survival with and without nephrectomy was 46 and 28 months, respectively; the adjusted hazard ratio was 0.63 (95% confidence interval = 0.51 to 0.77). Objective response was 60% of patients with vs 46% of patients without cytoreductive nephrectomy., Conclusions: Patients with metastatic renal cell carcinoma who undergo cytoreductive nephrectomy before immune checkpoint inhibitor plus antiangiogenic therapy had improved outcomes compared with patients without cytoreductive nephrectomy. Selection factors for cytoreductive nephrectomy may be prognostic and could not be fully controlled for in this retrospective analysis. Prospective determination of and stratification by prior cytoreductive nephrectomy may be considered when designing clinical trials to assess the impact of this factor on prognosis., (Published by Oxford University Press 2024.)

On April 3, 2023, the FDA granted accelerated approval to enfortumab vedotin-ejfv (EV) plus pembrolizumab for treatment of patients with locally advanced or metastatic urothelial carcinoma who are ineligible for cisplatin-containing chemotherapy. Substantial evidence of effectiveness was obtained from EV-103/KEYNOTE-869 (NCT03288545), a multicohort study. Across cohorts, a total of 121 patients received EV 1.25 mg/kg (maximum of 125 mg) intravenously on days 1 and 8 of a 21-day cycle plus pembrolizumab 200 mg intravenously on day 1 of each 21-day cycle until disease progression or unacceptable toxicity. The major efficacy outcome measures were objective response rate (ORR) and duration of response (DoR), determined by blinded independent central review using RECIST v1.1. The confirmed ORR in 121 patients was 68% (95% confidence interval, 59-76), including 12% with complete responses. The median DoR for the 82 responders was 22 months (range: 1+ to 46+). The safety profile of the combination comprised adverse reactions expected to occur with the corresponding monotherapies, but with overall increased frequency of adverse reactions, including skin toxicity, pneumonitis, and peripheral neuropathy. The article summarizes the data and the FDA thought process supporting accelerated approval of EV + pembrolizumab, as well as additional exploratory analyses conducted by the FDA., (©2024 American Association for Cancer Research.)

Purpose: We performed a pooled analysis of multiple trials of poly(ADP-ribose) polymerase inhibitors (PARPi) in metastatic castration-resistant prostate cancer (mCRPC) to investigate the efficacy of PARPi in each individual homologous recombination repair (HRR) mutated (m) gene., Patients and Methods: We pooled patient-level data from trials of PARPi in mCRPC that reported mutation status in individual HRR genes. Any HRR gene with available data across all the randomized trials of PARPi in first-line mCRPC was selected. The hazard ratios (HRs; 95% CI) for radiographic progression-free survival (rPFS; by blinded independent review) and overall survival (OS) of a PARPi plus an androgen receptor pathway inhibitor (ARPI) relative to placebo plus an ARPI in the pool of three randomized trials in first-line mCRPC were calculated using Kaplan-Meier estimates and a Cox proportional hazards model., Results: In ATM m (N = 268), rPFS HR was 1.05 (0.74 to 1.49) and OS HR was 1.18 (0.82 to 1.71). In BRCA1 m (N = 64), rPFS HR was 0.51 (0.23 to 1.1) and OS HR was 0.74 (0.34 to 1.61). In BRCA2 m (N = 422), rPFS HR was 0.31 (0.23 to 0.42) and OS HR was 0.66 (0.49 to 0.89). In CDK12 m (N = 164), rPFS HR was 0.50 (0.32 to 0.80) and OS HR was 0.63 (0.39 to 0.99). In CHEK2 m (N = 172), rPFS HR was 1.06 (0.67 to 1.66) and OS HR was 1.53 (0.95 to 2.46). In PALB2 m (N = 41) rPFS HR was 0.52 (0.23 to 1.17) and OS HR was 0.78 (0.34 to 1.8)., Conclusion: In this pooled analysis, benefit from PARPi appeared greatest for patients with BRCA1 m, BRCA2 m, CDK12 m, and PALB2 m. Given limitations of this exploratory analysis, the apparent lack of benefit from PARPi in patients with CHEK2 m or ATM m should be further explored in future clinical trials.

Background: While frontline immuno-oncology/tyrosine kinase inhibitor (IO/TKI) combination therapy has established a benefit in metastatic renal cell carcinoma (mRCC), this may differ by International Metastatic RCC Database Consortium (IMDC) risk grouping. Looking at individual trials, we noted an apparently smaller magnitude of benefit for favorable-risk disease., Objective: We aimed to assess treatment benefit by risk groupings, especially in favorable-risk, augmenting patient numbers via a pooled analysis., Design, Setting, and Participants: We pooled four frontline mRCC trials of IO/TKI combinations including 3,098 patients (839 favorable-risk) with approvals from 2019 to 2021., Intervention: All trials used IO/TKI combinations as the treatment option and sunitinib as the control., Outcome Measurements and Statistical Analysis: We analyzed progression-free survival (PFS) and overall survival (OS) by IMDC groupings. To specifically address the favorable-risk group, we combined all others into an intermediate/poor-risk group., Results and Limitations: In this exploratory analysis adjusted for baseline covariates, IO/TKI combinations have yet to demonstrate an OS benefit in favorable-risk (hazard ratio [HR] 1.24; 95% confidence interval [CI]: 0.86, 1.78) despite demonstrating an OS benefit in the intermediate/poor-risk group (HR 0.64; 95% CI: 0.55, 0.75). In contrast, IO/TKI demonstrated a PFS benefit for both the favorable-risk (HR 0.63; 95% CI: 0.50, 0.79) and the intermediate/poor-risk (HR 0.52; 95% CI: 0.45, 0.60) group. For objective response rate, a smaller difference was observed between the combination and sunitinib arms in favorable-risk (68.2% vs 49.9%) versus intermediate/poor-risk (59.9% vs 36.5%) groups, while the difference in complete response rate was larger for favorable-risk (15.3% vs 6.0%) versus intermediate/poor-risk (9.1% vs 3.4%) groups., Conclusions: The frontline IO/TKI combination therapy benefit was shown to be greater in the intermediate/poor-risk group than in the favorable-risk group. The OS benefit observed with IO/TKI for mRCC has yet to be demonstrated for favorable-risk patients; longer follow-up is needed., Patient Summary: Patients with intermediate/poor-risk metastatic renal cell carcinoma derive an overall survival benefit from immuno-oncology/tyrosine kinase inhibitor combinations, while data for favorable-risk remain immature., (Published by Elsevier B.V.)

Importance: Single-arm trials have allowed for transformative therapies to be made available to patients expeditiously. However, using single-arm trials to support drug approval presents several challenges that must be carefully considered., Observations: Between January 1, 2002, and December 31, 2021, the US Food and Drug Administration granted 176 new malignant hematology and oncology indications based on single-arm trials, including 116 accelerated approvals (AAs) and 60 traditional approvals. Overall, 87 approvals (49%) were for new molecular entities or original biologics and 89 (51%) were supplemental indications. Response rate (RR) was the most common end point used to support approval in these single-arm trials (173 of 176 [98%]). Of the 116 AAs based on single-arm trials, 45 (38%) fulfilled their postmarketing requirement to verify clinical benefit, 61 (52%) are pending verification of benefit, and 10 (9%) were withdrawn from the market as of December 31, 2021. Most (56 of 61 [92%]) AAs based on single-arm trials pending verification of benefit occurred during the previous 5 years and have ongoing confirmatory trials as of December 2021., Conclusions and Relevance: Single-arm trials have been a common development strategy to support regulatory approval as early-stage expansion cohorts with promising durable RRs have become more prevalent. In the appropriate context, single-arm trials using durable RRs can allow patients expedited access to novel therapies and will continue to serve a role in advancing drug development in oncology. However, single-arm trials have a smaller noncomparative safety data set, inability to use time-to-event end points, and other limitations that require careful consideration within the context of the disease and available therapies. The randomized clinical trial remains the preferred approach in clinical investigation.

The COVID-19 pandemic presented enormous data challenges in the United States. Policy makers, epidemiological modelers, and health researchers all require up-to-date data on the pandemic and relevant public behavior, ideally at fine spatial and temporal resolution. The COVIDcast API is our attempt to fill this need: Operational since April 2020, it provides open access to both traditional public health surveillance signals (cases, deaths, and hospitalizations) and many auxiliary indicators of COVID-19 activity, such as signals extracted from deidentified medical claims data, massive online surveys, cell phone mobility data, and internet search trends. These are available at a fine geographic resolution (mostly at the county level) and are updated daily. The COVIDcast API also tracks all revisions to historical data, allowing modelers to account for the frequent revisions and backfill that are common for many public health data sources. All of the data are available in a common format through the API and accompanying R and Python software packages. This paper describes the data sources and signals, and provides examples demonstrating that the auxiliary signals in the COVIDcast API present information relevant to tracking COVID activity, augmenting traditional public health reporting and empowering research and decision-making., Competing Interests: The authors declare no competing interest., (Copyright © 2021 the Author(s). Published by PNAS.)

The US Food and Drug Administration (FDA) has approved multiple systemic vascular endothelial growth factor (VEGF) inhibitors since 2004 to treat various malignancies. Inhibition of the VEGF signaling pathway can result in impairment of vascular wall integrity through medial degeneration and endothelial dysfunction, potentially resulting in arterial (including aortic) aneurysm/dissection. We performed a postmarketing review to evaluate arterial aneurysm/dissection as a potential safety risk for patients with cancer treated with VEGF inhibitors. We searched the FDA Adverse Event Reporting System (FAERS) database and literature for reports of arterial (including aortic) aneurysm/dissection with VEGF inhibitors currently approved by the FDA for a cancer indication. We identified 240 cases of arterial aneurysm/dissection associated with VEGF inhibitors. The median time to onset of an arterial aneurysm/dissection event from the initiation of a VEGF inhibitor was 94 days (range 1-1955 days). Notably, 22% (53/240) of cases reported fatal outcomes related to arterial aneurysm/dissection. We determined the drug-event association as probable in 15 cases that lacked relevant confounding factors for arterial aneurysm/dissection, which is supported by unremarkable computed tomography (CT) findings prior to starting VEGF inhibitor therapy, despite nondrug-associated background arterial aneurysm/dissection generally demonstrating preexisting arterial abnormalities. FAERS and literature case-level evidence suggests that VEGF inhibitors may have contributed to arterial aneurysm/dissection, as a class effect, based on short onset relative to natural history of disease and biologic plausibility. Cardiovascular and oncology healthcare professionals should be aware of this rare, but life-threatening safety risk associated with VEGF inhibitors.

Background: Little is known about the benefit-risk profile of second-generation androgen receptor inhibitors in older men with non-metastatic castration-resistant prostate cancer. We aimed to examine the efficacy and safety of second-generation androgen receptor inhibitors in men aged 80 years or older with non-metastatic castration-resistant prostate cancer., Methods: We searched for all randomised controlled clinical trials evaluating second-generation androgen receptor inhibitors in patients with non-metastatic castration-resistant prostate cancer submitted to the US Food and Drug Administration before Aug 15, 2020, and pooled data from three trials that met the selection criteria. All three trials enrolled patients who were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-1, castration-resistant prostate cancer, prostate-specific antigen (PSA) 2·0 μg/L or greater, PSA doubling time of 10 months or less, and no evidence of distant metastatic disease on conventional imaging per the investigator's assessment at the time of screening. All patients had histologically or cytologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small-cell features. All patients who were randomly assigned to androgen receptor inhibitor or placebo groups in these trials were considered assessable and were included in this pooled analysis. We evaluated the effect of age on metastasis-free survival and overall survival across age groups (<80 years vs ≥80 years) in the intention-to-treat population. Safety analyses were done in patients who received at least one dose of study treatment., Findings: Between Oct 14, 2013, and March 9, 2018, 4117 patients were assigned to androgen receptor inhibitor (apalutamide, enzalutamide, or daralutamide; n=2694) or placebo (n=1423) across three randomised trials. The median follow-up duration for metastasis-free survival was 18 months (IQR 11-26) and for overall survival was 44 months (32-55). In patients aged 80 years or older (n=1023), the estimated median metastasis-free survival was 40 months (95% CI 36-41) in the androgen receptor inhibitor groups and 22 months (18-29) in the placebo groups (adjusted hazard ratio [HR] 0·37 [95% CI 0·28-0·47]), and the median overall survival was 54 months (50-61) versus 49 months (43-58), respectively (adjusted HR 0·79 [0·64-0·98]). In patients younger than 80 years of age (n=3094), the estimated median metastasis-free survival was 41 months (95% CI 36-not estimable [NE]) in the androgen receptor inhibitor groups and 16 months (15-18) in the placebo groups (adjusted HR 0·31 [95% CI 0·27-0·35]), and the median overall survival was 74 months (74-NE) versus 61 months (56-NE), respectively (adjusted HR 0·69 [0·60-0·80]). In patients aged 80 years or older, grade 3 or worse adverse events were reported in 371 (55%) of 672 patients in the androgen receptor inhibitor groups and 140 (41%) of 344 patients in the placebo groups, compared with 878 (44%) of 2015 patients in the androgen receptor inhibitor groups and 321 (30%) of 1073 patients in the placebo groups among patients younger than 80 years. The most common grade 3-4 adverse events were hypertension (168 [8%] of 2015 patients aged <80 years and 51 [8%] of 672 patients aged ≥80 years in the androgen receptor inhibitor groups vs 53 [5%] of 1073 patients aged <80 years and 22 [6%] of 344 patients aged ≥80 years in the placebo groups) and fracture (61 [3%] and 36 [5%] in the androgen receptor inhibitor groups vs 15 [1%] and 11 [3%] in the placebo groups)., Interpretation: The findings of this pooled analysis support the use of androgen receptor inhibitors in older men with non-metastatic castration-resistant prostate cancer. Incorporating geriatric assessment tools in the care of older adults with non-metastatic castration-resistant prostate cancer might help clinicians to offer individualised treatment to each patient., Funding: None., Competing Interests: Declaration of interests We declare no competing interests. BK-K worked on this manuscript before joining LunGevity Foundation. YG worked on this manuscript before joining BeiGene., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Many patients with advanced melanoma are resistant to immune checkpoint inhibition. In the ILLUMINATE-204 phase I/II trial, we assessed intratumoral tilsotolimod, an investigational Toll-like receptor 9 agonist, with systemic ipilimumab in patients with anti-PD-1- resistant advanced melanoma. In all patients, 48.4% experienced grade 3/4 treatment-emergent adverse events. The overall response rate at the recommended phase II dose of 8 mg was 22.4%, and an additional 49% of patients had stable disease. Responses in noninjected lesions and in patients expected to be resistant to ipilimumab monotherapy were observed. Rapid induction of a local IFNα gene signature, dendritic cell maturation and enhanced markers of antigen presentation, and T-cell clonal expansion correlated with clinical response. A phase III clinical trial with this combination (NCT03445533) is ongoing. SIGNIFICANCE: Despite recent developments in advanced melanoma therapies, most patients do not experience durable responses. Intratumoral tilsotolimod injection elicits a rapid, local type 1 IFN response and, in combination with ipilimumab, activates T cells to promote clinical activity, including in distant lesions and patients not expected to respond to ipilimumab alone. This article is highlighted in the In This Issue feature, p. 1861 ., (©2021 American Association for Cancer Research.)

Background: Preoperative smoking is an easily modifiable risk factor and has associations with increased postoperative morbidity and mortality. It is important to clarify these risks for specific procedures to provide improved and evidence-based quality of care. The purpose of the present study aims to identify the associations between preoperative smoking and 30-day postoperative outcomes in patients undergoing total hip arthroplasty., Methods: We used R statistics to conduct a multivariable logistic regression analysis followed by a propensity score matching analysis to explore the association between preoperative smoking and postoperative outcomes., Results: A final cohort of 67,897 patients who underwent total hip arthroplasty was selected for analysis. After adjusting for potential confounders, the odds of postoperative pulmonary complications (odds ratio [OR], 1.352; 95% confidence interval [95% CI], 1.075-1.700; P = .01), infectious complications (OR, 1.310; 95% CI, 1.094-1.567; P = .003), and extended hospital stay (OR, 1.17; 95% CI, 1.099-1.251; P < .001) were all significantly higher in the smoking population. After propensity matching these cohorts, both infectious complications (P = .017) and extended hospital stays (P = .001) were significantly higher in smoking patients., Conclusions: After controlling for potential confounding variables, our multivariable regression analysis revealed a significant increase in pulmonary and infectious complications as well as significantly longer hospital stays in our smoking population. When using a propensity score matching analysis, an increase in infectious complications as well as extended hospital stay was observed. Given the concerning prevalence of smoking in the United States, our data provide updated information toward a growing mass of literature supporting smoking cessation before surgical operations., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The goal of the National Cancer Institute's (NCI's) Genomic Data Commons (GDC) is to provide the cancer research community with a data repository of uniformly processed genomic and associated clinical data that enables data sharing and collaborative analysis in the support of precision medicine. The initial GDC dataset include genomic, epigenomic, proteomic, clinical and other data from the NCI TCGA and TARGET programs. Data production for the GDC started in June, 2015 using an OpenStack-based private cloud. By June of 2016, the GDC had analyzed more than 50,000 raw sequencing data inputs, as well as multiple other data types. Using the latest human genome reference build GRCh38, the GDC generated a variety of data types from aligned reads to somatic mutations, gene expression, miRNA expression, DNA methylation status, and copy number variation. In this paper, we describe the pipelines and workflows used to process and harmonize the data in the GDC. The generated data, as well as the original input files from TCGA and TARGET, are available for download and exploratory analysis at the GDC Data Portal and Legacy Archive ( https://gdc.cancer.gov/ ).

The FDA conducts independent reviews of scientific data obtained with investigational drug products to ensure that they are safe and effective. As a result of this process, FDA-approved product labeling is generated that is considered one of the most trusted sources of information for use of an approved drug. But FDA approval is only the beginning of the life cycle of a new drug; the first oncology drugs now have more than 7 decades of clinical experience in the postmarketing setting. Due, in part, to lack of incentives, some companies may not seek inclusion of new data, other than new safety information, in FDA-approved product labeling. Ensuring that product labeling provides adequate directions for use is important for all drugs, including older therapies that may form the backbone of many standard combination regimens for pediatric and adult cancers. Project Renewal is an FDA Oncology Center of Excellence pilot program that leverages expertise from the clinical and scientific oncology communities to review published literature and generate a drug-specific product report summarizing data that may support updates to FDA-approved product labeling. This article provides a broad overview of Project Renewal's collaborative pilot process for identifying and assessing literature supporting potential labeling updates, while engaging the oncology community to increase awareness of FDA's evidentiary standards and deliberative processes used when considering the addition of new indications and dosing regimens to product labeling., (©2020 American Association for Cancer Research.)

The development and review of combination drug regimens in oncology may present unique challenges to investigators and regulators. For regulatory approval of combination regimens, it is necessary to demonstrate the contribution of effect of each monotherapy to the overall combination. Alternative approaches to traditional designs may be needed to accelerate oncology drug development, for example, when combinations are substantially superior to available therapy, to reduce exposure to less effective therapies, and for drugs that are inactive as single agents and that in combination potentiate activity of another drug. These approaches include demonstration of activity in smaller randomized trials and/or monotherapy trials conducted in a similar disease setting. This article will discuss alternative approaches used in the development of approved drugs in combination, based on examples of recent approvals of combination regimens in renal cell carcinoma., (©2020 American Association for Cancer Research.)

We tested the hypothesis that underrepresented students in active-learning classrooms experience narrower achievement gaps than underrepresented students in traditional lecturing classrooms, averaged across all science, technology, engineering, and mathematics (STEM) fields and courses. We conducted a comprehensive search for both published and unpublished studies that compared the performance of underrepresented students to their overrepresented classmates in active-learning and traditional-lecturing treatments. This search resulted in data on student examination scores from 15 studies (9,238 total students) and data on student failure rates from 26 studies (44,606 total students). Bayesian regression analyses showed that on average, active learning reduced achievement gaps in examination scores by 33% and narrowed gaps in passing rates by 45%. The reported proportion of time that students spend on in-class activities was important, as only classes that implemented high-intensity active learning narrowed achievement gaps. Sensitivity analyses showed that the conclusions are robust to sampling bias and other issues. To explain the extensive variation in efficacy observed among studies, we propose the heads-and-hearts hypothesis, which holds that meaningful reductions in achievement gaps only occur when course designs combine deliberate practice with inclusive teaching. Our results support calls to replace traditional lecturing with evidence-based, active-learning course designs across the STEM disciplines and suggest that innovations in instructional strategies can increase equity in higher education., Competing Interests: The authors declare no competing interest., (Copyright © 2020 the Author(s). Published by PNAS.)

The U.S. Food and Drug Administration (FDA) granted accelerated approval to atezolizumab and pembrolizumab in April and May 2017, respectively, for the treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy. These approvals were based on efficacy and safety data demonstrated in the two single-arm trials, IMvigor210 (atezolizumab) and KEYNOTE-052 (pembrolizumab). The primary endpoint, confirmed objective response rate, was 23.5% (95% confidence interval [CI]: 16.2%-32.2%) in patients receiving atezolizumab and 28.6% (95% CI: 24.1%-33.5%) in patients receiving pembrolizumab. The median duration of response was not reached in either study and responses were seen regardless of PD-L1 status. The safety profiles of both drugs were generally consistent with approved agents targeting PD-1/PD-L1. Two ongoing trials (IMvigor130 and KEYNOTE-361) are verifying benefit of these drugs. Based on concerning preliminary reports from these trials, FDA revised the indications for both agents in cisplatin-ineligible patients. Both drugs are now indicated for patients not eligible for any platinum-containing chemotherapy or not eligible for cisplatin-containing chemotherapy and whose tumors/infiltrating immune cells express a high level of PD-L1. The indications for atezolizumab and pembrolizumab in patients who have received prior platinum-based therapy have not been changed. This article summarizes the FDA thought process and data supporting the accelerated approval of both agents and the subsequent revision of the indications. IMPLICATIONS FOR PRACTICE: The accelerated approvals of atezolizumab and pembrolizumab for cisplatin-ineligible patients with advanced urothelial carcinoma represent the first approved therapies for this patient population. These approvals were based on single-arm trials demonstrating reasonable objective response rates and favorable durations of response with an acceptable toxicity profile compared with available non-cisplatin-containing chemotherapy regimens. However, based on concerning preliminary reports from two ongoing phase III trials, the FDA revised the indication for both agents in cisplatin-ineligible patients. Both are now indicated either for patients not eligible for any platinum-containing chemotherapy or not eligible for cisplatin-containing chemotherapy and whose tumors have high expression of PD-L1., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (Published 2018. This article is a U.S. Government work and is in the public domain in the USA.)

Importance: Transmucosal immediate-release fentanyl (TIRF) drugs are potent, rapid-acting opioids approved to treat breakthrough pain in patients with cancer who are tolerant to other around-the-clock opioid analgesics. In March 2012, a US Food and Drug Administration-approved Risk Evaluation and Mitigation Strategy (REMS) was implemented, mandating prescribers, distributors, pharmacies, and patients to enroll in the REMS to prescribe, dispense, or receive TIRF drugs., Objective: To evaluate the association of the TIRF-REMS Access Program with TIRF prescribing., Design, Setting, and Participants: Cohort study using an interrupted time series analysis of TIRF prescriptions to Medicare Part D beneficiaries nationwide from 2010 to 2014. Data were analyzed from August 2017 through July 2018., Main Outcomes and Measures: Prescribing of TIRF per 100 000 Medicare Part D beneficiaries, overall and stratified by cancer status; percentage of TIRF prescriptions for patients without cancer, overall and by brand; and percentage of TIRF prescriptions for patients without known opioid tolerance, defined as patients prescribed at least 60 morphine milligram equivalents per day, overall and by brand., Results: There were 99 601 TIRF prescriptions written by 8619 clinicians to 10 472 patients. Most of the patients (79%) were younger than 65 years (mean [SD] age, 56 [13] years), and most (67%) did not have cancer. Implementation of TIRF-REMS was associated with a 26.7% relative level decrease in TIRF prescribing (95% CI, -33.3% to -19.4%; P < .001) but was followed by 2.0% monthly increases in prescribing (95% CI, 1.3% to 2.7%; P < .001). Sensitivity analyses that accounted for overall opioid prescribing trends were consistent with these findings. Furthermore, there were no significant changes associated with REMS implementation in the level (0.47%; 95% CI, -5.36% to 4.69%; P = .85) or trend (0.16%; 95% CI, -0.06% to 0.37%; P = .15) of the percentage of prescriptions for patients without cancer. However, a sensitivity analysis that used a broader cancer definition found implementation was associated with a 7.2% (95% CI, -13.5% to -0.48%; P = .04) level decrease in the percentage of TIRF prescriptions for patients without cancer. Lastly, the TIRF-REMS was associated with a 22.5% level decline in the percentage of TIRF prescriptions for patients without known opioid tolerance (95% CI, -36.1% to -5.95%; P = .01) followed by 1.98% monthly decreases (95% CI, -3.19% to -0.80%; P = .001)., Conclusions and Relevance: Implementation of the TIRF-REMS Access Program, a restrictive drug distribution program, was associated with a temporary reduction in the rate of TIRF prescribing to Medicare Part D beneficiaries, and with a sustained decrease in the percentage of TIRF prescriptions for patients without known opioid tolerance. Implementation may have also been associated with a temporary decrease in the percentage of TIRF prescriptions for patients without cancer.

Importance: Antipsychotic agents, such as quetiapine fumarate, are frequently overprescribed for indications not supported by clinical evidence, potentially causing harm., Objective: To investigate if peer comparison letters targeting high-volume primary care prescribers of quetiapine meaningfully reduce their prescribing., Design, Setting, and Participants: Randomized clinical trial (intent to treat) conducted from 2015 to 2017 of prescribers and their patients nationwide in the Medicare program. The trial targeted the 5055 highest-volume primary care prescribers of quetiapine in 2013 and 2014 (approximately 5% of all primary care prescribers of quetiapine)., Interventions: Prescribers were randomized (1:1 ratio) to receive a placebo letter or 3 peer comparison letters stating that their quetiapine prescribing was high relative to their peers and was under review by Medicare., Main Outcomes and Measures: The primary outcome was the total quetiapine days supplied by prescribers from the intervention start to 9 months. Secondary outcomes included quetiapine receipt from all prescribers by baseline patients, quetiapine receipt by patients with low-value or guideline-concordant indications for therapy, mortality, and hospital use. In exploratory analyses, the study followed outcomes to 2 years., Results: Of the 5055 prescribers, 231 (4.6%) were general practitioners, 2428 (48.0%) were in family medicine, and 2396 (47.4%) were in internal medicine; 4155 (82.2%) were male. All were included in the analyses. Over 9 months, the treatment arm supplied 11.1% fewer quetiapine days per prescriber vs the control arm (2456 vs 2864 days; percentage difference, 11.1% fewer days; 95% CI, -13.1% to -9.2% days; P < .001; adjusted difference, -319 days; 95% CI, -374 to -263 days; P < .001), which persisted through 2 years (15.6% fewer days; 95% CI, -18.1% to -13.0%; P < .001). At the patient level, individuals in the treatment arm received 3.9% (95% CI, -5.0% to -2.9%; P < .001) fewer days of quetiapine from all prescribers over 9 months, with a larger decrease among patients with low-value vs guideline-concordant indications (-5.9% [95% CI, -8.0% to -3.9%] vs -2.4% [95% CI, -4.0% to -0.9%], P = .01 for test that effects were equal for both patient groups). There was no evidence of substitution to other antipsychotics, and 9-month mortality and hospital use were similar between the treatment vs control arms., Conclusions and Relevance: Peer comparison letters caused substantial and durable reductions in quetiapine prescribing, with no evidence of negative effects on patients., Trial Registration: ClinicalTrials.gov identifier: NCT02467933.

While the human papillomavirus (HPV) vaccine is medically indicated to reduce the risk of genital warts and certain types of cancer, rates of HPV vaccination repeatedly fall short of public health goals. Individual-level factors contributing to low vaccination rates are well documented. However, system-level barriers, particularly the need for parental consent, have been less explored. To date, there is no legal or ethical consensus in the USA regarding whether adolescents might permissibly self-consent to the HPV vaccine. Consequently, there is considerable variability in medical practice at the provider and state level. In this essay, we explore the ethical acceptability of vaccinating adolescents for HPV without parental consent. We argue that the same ethical considerations that justify permitting minors to consent to treatment for sexual and reproductive health care-namely, public health benefit and adolescents' developing autonomy-similarly justify permitting minors to consent to HPV vaccination. Based on this analysis, we conclude that allowing adolescents to self-consent to the HPV vaccine is ethically justifiable and should be reflected in US state policies., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Length of stay after surgery has become an important quality measure for many common surgical procedures and is now also tied to reimbursement. Currently, little is known about the perioperative factors that contribute to prolonged hospital length of stay in women who undergo hysterectomy for benign conditions., Objective: We performed a population-based analysis to investigate the association between perioperative factors and prolonged length of stay in women who undergo minimally invasive, abdominal, and vaginal hysterectomy., Study Design: We used the National Surgical Quality Improvement Program database to identify women from 2006-2015 who underwent benign hysterectomy. The primary outcome was length of stay >75th percentile. Demographic, preoperative, intraoperative, and postoperative factors were analyzed to determine individual predictors of prolonged length of stay. Model fit statistics were used to assess the importance of each group of perioperative factors on prolonged length of stay., Results: We identified a total of 157,589 women, including 83,172 (52.8%) of whom underwent minimally invasive hysterectomy, 45,149 (28.6%) of whom underwent abdominal hysterectomy, and 29,268 (18.6%) of whom underwent vaginal hysterectomy. The 75th percentile for length of stay was 1 day for minimally invasive, 3 days for abdominal, and 2 days for vaginal hysterectomy. The measured factors accounted for 11.0% of the ability to predict a prolonged length of stay for minimally invasive, 20.3% for abdominal, and 16.2% for vaginal hysterectomy. Intraoperative factors were the most important contributors to length of stay for minimally invasive and abdominal hysterectomy; demographic factors dominated for vaginal hysterectomy., Conclusion: The most important perioperative factors that contributed to prolonged length of stay for hysterectomy were, in large part, not modifiable and suggest that targeted interventions to reduce length of stay will be challenging., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Recent trends on outcomes in cardiogenic shock (CS) complicating acute myocardial infarction (AMI) suggest improvements in early survival. However, with the ever-changing landscape in management of CS, we sought to identify age-based trends in these outcomes and mechanical circulatory support (MCS) use among patients with both AMI and non-AMI associated shock., Methods: We queried the 2005-2014 Nationwide Inpatient Sample databases to identify patients with a diagnosis of cardiogenic shock. Trends in the incidence of hospital-mortality, and use of MCS such as intra-aortic balloon pump (IABP), Impella/TandemHeart (IMP), and extra corporeal membrane oxygenation (ECMO) were analyzed within the overall population and among different age-categories (50 and under, 51-65, 66-80 and 81-99 years). We also made comparisons between patient groups admitted with CS complicating AMI and those with non-AMI associated CS., Results: We studied 144,254 cases of CS, of which 55.4% cases were associated with an AMI. Between 2005 and 2014, an overall decline in IABP use (29.8-17.7%; ptrend < 0.01), and an uptrend in IMP use (0.1-2.6%; ptrend < 0.01), ECMO use (0.3-1.8%; ptrend < 0.01) and in-hospital mortality (44.1-52.5% AMI related, 49.6-53.5% non-AMI related; ptrend < 0.01) was seen. Patients aged 81-99 years had the lowest rate of MCS use (14.8%), whereas those aged 51-65 years had highest rate of MCS use (32.3%). Multivariable analysis revealed that patients aged 51-65 years (aOR 1.46, 95% CI 1.40-1.52; p<0.001), 66-80 years (aOR 2.51, 95% CI 2.39-2.63; p<0.01) and 81-99 years (aOR 5.04, 95% CI 4.78-5.32; p<0.01) had significantly higher hospital mortality compared to patients aged ≤ 50 years. Patients admitted with CS complicating AMI were older and had more comorbidities, but lower hospital mortality (45.0 vs. 48.2%; p < 0.001) when compared to non-AMI related CS. We also noted that the proportion of patients admitted with CS complicating AMI significantly decreased from 2005 to 2014 (65.3-45.6%; ptrend < 0.01) whereas those admitted without an associated AMI increased., Conclusions: IABP use has declined whereas IMP and ECMO use has increased over time among CS admissions. Older age was associated with an incrementally higher independent risk for hospital mortality. Recent trends indicate an increase in both proportion of patients admitted with CS without associated AMI and in-hospital mortality across all CS admissions irrespective of AMI status.

Atrial fibrillation (AF) is a common co-morbidity among patients presenting with acute ST-segment elevation myocardial infarction (STEMI). Previously, small studies have reported an association between AF and poorer outcomes among patients with STEMI. We performed this study to investigate the impact of AF on in-hospital outcomes in patients with STEMI treated with primary percutaneous coronary intervention (PPCI) using a large national database. The study population constituted of patients 18 years and older with a primary discharge diagnosis of STEMI and who underwent PPCI. Using a 2:1 matching protocol, matched groups of patients with AF (N = 24,680) and without (N = 49,198) were developed. Among 1,493,859 patients with STEMI who underwent PPCI, 129,354 patients (8.7%) had AF. In the propensity-matched cohort, adjusted in-hospital mortality was significantly higher for patients with AF compared with patients with no AF (10.3% vs 9.4%) (adjusted odds ratio [OR] 1.10; confidence interval [CI] 1.06 to 1.16; p <0.0001). Patients with AF were also at higher risk of heart failure, cardiogenic shock, acute stroke, acute kidney injury, vascular complications, need for blood transfusion, and a composite outcome of gastrointestinal and retroperitoneal bleeding. Patients with AF were less likely to be treated with drug-eluting stent compared with patients without AF (51.4% vs 56.6%) (adjusted OR 0.81; CI 0.79 to 0.84; p <0.001). Among patients presenting with STEMI and who underwent PPCI, AF is present in about 8% of patients. In a propensity-matched analysis using a large national database, AF was found to be independently associated with a higher risk of in-hospital mortality and of other complications in these patients., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objectives: The study aimed to assess the impact of therapeutic hypothermia (TH) on bleeding and in-hospital mortality among patients with coagulation disorders (CD)., Background: TH affects coagulation factors and platelets putting patients at risk for bleeding and worse outcomes. Effect of TH among patients with CD remains understudied., Methods: Between 2009 and 2014, a total of 6469 cases of TH were identified using the National Inpatient Sample out of which 1036 (16.02%) had a CD. The incidence of bleeding events, blood product transfusion and in-hospital mortality was compared between patients with and without CD using one to one propensity score matching., Results: Proportion of patients with CD increased during study duration from 13.0% to 17.4% from 2009 to 2014. Propensity matching was performed to adjust for baseline differences with 799 patients in both groups depending on presence or absence of CD. Patients with CD had a higher rate of bleeding events (13% vs. 8.5%; adjusted odds ratio 1.60; 95% confidence interval 1.16-2.23; P = 0.004), and blood product transfusion (25.0% vs. 14.1%; aOR 2.03; 95% CI 1.56-2.63; p < 0.001) compared to those without CD. There was no difference in rate of intracranial bleeding or hemorrhagic strokes between those with and without CD (3.3% vs. 3.2%; p = 0.88). There was no difference in mortality between patients with CD and those without (74.5% vs. 74.8%, aOR 0.98, 95% CI 0.78-1.23; P = 0.86)., Conclusions: Use of TH with CD resulted in more bleeding events and blood product transfusion but there was no difference in hospital mortality., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Early readmissions contribute significantly to heart failure-related morbidity and negatively affect quality of life. Data on left ventricular assist device (LVAD)-related 30-day readmissions are scarce and limited to small studies., Methods and Results: Patients undergoing LVAD implantation between January 2013 and November 2014 who survived the index hospitalization were identified in the Nationwide Readmissions Database. We analyzed the incidence, predictors, causes, and costs of 30-day readmissions. Of 2510 LVAD recipients, 788 (31%) were readmitted within 30 days. Length of index hospitalization ≥31 days (hazard ratio [HR], 1.26; 95% confidence interval [CI], 1.07-1.50) and female sex (HR, 1.19; 95% CI, 1.01-1.42) were associated with a higher risk of 30-day readmission, whereas private insurance (HR, 0.83; 95% CI, 0.70-0.99), pre-LVAD use of short-term mechanical circulatory support (HR, 0.53; 95% CI, 0.29-0.98), and discharge to a short-term hospital facility (HR, 0.41; CI, 0.21-0.78) were associated with a lower risk. Cardiac causes accounted for 23.8% of readmissions: heart failure (13.4%) and arrhythmias (8.1%). Noncardiovascular causes accounted for 76.2% of readmissions: infection (30.2%), bleeding (17.6%), and device-related causes (8.2%). Mean length of stay for readmission was 10.7 days (median, 6 days), and average hospital cost per readmission was $34 948±2457., Conclusions: Early readmissions are frequent after LVAD implantation even in contemporary times. Preimplant identification of high-risk patients, and a protocol-driven follow-up using a multidisciplinary approach will be needed to reduce readmissions and improve outcomes., (© 2018 American Heart Association, Inc.)

Inappropriate prescribing is a rising threat to the health of Medicare beneficiaries and a drain on Medicare's finances. In this study we used a randomized controlled trial approach to evaluate a low-cost, light-touch intervention aimed at reducing the inappropriate provision of Schedule II controlled substances in the Medicare Part D program. Potential overprescribers were sent a letter explaining that their practice patterns were highly unlike those of their peers. Using rich administrative data, we were unable to detect an effect of these letters on prescribing. We describe ongoing efforts to build on this null result with alternative interventions. Learning about the potential of light-touch interventions, both effective and ineffective, will help produce a better toolkit for policy makers to improve the value and safety of health care., (Project HOPE—The People-to-People Health Foundation, Inc.)

Building upon extensive research from 2 validated well-being instruments, the objective of this research was to develop and validate a comprehensive and actionable well-being instrument that informs and facilitates improvement of well-being for individuals, communities, and nations. The goals of the measure were comprehensiveness, validity and reliability, significant relationships with health and performance outcomes, and diagnostic capability for intervention. For measure development and validation, questions from the Well-being Assessment and Wellbeing Finder were simultaneously administered as a test item pool to over 13,000 individuals across 3 independent samples. Exploratory factor analysis was conducted on a random selection from the first sample and confirmed in the other samples. Further evidence of validity was established through correlations to the established well-being scores from the Well-Being Assessment and Wellbeing Finder, and individual outcomes capturing health care utilization and productivity. Results showed the Well-Being 5 score comprehensively captures the known constructs within well-being, demonstrates good reliability and validity, significantly relates to health and performance outcomes, is diagnostic and informative for intervention, and can track and compare well-being over time and across groups. With this tool, well-being deficiencies within a population can be effectively identified, prioritized, and addressed, yielding the potential for substantial improvements to the health status, performance, and quality of life for individuals and cost savings for stakeholders.

Program integrity (PI) spans the entire spectrum of improper payments from fraud to abuse, errors, and waste in the health care system. Few physicians will perpetrate fraud or abuse during their careers, but nearly all will contribute to the remaining spectrum of improper payments, making preventive education in this area vital. Despite the enormous impact that PI issues have on government-sponsored and private insurance programs, physicians receive little formal education in this area. Physicians' lack of awareness of PI issues not only makes them more likely to submit inappropriate claims, generate orders that other providers and suppliers will use to submit inappropriate claims, and document improperly in the medical record but also more likely to become victims of fraud schemes themselves.In this article, the authors provide an overview of the current state of PI issues in general, and fraud in particular, as well as a description of the state of formal education for practicing physicians, residents, and fellows. Building on the lessons from pilot programs conducted by the Centers for Medicare and Medicaid Services and partner organizations, the authors then propose a model PI education curriculum to be implemented nationwide for physicians at all levels. They recommend that various stakeholder organizations take part in the development and implementation process to ensure that all perspectives are included. Educating physicians is an essential step in establishing a broader culture of compliance and improved integrity in the health care system, extending beyond Medicare and Medicaid.

One of the primary barriers to the acceptance of surgical simulators is that most simulators still require a significant amount of an instructing surgeon's time to evaluate and provide feedback to the students using them. Thus, an important area of research in this field is the development of metrics that can enable a simulator to be an essentially self-contained teaching tool, capable of identifying and explaining the user's weaknesses. However, it is essential that these metrics be validated in able to ensure that the evaluations provided by the "virtual instructor" match those that the real instructor would provide were he/she present. We have previously proposed a number of algorithms for providing automated feedback in the context of a mastoidectomy simulator. In this paper, we present the results of a user study in which we attempted to establish construct validity (with inter-rater reliability) for our simulator itself and to validate our metrics. Fifteen subjects (8 experts, 7 novices) were asked to perform two virtual mastoidectomies. Each virtual procedure was recorded, and two experienced instructing surgeons assigned global scores that were correlated with subjects' experience levels. We then validated our metrics by correlating the scores generated by our algorithms with the instructors' global ratings, as well as with metric-specific sub-scores assigned by one of the instructors.

Colorectal cancer in African Americans has an increased incidence and mortality relative to Whites. The mean age of CRC development in African Americans is younger than that of Whites. There is also evidence for a more proximal colonic distribution of cancers and adenomas in African Americans. African Americans are less likely to have undergone diagnostic testing and screening for colorectal cancer. Special efforts are needed to improve colorectal cancer screening participation rates in African Americans. Clinical gastroenterologists should play an active role in educating the public and primary care physicians about special issues surrounding colorectal cancer in African Americans. Community healthcare groups and gastrointestinal specialists should develop culturally sensitive health education programs for African Americans regarding colorectal cancer. The high incidence and younger age at presentation of colorectal cancer in African Americans warrant initiation of colorectal cancer screening at the age 45 yr rather than 50 yr.

This study was carried out to stratify the risk of stent thrombosis by using three predictors: stent size, poststenting residual dissection, and residual filling defect. In the multicenter clinical trial, 1318 patients had successful deployment of Gianturco-Roubin coronary stent for threatened and acute closure. The 714 (54.2%) patients having none of these risk factors were designated a low-risk group; 484 (36.6%) had one factor and were designated an intermediate-risk group; 120 (9.1%) had two or all three factors and were designated a high-risk group. The incidence of stent thrombosis was 5.6%, 9.4%, and 16.7% in the low-, intermediate-, and high-risk groups; the difference among the three groups was highly significant (p < 0.0001). With these three predictors, the risk of stent thrombosis can be stratified. Avoiding the use of small stents (< 3.0 mm) and achieving optimal angiographic results after stenting for acute or threatened closure are useful strategies in reducing stent thrombosis.