The association between telemedicine, advance care planning, and unplanned hospitalizations among high-risk patients with cancer.

BACKGROUND: Despite the widespread implementation of telemedicine, there are limited data regarding its impact on key components of care for patients with incurable or high-risk cancer. For these patients, high-quality care requires detailed conversations regarding treatment priorities (advance care planning) and clinical care to minimize unnecessary acute care (unplanned hospitalizations). Whether telemedicine affects these outcomes relative to in-person clinic visits was examined among patients with cancer at high risk for 6-month mortality. METHODS: This retrospective cohort study included adult patients with cancer with any tumor type treated at the University of Pennsylvania who were newly identified between April 1 and December 31, 2020, to be at high risk for 6-month mortality via a validated machine learning algorithm. Separate modified Poisson regressions were used to assess the occurrence of advance care planning and unplanned hospitalizations for telemedicine as compared to in-person visits. Additional analyses were done comparing telemedicine type (video or phone) as compared to in-person clinic visits. RESULTS: The occurrence of advance care planning was similar between telemedicine and in-person visits (6.8% vs. 6.0%; adjusted risk ratio [aRR], 1.25; 95% CI, 0.92-1.69). In regard to telemedicine subtype, patients exposed to video encounters were modestly more likely to have documented advance care planning in comparison to those seen in person (7.5% vs. 6.0%; aRR, 1.48; 95% CI, 1.03-2.11). The 3-month risk for unplanned hospitalization was comparable for telemedicine compared to in-person clinic encounters (21% vs. 18%; aRR, 1.06; 95% CI, 0.81-1.38). CONCLUSIONS: In this study, care delivered by telemedicine, compared to in-person clinic visits, produced comparable rates of advance care planning conversations without increasing hospitalizations, which suggests that vulnerable patients can be managed safely by telemedicine.

NCCN Guidelines® Insights: Bladder Cancer, Version 3.2024.

Bladder cancer, the sixth most common cancer in the United States, is most commonly of the urothelial carcinoma histologic subtype. The clinical spectrum of bladder cancer is divided into 3 categories that differ in prognosis, management, and therapeutic aims: (1) non-muscle-invasive bladder cancer (NMIBC); (2) muscle invasive, nonmetastatic disease; and (3) metastatic bladder cancer. These NCCN Guidelines Insights detail recent updates to the NCCN Guidelines for Bladder Cancer, including changes in the fifth edition of the WHO Classification of Tumours: Urinary and Male Genital Tumours and how the NCCN Guidelines aligned with these updates; new and emerging treatment options for bacillus Calmette-Guérin (BCG)-unresponsive NMIBC; and updates to systemic therapy recommendations for advanced or metastatic disease.

Comparing survival in trial- versus routine-care advanced urothelial cancer patients on immune checkpoint blockade.

PURPOSE: Although recent trials involving first-line immune checkpoint inhibitors have expanded treatment options for patients with advanced urothelial carcinoma (aUC) who are ineligible for standard cisplatin-based chemotherapy, there exists limited evidence for whether trial efficacy translates into real-world effectiveness for patients seen in routine care. This retrospective cohort study compares differences in overall survival (OS) between KEYNOTE-052 trial participants and routine-care patients receiving first-line pembrolizumab monotherapy. METHODS: A routine-care patient cohort was constructed from the Flatiron Health database using trial eligibility criteria and was weighted to balance EHR and trial patient characteristics using matching-adjusted indirect comparisons. RESULTS: The routine-care cohort was older, more likely to be female, and more often cisplatin-ineligible due to renal dysfunction. ECOG performance status was comparable between the cohorts. Median OS was 9 months (95% CI 7-16) in the weighted routine-care cohort and 11.3 months (9.7-13.1) in the trial cohort. No significant differences between the Kaplan-Meier OS curves were detected (p = 0.76). Survival probabilities were similar between the weighted routine-care and trial cohorts at 12-, 24-, and 36- months (0.45 vs. 0.47, 0.31 vs. 0.31, 0.26 vs. 0.23, respectively). Notably, routine care patients had modestly lower survival at 3 months compared to trial participants (0.69 vs. 0.83, respectively). CONCLUSION: Our results provide reassurance that cisplatin-ineligible aUC patients receiving first-line immunotherapy in routine care experience similar benefits to those observed in trial patients.

Inverse Probability of Treatment Weighting and Confounder Missingness in Electronic Health Record-based Analyses: A Comparison of Approaches Using Plasmode Simulation.

BACKGROUND: Electronic health record (EHR) data represent a critical resource for comparative effectiveness research, allowing investigators to study intervention effects in real-world settings with large patient samples. However, high levels of missingness in confounder variables is common, challenging the perceived validity of EHR-based investigations. METHODS: We investigated performance of multiple imputation and propensity score (PS) calibration when conducting inverse probability of treatment weights (IPTW)-based comparative effectiveness research using EHR data with missingness in confounder variables and outcome misclassification. Our motivating example compared effectiveness of immunotherapy versus chemotherapy treatment of advanced bladder cancer with missingness in a key prognostic variable. We captured complexity in EHR data structures using a plasmode simulation approach to spike investigator-defined effects into resamples of a cohort of 4361 patients from a nationwide deidentified EHR-derived database. We characterized statistical properties of IPTW hazard ratio estimates when using multiple imputation or PS calibration missingness approaches. RESULTS: Multiple imputation and PS calibration performed similarly, maintaining ≤0.05 absolute bias in the marginal hazard ratio even when ≥50% of subjects had missing at random or missing not at random confounder data. Multiple imputation required greater computational resources, taking nearly 40 times as long as PS calibration to complete. Outcome misclassification minimally increased bias of both methods. CONCLUSION: Our results support multiple imputation and PS calibration approaches to missingness in missing completely at random or missing at random confounder variables in EHR-based IPTW comparative effectiveness analyses, even with missingness ≥50%. PS calibration represents a computationally efficient alternative to multiple imputation.

Tumor Differentiation as a Prognostic Marker in Clinically Staged T1bN0 Esophageal Adenocarcinoma.

Current guidelines recommend that clinically staged T1N0 esophageal cancers are to be referred to surgery or endoscopic resection. Using the National Cancer Database, we identified 733 individuals with clinically staged T1N0 esophageal carcinoma, who underwent upfront surgery and did not receive any prior treatment. We assessed upstaging, which was defined as ≥ T2 disease or positive lymph nodes. Poorly differentiated adenocarcinomas were associated with upstaging, whereas squamous cell carcinomas were not. Specifically, the percentage of upstaging among individuals with clinically staged T1b and poorly differentiated tumor was 33.8%. Therefore, clinically staged T1bN0 poorly differentiated esophageal adenocarcinomas are at high risk for upstaging following surgery.

Association between timely targeted treatment and outcomes in patients with metastatic HER2-overexpressing gastroesophageal adenocarcinoma.

BACKGROUND: Timely targeted treatment initiation can be challenging because additional biomarker testing is needed for eligibility. The authors hypothesized that timely targeted treatment improves survival relative to nontimely initiation in metastatic HER2+ gastroesophageal adenocarcinoma (GEA). METHODS: The authors performed a retrospective cohort study of metastatic HER2+ GEA treated with first-line (1L) systemic therapy from January 2011 to December 2017 using a nationwide electronic health record-derived deidentified database. Timely targeted treatment-trastuzumab initiation within 14 days after starting 1L chemotherapy-was assessed as a time-varying exposure. Nontimely targeted treatment included patients who initiated trastuzumab after 14 days or who lacked documentation of receiving trastuzumab. Extended Cox regressions compared overall survival (OS) and progression-free survival (PFS) between timely and nontimely groups. RESULTS: A total of 320 patients were included; 59.1% received timely trastuzumab. Relative to nontimely initiation, timely trastuzumab was associated with significantly higher OS (2-year OS, 32.1% vs 15.3%; adjusted hazard ratio [HR], 0.67; 95% CI, 0.51-0.88) and PFS (2-year PFS, 9.2% vs 3.7%; adjusted HR, 0.71; 95% CI, 0.55-0.93). Results remained similar in sensitivity analyses 1) using alternative "timeliness" definitions up to 70 days after starting 1L chemotherapy, 2) comparing any trastuzumab, regardless of timing of initiation, to no trastuzumab, and 3) excluding patients lacking documentation of receiving trastuzumab. CONCLUSIONS: Improved survival was observed among metastatic HER2+ GEA patients treated with trastuzumab versus those who were not, regardless of timing of initiation. Although these results reassure clinicians that modest targeted treatment delays may not be detrimental to outcomes, efforts should still ensure that all metastatic HER2+ GEA patients receive trastuzumab.

NCCN Guidelines® Insights: Bladder Cancer, Version 2.2022.

The NCCN Guidelines for Bladder Cancer provide recommendations for the diagnosis, evaluation, treatment, and follow-up of patients with bladder cancer and other urinary tract cancers (upper tract tumors, urothelial carcinoma of the prostate, primary carcinoma of the urethra). These NCCN Guidelines Insights summarize the panel discussion behind recent important updates to the guidelines regarding the treatment of non-muscle-invasive bladder cancer, including how to treat in the event of a bacillus Calmette-Guérin (BCG) shortage; new roles for immune checkpoint inhibitors in non-muscle invasive, muscle-invasive, and metastatic bladder cancer; and the addition of antibody-drug conjugates for metastatic bladder cancer.

Very high PD-L1 expression as a prognostic indicator of overall survival among patients with advanced non-small cell lung cancer receiving anti-PD-(L)1 monotherapies in routine practice.

PURPOSE: Programmed death or ligand-1 (PD-(L)1) pathway inhibitors confer improved survival as the first-line treatment for advanced non-small cell lung cancer (aNSCLC) in patients with PD-L1 expression (PD-L1 + e ≥ 50%) compared to platinum-doublet chemotherapy and have become a standard therapy. Some recent evidence suggests that among aNSCLC patients with PD-L1 + e of ≥50% receiving pembrolizumab monotherapy, very high levels of PD-L1 + e (≥90%) may be associated with better outcomes. We sought to assess whether very high PD-L1 + e (≥90%) compared to high PD-L1 + e (50%-89%) is associated with an overall survival benefit in aNSCLC patients receiving anti-PD-(L)1 monotherapies. METHODS: We conducted a single-site retrospective cohort study of aNSCLC patients who initiated PD-(L)1 inhibitor monotherapy as the first-line treatment from October 24, 2016, to August 25, 2021, and had a PD-L1 + e ≥ 50%. The primary outcome was overall survival, measured from the start of the first-line PD-(L)1 inhibitor monotherapy (index date) to date of death or last confirmed activity prior to the cohort exit date. Propensity score-based inverse probability weighting (IPW) was used to control for confounding in Kaplan-Meier curves and Cox proportional hazard regression analysis. RESULTS: One hundred sixty-six patients with aNSCLC receiving PD-(L)1 inhibitor monotherapy met inclusion criteria. 54% were female, 90% received pembrolizumab, median age was 68 years, 70% had non-squamous cell carcinoma, 94% had a history of smoking, 29% had a KRAS mutation, and 37% had very high PD-L1 + e. Unweighted covariates at cohort entry were similar between groups (absolute standardized mean differences [SMDs] <0.1) except for race (SMD = 0.2); age at therapy initiation (SMD = 0.13); smoking status (SMD = 0.13), and BRAF mutation status (SMD = 0.11). After weighting, baseline covariates were well balanced (all absolute SMDs <0.1). In the weighted analysis, having a very high PD-L1 + e was associated with lower mortality (weighted hazard ratio 0.57, 95% CI 0.36-0.90) and longer median survival: 3.85 versus 1.49 years. CONCLUSIONS: Very high PD-L1 + e (≥90%) was associated with an overall survival benefit over high PD-L1 + e (50%-89%) in patients receiving the first-line PD-(L)1 inhibitor monotherapy in a model controlling for potential confounders. These findings should be confirmed in a larger real-world data set.

Integrating real world data and clinical trial results using survival data reconstruction and marginal moment-balancing weights.

Outcomes in electronic health records (EHR)-derived cohorts can be compared to similarly treated clinical trial cohorts to estimate the efficacy-effectiveness gap, the discrepancy in performance of an intervention in a trial compared to the real world. However, because clinical trial data may only be available in the form of published summary statistics and Kaplan-Meier curves, survival data reconstruction methods are needed to recreate individual-level survival data. Additionally, marginal moment-balancing weights can adjust for differences in the distributions of patient characteristics between the trial and EHR cohorts. We evaluated bias in hazard ratio (HR) estimates by comparing trial and EHR cohorts using survival data reconstruction and marginal moment-balancing weights through simulations and analysis of real-world data. This approach produced nearly unbiased HR estimates. In an analysis of overall survival for patients with metastatic urothelial carcinoma treated with gemcitabine-carboplatin captured in the nationwide Flatiron Health EHR-derived de-identified database and patients enrolled in a trial of the same therapy, survival was similar in the EHR and trial cohorts after using weights to balance age, sex, and performance status (HR = 0.93, 95% confidence interval (0.74, 1.18)). Overall, we conclude that this approach is feasible for comparison of trial and EHR cohorts and facilitates evaluation of outcome differences between trial and real-world populations.

Pembrolizumab alone or combined with chemotherapy versus chemotherapy as first-line therapy for advanced urothelial carcinoma (KEYNOTE-361): a randomised, open-label, phase 3 trial.

BACKGROUND: PD-1 and PD-L1 inhibitors are active in metastatic urothelial carcinoma, but positive randomised data supporting their use as a first-line treatment are lacking. In this study we assessed outcomes with first-line pembrolizumab alone or combined with chemotherapy versus chemotherapy for patients with previously untreated advanced urothelial carcinoma. METHODS: KEYNOTE-361 is a randomised, open-label, phase 3 trial of patients aged at least 18 years, with untreated, locally advanced, unresectable, or metastatic urothelial carcinoma, with an Eastern Cooperative Oncology Group performance status of up to 2. Eligible patients were enrolled from 201 medical centres in 21 countries and randomly allocated (1:1:1) via an interactive voice-web response system to intravenous pembrolizumab 200 mg every 3 weeks for a maximum of 35 cycles plus intravenous chemotherapy (gemcitabine [1000 mg/m2] on days 1 and 8 and investigator's choice of cisplatin [70 mg/m2] or carboplatin [area under the curve 5] on day 1 of every 3-week cycle) for a maximum of six cycles, pembrolizumab alone, or chemotherapy alone, stratified by choice of platinum therapy and PD-L1 combined positive score (CPS). Neither patients nor investigators were masked to the treatment assignment or CPS. At protocol-specified final analysis, sequential hypothesis testing began with superiority of pembrolizumab plus chemotherapy versus chemotherapy alone in the total population (all patients randomly allocated to a treatment) for the dual primary endpoints of progression-free survival (p value boundary 0·0019), assessed by masked, independent central review, and overall survival (p value boundary 0·0142), followed by non-inferiority and superiority of overall survival for pembrolizumab versus chemotherapy in the patient population with CPS of at least 10 and in the total population (also a primary endpoint). Safety was assessed in the as-treated population (all patients who received at least one dose of study treatment). This study is completed and is no longer enrolling patients, and is registered at ClinicalTrials.gov, number NCT02853305. FINDINGS: Between Oct 19, 2016 and June 29, 2018, 1010 patients were enrolled and allocated to receive pembrolizumab plus chemotherapy (n=351), pembrolizumab monotherapy (n=307), or chemotherapy alone (n=352). Median follow-up was 31·7 months (IQR 27·7-36·0). Pembrolizumab plus chemotherapy versus chemotherapy did not significantly improve progression-free survival, with a median progression-free survival of 8·3 months (95% CI 7·5-8·5) in the pembrolizumab plus chemotherapy group versus 7·1 months (6·4-7·9) in the chemotherapy group (hazard ratio [HR] 0·78, 95% CI 0·65-0·93; p=0·0033), or overall survival, with a median overall survival of 17·0 months (14·5-19·5) in the pembrolizumab plus chemotherapy group versus 14·3 months (12·3-16·7) in the chemotherapy group (0·86, 0·72-1·02; p=0·0407). No further formal statistical hypothesis testing was done. In analyses of overall survival with pembrolizumab versus chemotherapy (now exploratory based on hierarchical statistical testing), overall survival was similar between these treatment groups, both in the total population (15·6 months [95% CI 12·1-17·9] with pembrolizumab vs 14·3 months [12·3-16·7] with chemotherapy; HR 0·92, 95% CI 0·77-1·11) and the population with CPS of at least 10 (16·1 months [13·6-19·9] with pembrolizumab vs 15·2 months [11·6-23·3] with chemotherapy; 1·01, 0·77-1·32). The most common grade 3 or 4 adverse event attributed to study treatment was anaemia with pembrolizumab plus chemotherapy (104 [30%] of 349 patients) or chemotherapy alone (112 [33%] of 342 patients), and diarrhoea, fatigue, and hyponatraemia (each affecting four [1%] of 302 patients) with pembrolizumab alone. Six (1%) of 1010 patients died due to an adverse event attributed to study treatment; two patients in each treatment group. One each occurred due to cardiac arrest and device-related sepsis in the pembrolizumab plus chemotherapy group, one each due to cardiac failure and malignant neoplasm progression in the pembrolizumab group, and one each due to myocardial infarction and ischaemic colitis in the chemotherapy group. INTERPRETATION: The addition of pembrolizumab to first-line platinum-based chemotherapy did not significantly improve efficacy and should not be widely adopted for treatment of advanced urothelial carcinoma. FUNDING: Merck Sharp and Dohme, a subsidiary of Merck, Kenilworth, NJ, USA.

Adherence to and determinants of guideline-recommended biomarker testing and targeted therapy in patients with gastroesophageal adenocarcinoma: Insights from routine practice.

BACKGROUND: Anti human epidermal growth factor receptor 2 (anti-HER2) therapy with trastuzumab improves overall survival in patients with advanced, HER2-positive gastroesophageal adenocarcinoma (GEA) and is now incorporated into national guidelines. However, little is known about adherence to and determinants of timely HER2 testing and trastuzumab initiation in routine practice. METHODS: The authors performed a cross-sectional study of patients who had advanced GEA diagnosed between January 2011 and June 2019 in a nationwide electronic health record-derived database. The annual prevalences of both timely HER2 testing (defined within 21 days after advanced diagnosis) and timely trastuzumab initiation (defined within 14 days after a positive HER2 result) were calculated. Log-binomial regressions estimated adjusted prevalence ratios comparing timely HER2 testing and trastuzumab initiation by patient and tumor characteristics. RESULTS: In total, the cohort included 6032 patients with advanced GEA of whom 1007 were HER2-positive. Between 2011 and 2019, timely HER2 testing increased from 22.4% to 44.5%, whereas timely trastuzumab initiation remained stable at 16.3%. No appreciable differences in timely testing or trastuzumab initiation were noted by age, sex, race, or insurance status. Compared with patients who had metastatic disease at diagnosis, patients who had early stage GEA who did not undergo surgery were less likely to receive timely HER2 testing and trastuzumab initiation (testing prevalence ratio, 0.69; 95% CI, 0.64-0.75; treatment prevalence ratio, 0.32; 95% CI, 0.18-0.56), as were patients with early stage disease who subsequently developed a distant recurrence (testing prevalence ratio, 0.56; 95% CI, 0.47-0.65; treatment prevalence ratio, 0.61; 95% CI, 0.24-1.55). CONCLUSIONS: In patients with advanced GEA, guideline-recommended HER2 testing and anti-HER2 therapy remain underused. Uptake may improve with universal HER2 testing regardless of stage.

Prognostic Implications of Tumor Differentiation in Clinical T1N0 Gastric Adenocarcinoma.

BACKGROUND: Current guidelines recommend neoadjuvant chemotherapy in patients with locoregional gastric adenocarcinoma. Patients diagnosed with early stage gastric adenocarcinoma are usually managed with upfront surgical intervention. However, pathologic staging in a subset of these clinically staged patients identifies more advanced locoregional disease requiring adjuvant treatment. Therefore, identifying these patients prior to surgical intervention is critical to ensure employment of the appropriate treatment paradigm. The aim of the current study was to define patient characteristics associated with clinical understaging in early gastric cancer. METHODS: Using the National Cancer Database (2004-2014) we identified 3,892 individuals with clinical T1N0 gastric adenocarcinoma who underwent upfront definitive surgery, had negative surgical margins, and did not receive preoperative chemotherapy or radiotherapy. Patient characteristics were compared between those with pathologic stage T1N0 disease and those who were upstaged upon surgery. RESULTS: Twenty-seven percent of clinical T1N0 gastric adenocarcinomas had a change in stage because of pathologically defined ≥T2 disease or positive lymph nodes. Individuals who were upstaged had a higher tumor grade compared with those with pathologic stage T1N0 disease. Specifically, 41.9% (530/1,264) of individuals with a poorly differentiated tumor were upstaged, compared with only 10.7% (70/656) with a well-differentiated tumor. Approximately 75% of cases involved upstaging because of T misclassification. The highest percentage of upstaging was shown for tumors located at the fundus and body of the stomach. CONCLUSION: Upstaging of clinical T1N0 gastric adenocarcinoma is characterized by higher tumor grade and is mostly a result of a change in T stage. These findings mandate thorough workup in order to identify patients with clinically staged T1N0 disease requiring preoperative chemotherapy. IMPLICATIONS FOR PRACTICE: Upstaging of clinical T1N0 gastric adenocarcinoma is characterized by higher tumor grade and is mostly a result of a change in T stage. These findings mandate thorough workup in order to identify patients with clinically staged T1N0 disease requiring preoperative chemotherapy.

Identification of the Most Effective Position for Ustekinumab in Treatment Algorithms for Crohn's Disease.

BACKGROUND & AIMS: Ustekinumab is a monoclonal antibody against interleukin 12 and interleukin 23 that has been approved by the Food and Drug Administration for treatment of Crohn's disease (CD). We sought to identify the ideal position for ustekinumab in treatment algorithms for CD. METHODS: We constructed a Markov model to identify an optimal treatment sequence for CD that included ustekinumab for 1 year or more. The base case was a 35-year old male with moderate to severe CD who had not previously received biologic or immunomodulator therapy. The standard of care treatment algorithm was defined as initial therapy with infliximab and azathioprine, followed by adalimumab and azathioprine, vedolizumab, and lastly surgical resection. The model assessed positions for ustekinumab before standard of care, ustekinumab after infliximab and azathioprine but before the remaining treatments, after infliximab, azathioprine, and adalimumab but before vedolizumab and surgery, or after the other biologics but before surgery. We derived transition probabilities and quality adjusted life years (QALYs) from relevant trials, observational studies, and time trade-off analyses. Primary analyses consisted of first order Monte Carlo simulation of 100 trials of cohorts of 100,000 individuals. RESULTS: Ustekinumab as first-line therapy yielded the greatest QALYs (incremental effectiveness, 0.016-0.020 QALYs), resulting in 10% more patients in remission or response, and 2% fewer surgeries at 1 year, compared with other algorithms. The model was not sensitive to 25% variation in transition probabilities. CONCLUSIONS: In a simulation based on a 35-year old male patient with moderate to severe CD, we found that ustekinumab as the first-line biologic therapy yields greater QALYs at the end of 1 year than compared with use later in the CD treatment algorithm.

Digoxin use is associated with pancreatic cancer risk but does not affect survival.

PURPOSE: Digoxin affects several cellular pathways involved in tumorigenesis. We sought to determine the association between digoxin use and pancreatic cancer risk and survival. METHODS: A nested case-control study using The Health Improvement Network (THIN), a population-representative database from the United Kingdom (UK). Cases included all individuals with incident diagnosis of pancreatic cancer. Each case was matched to up to four controls using incidence density sampling based on age, sex, practice site, calendar time, and duration of follow-up. Exposure of interest was digoxin therapy before cancer diagnosis. Odds ratios (ORs) and 95% confidence intervals (CIs) for the association between digoxin use and pancreatic cancer risk were estimated using conditional logistic regression. We further conducted a retrospective cohort study among pancreatic cancer cases using Cox regression model in order to evaluate the association between digoxin use and overall survival. RESULTS: We identified 4,113 cases with incident pancreatic cancer and 16,072 matched controls. The adjusted OR for diagnosis of pancreatic cancer among active digoxin users was 1.41 (95% CI 1.16-1.72). The risk did not change among active users with duration of therapy of more than 1 year (adjusted OR of 1.39, 95% CI 1.11-1.76). Digoxin was not associated with change in overall survival with an adjusted hazard ratio of 0.97 (95% CI 0.81-1.18). CONCLUSIONS: Digoxin use was associated with modestly increased pancreatic cancer risk but did not affect overall survival.

Inflammatory Bowel Diseases Are Associated With an Increased Risk for Chronic Kidney Disease, Which Decreases With Age.

BACKGROUND & AIMS: It is not clear what factors affect risk of chronic kidney disease (CKD) in patients with inflammatory bowel disease (IBD); increased risk has been inconsistently associated with use of 5-aminosalicylates (5-ASAs). We aimed to calculate the relative hazard of CKD among patients with IBD, adjusted for CKD risk factors, and to determine whether IBD medications are associated with change in estimated glomerular filtration rate (eGFR). METHODS: We performed a retrospective cohort study of data from The Health Improvement Network. Patients with IBD (n = 17,807) were matched for age, sex, and practice to individuals without IBD (n = 63,466). The relative hazard of CKD, stages 3 through 5D, in patients with IBD was calculated using a Cox proportional hazards model adjusted for common CKD risk factors. We also evaluated the association of 5-ASAs, azathioprine, and methotrexate with change in eGFR using a longitudinal model. RESULTS: After we controlled for risk factors associated with CKD, we found IBD to be associated with development of CKD in patients 16-77 years old. As patient age increased, the adjusted hazard ratio for CKD decreased monotonically, from 7.88 (95% CI, 2.56-24.19) at age 16 to 1.13 (95% CI, 1.01-1.25) at age 77. In the longitudinal analysis, exposure to 5-ASAs or methotrexate was not associated with change in eGFR, whereas azathioprine was associated with a slightly higher eGFR (0.32 mL/min/1.73 m2; 95% CI, 0.16-0.48). CONCLUSIONS: In a retrospective study of more than 80,000 persons, we found that IBD is associated with increased risk of CKD, and the hazard ratio is highest among younger patients. Commonly used non-biologic therapeutic agents were not associated with lower eGFR.

Geographical affiliation with top 10 NIH-funded academic medical centers and differences between mortality from cardiovascular disease and cancer.

Community engagement and rapid translation of findings for the benefit of patients has been noted as a major criterion for NIH decisions regarding allocation of funds for research priorities. We aimed to examine whether the presence of top NIH-funded institutions resulted in a benefit on the cardiovascular and cancer mortality of their local population. METHODS AND RESULTS: Based on the annual NIH funding of every academic medical from 1995 through 2014, the top 10 funded institutes were identified and the counties where they were located constituted the index group. The comparison group was created by matching each index county to another county which lacks an NIH-funded institute based on sociodemographic characteristics. We compared temporal trends of age-standardized cardiovascular mortality between the index counties and matched counties and states. This analysis was repeated for cancer mortality as a sensitivity analysis. From 1980 through 2014, the annual cardiovascular mortality rates declined in all counties. In the index group, the average decline in cardiovascular mortality rate was 51.5 per 100,000 population (95% CI, 46.8-56.2), compared to 49.7 per 100,000 population (95% CI, 45.9-53.5) in the matched group (P = .27). Trends in cardiovascular mortality of the index counties were similar to the cardiovascular mortality trends of their respective states. Cancer mortality rates declined at higher rates in counties with top NIH-funded medical centers (P < .001). CONCLUSIONS: Cardiovascular mortality rates have decreased with no apparent incremental benefit for communities with top NIH-funded institutions, underscoring the need for an increased focus on implementation science in cardiovascular diseases.

First-line immune checkpoint inhibitor use in cisplatin-eligible patients with advanced urothelial carcinoma: a secular trend analysis.

Aim: Standard first-line treatment of advanced urothelial cell carcinoma involves cisplatin-based chemotherapy, with carboplatin or immune checkpoint inhibitor therapy (ICI) reserved for cisplatin-ineligible individuals. Methods: Using a large de-identified electronic health record-derived database of patients with advanced urothelial cell carcinoma in the USA, we examined trends in utilization of first-line systemic therapies in cisplatin-eligible patients from 1 January 2015 to 31 March 2018. Results: Among 1181 cisplatin-eligible patients, the quarterly proportion who received first-line ICI increased from 1 to 42% (ptrend <0.001), while the proportion who received cisplatin-based chemotherapy decreased from 53 to 33% (ptrend = 0.018). Patients receiving ICI were older than those receiving cisplatin (median age: 75 vs 68). Conclusion: Our analysis suggests rising off-label ICI use in cisplatin-eligible individuals, potentially because of ICI's favorable toxicity profile.

Assessing the effects of beta-blockers on pancreatic cancer risk: A nested case-control study.

PURPOSE: Both ß1- and ß2-adrenoceptor proteins were detected on the cell surface of pancreatic ductal adenocarcinoma. The current study evaluated the association between beta-blocker use and pancreatic cancer risk. METHODS: We conducted a nested case-control study in a large population representative database. Each pancreatic cancer case was matched with four controls based on age, sex, practice site, and duration of follow-up using incidence density sampling. Beta-blocker use was defined as any prescription prior to index date and was stratified into non-selective and selective ß1 -blockers. The odds ratios (ORs) and 95% confidence intervals (95% CIs) for pancreatic cancer risk associated with beta-blocker use was estimated using conditional logistic regression. RESULTS: The study included 4113 patients with pancreatic cancer and 16 072 matched controls. When compared to never users, there was no association between any beta-blocker use and pancreatic cancer risk (adjusted OR 1.06, 95% CI 0.97-1.16, P = .16). Analysis by receptor selectivity showed use of non-selective beta-blockers for more than 2 years was associated with a reduced pancreatic cancer risk (OR 0.75, 95% CI 0.57-1.00, P = .05). When compared to former users both users of selective ß1-blockers and non-selective beta-blockers had a reduced pancreatic cancer risk (OR 0.78, 95% CI 0.67-0.90, P = .001) and (OR 0.67, 95% CI 0.49-0.92, P = .01), respectively. CONCLUSION: Beta-blocker use was not associated with increased pancreatic cancer risk. However, long-term use of beta-blockers may be associated with decreased pancreatic cancer risk.

Association between age and sex and mortality after adjuvant therapy for renal cancer.

BACKGROUND: In phase 3 trials of patients with resected high-risk renal cell carcinoma, adjuvant sunitinib has demonstrated no overall survival (OS) benefit, an uncertain disease-free survival (DFS) benefit, and increased toxicity versus placebo. To identify patients who may derive benefit or harm from adjuvant therapy, the authors assessed the effects of age and sex on treatment outcomes in the phase 3 Adjuvant Sorafenib or Sunitinib for Unfavorable Renal Cancer (ASSURE) trial. METHODS: The authors conducted a post hoc subgroup analysis of age and sex among patients in the ASSURE trial. Adjusted hazard ratios (HRs) for OS and DFS were evaluated with sunitinib or sorafenib versus placebo in 4 patient subgroups defined by sex and median age at the time of the study. RESULTS: Sunitinib treatment was associated with decreased OS (HR, 2.21; 95% confidence interval, 1.29-3.80) among women aged >56 years, but not in women aged ≤56 years or men of any age. Similar associations with age and sex were observed for DFS, but these were not statistically significant (women aged >56 years: HR, 1.41 [95% confidence interval, 0.94-2.10]). No such association was found for sorafenib. The interaction by age and sex on mortality was found to be statistically significant for sunitinib (P = .01), but not sorafenib (P = .10). CONCLUSIONS: Adjuvant sunitinib may increase mortality among older women with renal cell carcinoma. Given the recent approval of adjuvant sunitinib for patients with high-risk resected renal cell carcinoma, additional studies are needed to confirm these findings.

Cisplatin versus cetuximab with definitive concurrent radiotherapy for head and neck squamous cell carcinoma: An analysis of Veterans Health Affairs data.

BACKGROUND: The addition of cisplatin or cetuximab to radiation therapy (RT) improves outcomes in comparison with RT alone in the nonoperative management of head and neck squamous cell carcinoma (HNSCC), but limited data exist for comparing these approaches. Using Veterans Health Affairs data, this study compared the outcomes of patients treated with RT plus cisplatin or cetuximab. METHODS: Patients with stage III to IVb HNSCC who had been treated nonsurgically with RT and cisplatin or cetuximab from 2000 to 2016 within the Veterans Health Affairs system were identified. Patients were analyzed by the drug used in the first treatment cycle (intent to treat). Overall survival (OS) was compared by treatment group with Cox regression models, and propensity score (PS) methods were used to account for a treatment allocation bias. The risk of toxicities was determined, with logistic regression models fit into propensity-matched cohorts. RESULTS: A total of 4520 patients were included in the analysis with a median follow-up of 3 years: 83% received cisplatin. Cisplatin patients were younger (P < .001) and had fewer comorbidities (P < .001). In an unmatched analysis, cetuximab was associated with inferior OS (P < .001). After PS matching, cetuximab treatment remained statistically significantly associated with inferior OS (1.7 vs 4.1 years; hazard ratio, 1.61; 95% confidence interval, 1.44-1.79; P < .001). These differences remained significant across all primary HNSCC subsites and in comparison with low- and high-dose cisplatin. CONCLUSIONS: Cetuximab with RT yields inferior OS in comparison with cisplatin for the nonoperative management of stage III to IVb HNSCC. According to this study, cisplatin may be the most appropriate partner for RT in this setting.