Revision Shoulder Arthroplasty: Predictors of Subsequent Revision Surgery and Economic Burden amongst Medicare Beneficiaries.

BACKGROUND: Revision shoulder arthroplasty continues to add an increasing burden on patients and the healthcare system. This study aimed to delineate long-term shoulder arthroplasty revision incidence, quantify associated Medicare spending, and identify relevant predictors of both revision and spending. METHODS: The complete 2016-2022(Q3) Medicare fee-for-service inpatient and outpatient claims data was analyzed. Patients receiving a primary total shoulder arthroplasty for osteoarthritis, rotator cuff pathology, or inflammatory arthropathy were included and subsequent ipsilateral revision surgeries were identified. The time to revision was modeled using the Prentice, Williams, and Peterson Gap Time Model. Medicare spending within 90 days post-discharge was modeled using a generalized linear model. The analysis was subdivided by index procedure type: anatomic total shoulder arthroplasty (TSA) and reverse shoulder arthroplasty (RSA). RESULTS: A total of 82,949 primary TSAs and 172,524 RSAs were identified. Compared to index TSA cases, index RSA cases had a lower first revision rate in an observation window of nearly 7 years (1.9% vs. 3.5%, p<0.001), but a higher rate of second (11.4% vs. 4.9%, p<0.001) as well as third revision (13.8% vs. 13.8%, p=0.449). TSA spending was significantly lower than RSA spending for the index procedure ($21,531 vs. $23,267, p<0.001), first ($23,096 vs. $26,414, p<0.001), and second ($25,060 vs. $29,983, p<0.001) revision. There was no statistically significant difference in third revision between TSA and RSA groups ($31,313 vs. $30,829, p=0.860). Age, sex, race, and rheumatoid arthritis were among the top predictors of revisions. Top predictors of Medicare spending included having a non-osteoarthritis surgical indication, a hospital stay of three or more days, a discharge to a setting other than home, malnutrition, dementia, stroke, major kidney diseases, and being operated on in a teaching hospital. CONCLUSION: Compared with TSA, RSA was associated with a lower first revision rate, but a higher subsequent revision rate. An index RSA procedure was also associated with higher initial Medicare spending as well as subsequent revision surgery spending compared with an index TSA procedure. Demographics and comorbid medical conditions were among the top predictors of revisions, while procedure-related factors predicted Medicare spending.

Utility of Machine Learning, Natural Language Processing, and Artificial Intelligence in Predicting Hospital Readmissions After Orthopaedic Surgery: A Systematic Review and Meta-Analysis.

BACKGROUND: Numerous applications and strategies have been utilized to help assess the trends and patterns of readmissions after orthopaedic surgery in an attempt to extrapolate possible risk factors and causative agents. The aim of this work is to systematically summarize the available literature on the extent to which natural language processing, machine learning, and artificial intelligence (AI) can help improve the predictability of hospital readmissions after orthopaedic and spine surgeries. METHODS: This is a systematic review and meta-analysis. PubMed, Embase and Google Scholar were searched, up until August 30, 2023, for studies that explore the use of AI, natural language processing, and machine learning tools for the prediction of readmission rates after orthopedic procedures. Data regarding surgery type, patient population, readmission outcomes, advanced models utilized, comparison methods, predictor sets, the inclusion of perioperative predictors, validation method, size of training and testing sample, accuracy, and receiver operating characteristics (C-statistic), among other factors, were extracted and assessed. RESULTS: A total of 26 studies were included in our final dataset. The overall summary C-statistic showed a mean of 0.71 across all models, indicating a reasonable level of predictiveness. A total of 15 articles (57%) were attributed to the spine, making it the most commonly explored orthopaedic field in our study. When comparing accuracy of prediction models between different fields, models predicting readmissions after hip/knee arthroplasty procedures had a higher prediction accuracy (mean C-statistic = 0.79) than spine (mean C-statistic = 0.7) and shoulder (mean C-statistic = 0.67). In addition, models that used single institution data, and those that included intraoperative and/or postoperative outcomes, had a higher mean C-statistic than those utilizing other data sources, and that include only preoperative predictors. According to the Prediction model Risk of Bias Assessment Tool, the majority of the articles in our study had a high risk of bias. CONCLUSION: AI tools perform reasonably well in predicting readmissions after orthopaedic procedures. Future work should focus on standardizing study methodologies and designs, and improving the data analysis process, in an attempt to produce more reliable and tangible results. LEVEL OF EVIDENCE: Level III. See Instructions for Authors for a complete description of levels of evidence.

A preoperative risk assessment tool for predicting adverse outcomes among total shoulder arthroplasty patients.

BACKGROUND: With the increased utilization of Total Shoulder Arthroplasty (TSA) in the outpatient setting, understanding the risk factors associated with complications and hospital readmissions becomes a more significant consideration. Prior developed assessment metrics in the literature either consisted of hard-to-implement tools or relied on postoperative data to guide decision-making. This study aimed to develop a preoperative risk assessment tool to help predict the risk of hospital readmission and other postoperative adverse outcomes. METHODS: We retrospectively evaluated the 2019-2022(Q2) Medicare fee-for-service inpatient and outpatient claims data to identify primary anatomic or reserve TSAs and to predict postoperative adverse outcomes within 90 days postdischarge, including all-cause hospital readmissions, postoperative complications, emergency room visits, and mortality. We screened 108 candidate predictors, including demographics, social determinants of health, TSA indications, prior 12-month hospital, and skilled nursing home admissions, comorbidities measured by hierarchical conditional categories, and prior orthopedic device-related complications. We used two approaches to reduce the number of predictors based on 80% of the data: 1) the Least Absolute Shrinkage and Selection Operator logistic regression and 2) the machine-learning-based cross-validation approach, with the resulting predictor sets being assessed in the remaining 20% of the data. A scoring system was created based on the final regression models' coefficients, and score cutoff points were determined for low, medium, and high-risk patients. RESULTS: A total of 208,634 TSA cases were included. There was a 6.8% hospital readmission rate with 11.2% of cases having at least one postoperative adverse outcome. Fifteen covariates were identified for predicting hospital readmission with the area under the curve of 0.70, and 16 were selected to predict any adverse postoperative outcome (area under the curve = 0.75). The Least Absolute Shrinkage and Selection Operator and machine learning approaches had similar performance. Advanced age and a history of fracture due to orthopedic devices are among the top predictors of hospital readmissions and other adverse outcomes. The score range for hospital readmission and an adverse postoperative outcome was 0 to 48 and 0 to 79, respectively. The cutoff points for the low, medium, and high-risk categories are 0-9, 10-14, ≥15 for hospital readmissions, and 0-11, 12-16, ≥17 for the composite outcome. CONCLUSION: Based on Medicare fee-for-service claims data, this study presents a preoperative risk stratification tool to assess hospital readmission or adverse surgical outcomes following TSA. Further investigation is warranted to validate these tools in a variety of diverse demographic settings and improve their predictive performance.

Racial and gender disparities in utilization of outpatient total shoulder arthroplasties.

BACKGROUND: Utilization in outpatient total shoulder arthroplasties (TSAs) has increased significantly in recent years. It remains largely unknown whether utilization of outpatient TSA differs across gender and racial groups. This study aimed to quantify racial and gender disparities both nationally and by geographic regions. METHODS: 168,504 TSAs were identified using Medicare fee-for-service inpatient and outpatient claims data and beneficiary enrollment data from 2020 to 2022Q4. The percentage of outpatient cases, defined as cases discharged on the same day of surgery, was evaluated by racial and gender groups and by different census divisions. A multivariate logistics regression model controlling for patient sociodemographic information (White vs. non-White race, age, gender, and dual eligibility for both Medicare and Medicaid), hierarchical condition category (HCC) score, hospital characteristics, year fixed effects, and patient residency state fixed effects was performed. RESULTS: The TSA volume per 1000 beneficiaries was 2.3 for the White population compared with 0.8, 0.6, and 0.3 for the Black, Hispanic, and Asian population, respectively. A higher percentage of outpatient TSAs were in White patients (25.6%) compared with Black patients (20.4%) (P < .001). The Black TSA patients were also younger, more likely to be female, more likely to be dually eligible for Medicaid, and had higher HCC risk scores. After controlling for patient sociodemographic characteristics and hospital characteristics, the odds of receiving outpatient TSAs were 30% less for Black than the White group (odds ratio 0.70). Variations were observed across different census divisions, with South Atlantic (0.67, P < .01), East North Central (0.56, P < .001), and Middle Atlantic (0.36, P < .01) being the 4 regions observed with significant racial disparities. Statistically significant gender disparities were also found nationally and across regions, with an overall odds ratio of 0.75 (P < .001). DISCUSSION: Statistically significant racial and gender disparities were found nationally in outpatient TSAs, with Black patients having 30% (P < .001) fewer odds of receiving outpatient TSAs than White patients, and female patients with 25% (P < .001) fewer odds than male patients. Racial and gender disparities continue to be an issue for shoulder arthroplasties after the adoption of outpatient TSAs.

Five-Year Mortality Rates Following Elective Shoulder Arthroplasty and Shoulder Arthroplasty for Fracture in Patients Over Age 65.

Background: To effectively counsel patients prior to shoulder arthroplasty, surgeons should understand the overall life trajectory and life expectancy of patients in the context of the patient's shoulder pathology and medical comorbidities. Such an understanding can influence both operative and nonoperative decision-making and implant choices. This study evaluated 5-year mortality following shoulder arthroplasty in patients ≥65 years old and identified associated risk factors. Methods: We utilized Centers for Medicare & Medicaid Services Fee-for-Service inpatient and outpatient claims data to investigate the 5-year mortality rate following shoulder arthroplasty procedures performed from 2014 to 2016. The impact of patient demographics, including fracture diagnosis, year fixed effects, and state fixed effects; patient comorbidities; and hospital-level characteristics on 5-year mortality rates were assessed with use of a Cox proportional hazards regression model. A p value of <0.05 was considered significant. Results: A total of 108,667 shoulder arthroplasty cases (96,104 nonfracture and 12,563 fracture) were examined. The cohort was 62.7% female and 5.8% non-White and had a mean age at surgery of 74.3 years. The mean 5-year mortality rate was 16.6% across all shoulder arthroplasty cases, 14.9% for nonfracture cases, and 29.9% for fracture cases. The trend toward higher mortality in the fracture group compared with the nonfracture group was sustained throughout the 5-year postoperative period, with a fracture diagnosis being associated with a hazard ratio of 1.63 for mortality (p < 0.001). Medical comorbidities were associated with an increased risk of mortality, with liver disease bearing the highest hazard ratio (3.07; p < 0.001), followed by chronic kidney disease (2.59; p < 0.001), chronic obstructive pulmonary disease (1.92; p < 0.001), and congestive heart failure (1.90; p < 0.001). Conclusions: The mean 5-year mortality following shoulder arthroplasty was 16.6%. Patients with a fracture diagnosis had a significantly higher 5-year mortality risk (29.9%) than those with a nonfracture diagnosis (14.9%). Medical comorbidities had the greatest impact on mortality risk, with chronic liver and kidney disease being the most noteworthy. This novel longer-term data can help with patient education and risk stratification prior to undergoing shoulder replacement. Level of Evidence: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Trends in the Adoption of Outpatient Joint Arthroplasties and Patient Risk: A Retrospective Analysis of 2019 to 2021 Medicare Claims Data.

INTRODUCTION: Total joint arthroplasties (TJAs) have recently been shifting toward outpatient arthroplasty. This study aims to explore recent trends in outpatient total joint arthroplasty (TJA) procedures and examine whether patients with a higher comorbidity burden are undergoing outpatient arthroplasty. METHODS: Medicare fee-for-service claims were screened for patients who underwent total hip, knee, or shoulder arthroplasty procedures between January 2019 and December 2022. The procedure was considered to be outpatient if the patient was discharged on the same date of the procedure. The Hierarchical Condition Category Score (HCC) and the Charlson Comorbidity Index (CCI) scores were used to assess patient comorbidity burden. Patient adverse outcomes included all-cause hospital readmission, mortality, and postoperative complications. Logistic regression analyses were used to evaluate if higher HCC/CCI scores were associated with adverse patient outcomes. RESULTS: A total of 69,520, 116,411, and 41,922 respective total knee, hip, and shoulder arthroplasties were identified, respectively. Despite earlier removal from the inpatient-only list, outpatient knee and hip surgical volume did not markedly increase until the pandemic started. By 2022Q4, 16%, 23%, and 36% of hip, knee, and shoulder arthroplasties were discharged on the same day of surgery, respectively. Both HCC and CCI risk scores in outpatients increased over time ( P < 0.001). DISCUSSION: TJA procedures are shifting toward outpatient surgery over time, largely driven by the COVID-19 pandemic. TJA outpatients' HCC and CCI risk scores increased over this same period, and additional research to determine the effects of this should be pursued. LEVEL OF EVIDENCE: Level III, therapeutic retrospective cohort study.

Trends and outcomes of outpatient total shoulder arthroplasty after its removal from CMS's inpatient-only list.

BACKGROUND: In January 2021, the US Medicare program approved reimbursement of outpatient total shoulder arthroplasties (TSA), including anatomic and reverse TSAs. It remains unclear whether shifting TSAs from the inpatient to outpatient setting has affected clinical outcomes. Herein, we describe the rate of outpatient TSA growth and compare inpatient and outpatient TSA complications, readmissions, and mortality. METHODS: Medicare fee-for-service claims for 2019-2022Q1 were analyzed to identify the trends in outpatient TSAs and to compare 90-day postoperative complications, all-cause hospital readmissions, and mortality between outpatients and inpatients. Outpatient cases were defined as those discharged on the same day of the surgery. To reduce the COVID-19 pandemic's impact and selection bias, we excluded 2020Q2-Q4 data and used propensity scores to match 2021-2022Q1 outpatients with inpatients from the same period (the primary analysis) and from 2019-2020Q1 (the secondary analysis), respectively. We performed both propensity score-matched and -weighted multivariate analyses to compare outcomes between the two groups. Covariates included sociodemographics, preoperative diagnosis, comorbid conditions, the Hierarchical Condition Category risk score, prior year hospital/skilled nursing home admissions, annual surgeon volume, and hospital characteristics. RESULTS: Nationally, the proportion of outpatient TSAs increased from 3% (619) in 2019Q1 to 22% (3456) in 2021Q1 and 38% (6778) in 2022Q1. A total of 55,166 cases were identified for the primary analysis (14,540 outpatients and 40,576 inpatients). Overall, glenohumeral osteoarthritis was the most common indication for surgery (70.8%), followed by rotator cuff pathology (14.6%). The unadjusted rates of complications (1.3 vs 2.4%, P < .001), readmissions (3.7 vs 6.1%, P < .001), and mortality (0.2 vs 0.4%, P = .024) were significantly lower among outpatient TSAs than inpatient TSAs. Using 1:1 nearest matching, 12,703 patient pairs were identified. Propensity score-matched multivariate analyses showed similar rates of postoperative complications, hospital readmissions, and mortality between outpatients and inpatients. Propensity score-weighted multivariate analyses resulted in similar conclusions. The secondary analysis showed a lower hospital readmission rate in outpatients (odds ratio: 0.8, P < .001). CONCLUSIONS: There has been accelerated growth in outpatient TSAs since 2019. Outpatient and inpatient TSAs have similar rates of postoperative complication, hospital readmission, and mortality.

Higher Surgeon Volume is Associated With a Lower Rate of Subsequent Revision Procedures After Total Shoulder Arthroplasty: A National Analysis.

BACKGROUND: Studies assessing the relationship between surgeon volume and outcomes have shown mixed results, depending on the specific procedure analyzed. This volume relationship has not been well studied in patients undergoing total shoulder arthroplasty (TSA), but it should be, because this procedure is common, expensive, and potentially morbid. QUESTIONS/PURPOSES: We performed this study to assess the association between increasing surgeon volume and decreasing rate of revision at 2 years for (1) anatomic TSA (aTSA) and (2) reverse TSA (rTSA) in the United States. METHODS: In this retrospective study, we used Centers for Medicare and Medicaid Services (CMS) fee-for-service inpatient and outpatient data from 2015 to 2021 to study the association between annual surgeon aTSA and rTSA volume and 2-year revision shoulder procedures after the initial surgery. The CMS database was chosen for this study because it is a national sample and can be used to follow patients over time. We included patients with Diagnosis-related Group code 483 and Current Procedural Terminology code 23472 for TSA (these codes include both aTSA and rTSA). We used International Classification of Diseases, Tenth Revision, procedural codes. Patients who underwent shoulder arthroplasty for fracture (10% [17,524 of 173,242]) were excluded. We studied the variables associated with the subsequent procedure rate through a generalized linear model, controlling for confounders such as patient age, comorbidity risk score, surgeon and hospital volume, surgeon graduation year, hospital size and teaching status, assuming a binomial distribution with the dependent variable being whether an episode had at least one subsequent procedure within 2 years. The regression was fitted with standard errors clustered at the hospital level, combining all TSAs and within the aTSA and rTSA groups, respectively. Hospital and surgeon yearly volumes were calculated by including all TSAs, primary procedure and subsequent, during the study period. Other hospital-level and surgeon-level characteristics were obtained through public files from the CMS. The CMS Hierarchical Condition Category risk score was controlled because it is a measure reflecting the expected future health costs for each patient based on the patient's demographics and chronic illnesses. We then converted regression coefficients to the percentage change in the odds of having a subsequent procedure. RESULTS: After controlling for confounding variables including patient age, comorbidity risk score, surgeon and hospital volume, surgeon graduation year, and hospital size and teaching status, we found that an annual surgeon volume of ≥ 10 aTSAs was associated with a 27% decreased odds of revision within 2 years (95% confidence interval 13% to 39%; p < 0.001), while surgeon volume of ≥ 29 aTSAs was associated with a 33% decreased odds of revision within 2 years (95% CI 18% to 45%; p < 0.001) compared with a volume of fewer than four aTSAs per year. Annual surgeon volume of ≥ 29 rTSAs was associated with a 26% decreased odds of revision within 2 years (95% CI 9% to 39%; p < 0.001). CONCLUSION: Surgeons should consider modalities such as virtual planning software, templating, or enhanced surgeon training to aid lower-volume surgeons who perform aTSA and rTSA. More research is needed to assess the value of these modalities and their relationship with the rates of subsequent revision. LEVEL OF EVIDENCE: Level III, therapeutic study.

The impact of the COVID-19 pandemic on racial disparities in patients undergoing total shoulder arthroplasty in the United States.

Introduction: The purpose of this study was to assess racial disparities in total shoulder arthroplasty (TSA) in the United States and to determine whether these disparities were affected by the COVID-19 pandemic. Methods: Centers for Medicare and Medicaid Services (CMS) 100% sample was used to examine primary TSA volume from April to December from 2019 to 2020. Utilization was assessed for White, Black, Hispanic, and Asian populations to determine if COVID-19 affected these groups differently. A regression model adjusted for age, sex, CMS-hierarchical condition categories (HCC) score, dual enrollment (proxy for socioeconomic status), time-fixed effects, and core-based statistical area fixed effects was used to study difference across groups. Results: In 2019, the TSA volume per 1000 beneficiaries was 1.51 for White and 0.57 for non-White, with a 2.6-fold difference. In 2020, the rate of TSA in White patients (1.30/1000) was 2.9 times higher than non-White (0.45/1000) during the COVID-19 pandemic (P < .01). There was an overall 14% decrease in TSA volume per 1000 Medicare beneficiaries in 2020; non-White patients had a larger percentage decrease in TSA volume than White (21% vs. 14%, estimated difference; 8.7%, P = .02). Black patients experienced the most pronounced disparity with estimated difference of 10.1%, P = .05, compared with White patients. Similar disparities were observed when categorizing procedures into anatomic and reverse TSA, but not proximal humerus fracture. Conclusions: During the COVID-19 pandemic, overall TSA utilization decreased by 14% with White patients experiencing a decrease of 14%, and non-White patients experiencing a decrease of 21%. This trend was observed for elective TSA, while disparities were less apparent for proximal humerus fracture.

Impact of the COVID-19 pandemic on shoulder arthroplasty: surgical trends and postoperative care pathway analysis.

BACKGROUND: COVID-19 triggered disruption in the conventional care pathways for many orthopedic procedures. The current study aims to quantify the impact of the COVID-19 pandemic on shoulder arthroplasty hospital surgical volume, trends in surgical case distribution, length of hospitalization, posthospital disposition, and 30-day readmission rates. METHODS: This study queried all Medicare (100% sample) fee-for-service beneficiaries who underwent a shoulder arthroplasty procedure (Diagnosis-Related Group code 483, Current Procedural Terminology code 23472) from January 1, 2019, to December 18, 2020. Fracture cases were separated from nonfracture cases, which were further subdivided into anatomic or reverse arthroplasty. Volume per 1000 Medicare beneficiaries was calculated from April to December 2020 and compared to the same months in 2019. Length of stay (LOS), discharged-home rate, and 30-day readmission for the same period were obtained. The yearly difference adjusted for age, sex, race (white vs. nonwhite), Centers for Medicare & Medicaid Services Hierarchical Condition Category risk score, month fixed effects, and Core-Based Statistical Area fixed effects, with standard errors clustered at the provider level, was calculated using a multivariate analysis (P < .05). RESULTS: A total of 49,412 and 41,554 total shoulder arthroplasty (TSA) cases were observed April through December for 2019 and 2020, respectively. There was an overall decrease in shoulder arthroplasty volume per 1000 Medicare beneficiaries by 14% (19% reduction in anatomic TSA, 13% reduction in reverse shoulder arthroplasty, and 3% reduction in fracture cases). LOS for all shoulder arthroplasty cases decreased by 16% (-0.27 days, P < .001) when adjusted for confounders. There was a 5% increase in the discharged-home rate (88.0% to 92.7%, P < .001), which was most prominent in fracture cases, with a 20% increase in discharged-home cases (65.0% to 73.4%, P < .001). There was no significant change in 30-day hospital readmission rates overall (P = .20) or when broken down by individual procedures. CONCLUSIONS: There was an overall decrease in shoulder arthroplasty volume per 1000 Medicare beneficiaries by 14% during the COVID-19 pandemic. A decrease in LOS and increase in the discharged-home rates was also observed with no significant change in 30-day hospital readmission, indicating that a shift toward an outpatient surgical model can be performed safely and efficiently and has the potential to provide value.

Return to Sport After Surgical Treatment for Anterior Shoulder Instability: A Systematic Review.

BACKGROUND: For athletes, a return to preinjury activity levels with minimal time away is a metric indicative of successful recovery. The knowledge of this metric would be helpful for the sports medicine specialist to advise patients on appropriate expectations after surgery. PURPOSE: To evaluate the rate and amount of time needed for athletes to return to sport (RTS) after different surgical treatments for anterior shoulder instability. STUDY DESIGN: Systematic review and meta-analysis. METHODS: The MEDLINE, EMBASE, and Cochrane databases were searched for articles relevant to athletes' RTS after surgical anterior shoulder stabilization with variants of the Latarjet and Bankart procedures. Article selection was based on relevant inclusion and exclusion criteria. After the articles were reviewed, the data pertinent to rates of and time to RTS were extracted, compiled, and analyzed. RESULTS: Sixteen articles met the inclusion criteria. Based on these articles, the rate of RTS was 97.5% after arthroscopic Bankart, 86.1% after open Bankart, 83.6% after open Latarjet, 94.0% after arthroscopic Latarjet, and 95.5% after arthroscopic Bankart with remplissage. Among the athletes who did RTS, arthroscopic Bankart had the highest rate of return to preinjury levels (91.5%), while arthroscopic Latarjet had the lowest rate (69.0%). The time to RTS was 5.9 months after arthroscopic Bankart, 8.2 months after open Bankart, 5.07 months after open Latarjet, 5.86 months after arthroscopic Latarjet, and 7 months after arthroscopic Bankart with remplissage. CONCLUSION: Of the pooled data, patients who underwent arthroscopic Bankart showed the highest rate of RTS, while patients who underwent open Latarjet showed the shortest time to RTS. Return to preinjury level was highest in the arthroscopic Bankart group and lowest in the arthroscopic Latarjet group. Physicians can utilize these data to set expectations for their patient-athletes regarding RTS after anterior shoulder stabilization procedures. CLINICAL RELEVANCE: When treating an athlete, many factors must be taken into account to weigh treatment options. Two important factors to consider with the patient-athlete are the rate of return to the previous activity level and the timeline for this to occur. This study provides a guide for physicians and a time frame for athletes with respect to the mean percentage and time for return to sport after different surgical procedures for anterior shoulder instability.

Assessment of programmed death-ligand 1 expression and tumor-associated immune cells in pediatric cancer tissues.

BACKGROUND: Programmed death 1 (PD-1) signaling in the tumor microenvironment dampens immune responses to cancer, and blocking this axis induces antitumor effects in several malignancies. Clinical studies of PD-1 blockade are only now being initiated in pediatric patients, and little is known regarding programmed death-ligand 1 (PD-L1) expression in common childhood cancers. The authors characterized PD-L1 expression and tumor-associated immune cells (TAICs) (lymphocytes and macrophages) in common pediatric cancers. METHODS: Whole slide sections and tissue microarrays were evaluated by immunohistochemistry for PD-L1 expression and for the presence of TAICs. TAICs were also screened for PD-L1 expression. RESULTS: Thirty-nine of 451 evaluable tumors (9%) expressed PD-L1 in at least 1% of tumor cells. The highest frequency histotypes comprised Burkitt lymphoma (80%; 8 of 10 tumors), glioblastoma multiforme (36%; 5 of 14 tumors), and neuroblastoma (14%; 17 of 118 tumors). PD-L1 staining was associated with inferior survival among patients with neuroblastoma (P = .004). Seventy-four percent of tumors contained lymphocytes and/or macrophages. Macrophages were significantly more likely to be identified in PD-L1-positive versus PD-L1-negative tumors (P < .001). CONCLUSIONS: A subset of diagnostic pediatric cancers exhibit PD-L1 expression, whereas a much larger fraction demonstrates infiltration with tumor-associated lymphocytes. PD-L1 expression may be a biomarker for poor outcome in neuroblastoma. Further preclinical and clinical investigation will define the predictive nature of PD-L1 expression in childhood cancers both at diagnosis and after exposure to chemoradiotherapy. Cancer 2017;123:3807-3815. © 2017 American Cancer Society.

Immunomodulatory Activity of Nivolumab in Metastatic Renal Cell Carcinoma.

PURPOSE: Nivolumab, an anti-PD-1 immune checkpoint inhibitor, improved overall survival versus everolimus in a phase 3 trial of previously treated patients with metastatic renal cell carcinoma (mRCC). We investigated immunomodulatory activity of nivolumab in a hypothesis-generating prospective mRCC trial. EXPERIMENTAL DESIGN: Nivolumab was administered intravenously every 3 weeks at 0.3, 2, or 10 mg/kg to previously treated patients and 10 mg/kg to treatment-naïve patients with mRCC. Baseline and on-treatment biopsies and blood were obtained. Clinical activity, tumor-associated lymphocytes, PD-L1 expression (Dako immunohistochemistry; ≥5% vs. <5% tumor membrane staining), tumor gene expression (Affymetrix U219), serum chemokines, and safety were assessed. RESULTS: In 91 treated patients, median overall survival [95% confidence interval (CI)] was 16.4 months [10.1 to not reached (NR)] for nivolumab 0.3 mg/kg, NR for 2 mg/kg, 25.2 months (12.0 to NR) for 10 mg/kg, and NR for treatment-naïve patients. Median percent change from baseline in tumor-associated lymphocytes was 69% (CD3+), 180% (CD4+), and 117% (CD8+). Of 56 baseline biopsies, 32% had ≥5% PD-L1 expression, and there was no consistent change from baseline to on-treatment biopsies. Transcriptional changes in tumors on treatment included upregulation of IFNγ-stimulated genes (e.g., CXCL9). Median increases in chemokine levels from baseline to C2D8 were 101% (CXCL9) and 37% (CXCL10) in peripheral blood. No new safety signals were identified. CONCLUSIONS: Immunomodulatory effects of PD-1 inhibition were demonstrated through multiple lines of evidence across nivolumab doses. Biomarker changes from baseline reflect nivolumab pharmacodynamics in the tumor microenvironment. These data may inform potential combinations. Clin Cancer Res; 22(22); 5461-71. ©2016 AACR.

Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma.

BACKGROUND: Nivolumab, a programmed death 1 (PD-1) checkpoint inhibitor, was associated with encouraging overall survival in uncontrolled studies involving previously treated patients with advanced renal-cell carcinoma. This randomized, open-label, phase 3 study compared nivolumab with everolimus in patients with renal-cell carcinoma who had received previous treatment. METHODS: A total of 821 patients with advanced clear-cell renal-cell carcinoma for which they had received previous treatment with one or two regimens of antiangiogenic therapy were randomly assigned (in a 1:1 ratio) to receive 3 mg of nivolumab per kilogram of body weight intravenously every 2 weeks or a 10-mg everolimus tablet orally once daily. The primary end point was overall survival. The secondary end points included the objective response rate and safety. RESULTS: The median overall survival was 25.0 months (95% confidence interval [CI], 21.8 to not estimable) with nivolumab and 19.6 months (95% CI, 17.6 to 23.1) with everolimus. The hazard ratio for death with nivolumab versus everolimus was 0.73 (98.5% CI, 0.57 to 0.93; P=0.002), which met the prespecified criterion for superiority (P≤0.0148). The objective response rate was greater with nivolumab than with everolimus (25% vs. 5%; odds ratio, 5.98 [95% CI, 3.68 to 9.72]; P<0.001). The median progression-free survival was 4.6 months (95% CI, 3.7 to 5.4) with nivolumab and 4.4 months (95% CI, 3.7 to 5.5) with everolimus (hazard ratio, 0.88; 95% CI, 0.75 to 1.03; P=0.11). Grade 3 or 4 treatment-related adverse events occurred in 19% of the patients receiving nivolumab and in 37% of the patients receiving everolimus; the most common event with nivolumab was fatigue (in 2% of the patients), and the most common event with everolimus was anemia (in 8%). CONCLUSIONS: Among patients with previously treated advanced renal-cell carcinoma, overall survival was longer and fewer grade 3 or 4 adverse events occurred with nivolumab than with everolimus. (Funded by Bristol-Myers Squibb; CheckMate 025 ClinicalTrials.gov number, NCT01668784.).

Genetic variation at the NPC1L1 gene locus, plasma lipoproteins, and heart disease risk in the elderly.

Niemann-Pick C1-like 1 protein (NPC1L1) plays a critical role in intestinal cholesterol absorption. Our objective was to examine whether five variants (-133A>G, -18A>C, L272L, V1296V, and U3_28650A>G) at the NPC1L1 gene have effects on lipid levels, prevalence, and incidence of coronary heart disease (CHD) and lipid-lowering response to pravastatin. We studied 5,804 elderly participants from the PROSPER study, who were randomized to prava-statin 40 mg/day or placebo and were followed on average for 3.2 years. In the adjusted gender-pooled analyses, homozygous carriers of the minor alleles at four NPC1L1 sites (-18A>C, L272L, V1296V, and U3_28650A>G, minor allele frequencies 0.15-0.33) had 2-8% higher LDL-cholesterol (LDL-C) levels at baseline than homozygous carriers of the common alleles (P < 0.05). Homozygotes for the rare alleles also had a significant increase in the risk of CHD events on trial (range of hazard ratios 1.50-1.67; P < 0.02), regardless of the treatment regimen. The -133 A>G polymorphism and not other variants was associated with 6 month LDL-C lowering (P = 0.02). Our data indicate that variation in the NPC1L1 gene is associated with plasma total and LDL-C levels and CHD risk.

Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance.

Chronic infection with hepatitis C virus (HCV) affects 170 million people worldwide and is the leading cause of cirrhosis in North America. Although the recommended treatment for chronic infection involves a 48-week course of peginterferon-alpha-2b (PegIFN-alpha-2b) or -alpha-2a (PegIFN-alpha-2a) combined with ribavirin (RBV), it is well known that many patients will not be cured by treatment, and that patients of European ancestry have a significantly higher probability of being cured than patients of African ancestry. In addition to limited efficacy, treatment is often poorly tolerated because of side effects that prevent some patients from completing therapy. For these reasons, identification of the determinants of response to treatment is a high priority. Here we report that a genetic polymorphism near the IL28B gene, encoding interferon-lambda-3 (IFN-lambda-3), is associated with an approximately twofold change in response to treatment, both among patients of European ancestry (P = 1.06 x 10(-25)) and African-Americans (P = 2.06 x 10(-3)). Because the genotype leading to better response is in substantially greater frequency in European than African populations, this genetic polymorphism also explains approximately half of the difference in response rates between African-Americans and patients of European ancestry.

Identification of single nucleotide polymorphisms of the human metabotropic glutamate receptor 1 gene and pharmacological characterization of a P993S variant.

mGluR1 receptors are believed to play major roles in the pathophysiology of diseases such as anxiety and chronic pain and are being actively investigated as targets for drug development. Sequence polymorphisms can potentially influence the efficacy of drugs in patient populations and are therefore an important consideration in the drug development process. To identify DNA sequence variants of the mGluR1 receptor, comparative DNA sequencing was performed on DNA samples (n=186) from apparently healthy subjects representing two ethnic groups. In total, eight non-synonymous single nucleotide polymorphisms (SNPs) were identified and one SNP (c2977>T) was found to be particularly common, this SNP results in a proline to serine substitution at residue 993 (P993S). The WT (P993) and S993 variants were expressed in an inducible system which allowed us to titrate gene expression to equivalent levels and were pharmacologically characterized. We determined the potency and affinity of standard antagonist compounds as well as the potency and efficacy of the endogenous ligand glutamate and other agonist compounds at both receptor variants. Agonist evoked increases in intracellular Ca(2+) were measured by fluorometric imaging plate reader (FLIPR). The potency of mGluR1 antagonists was evaluated by their ability to inhibit quisqualate induced increases in intracellular Ca(2+), while their affinities were determined by radio-ligand binding studies. This study demonstrates that the Pro993Ser amino acid exchange is highly frequent in the human mGluR1 gene. This polymorphism however, does not appear to affect the potency of agonist compounds or the potencies or affinities of small molecule antagonist compounds.

P518/Qrfp sequence polymorphisms in SAMP6 osteopenic mouse.

Mice lacking GPR103A expression display osteopenia. Analysis of mouse quantitative trait loci literature associated with bone mineral density suggested GPR103A ligand P518/Qrfp (chromosome 2qB) as a candidate osteoporosis gene. Promoter and coding regions of mouse P518/Qrfp were sequenced from genomic DNA obtained from the osteoporosis-prone strain SAMP6 and control strains SAMR1, A/J, AKR/J, BALB/c, C3H/HeJ, C57BL/6J, and DBA/2J. Four single-nucleotide polymorphisms (SNPs) were identified in only SAMP6 genomic DNA, g.-1773 T-->C, g.110 A-->G (N37S), g.188 G-->A (R63K), and g.135 T-->C (H45H). The promoter SNP generated a novel neuron-restrictive silencing factor binding site, a repressor that decreases gene expression in nonneuronal tissues. TaqMan analysis demonstrated fivefold lower P518/Qrfp liver expression in SAMP6 versus SAMR1 or C57BL/6J control strains. Tissue distribution of human, mouse, and rat P518/Qrfp and its receptors showed expression in bone and spinal cord. A direct role for P518/Qrfp function in maintaining bone mineral density is suggested.

Expression of the chemokine receptor CCR5 in psoriasis and results of a randomized placebo controlled trial with a CCR5 inhibitor.

Several reports have indicated that the chemokine receptor CCR5 and its ligands, especially CCL5 (formerly known as RANTES), may play a role in the pathogenesis of psoriasis. The purpose of this investigation was to examine the expression of CCR5 and its ligands in chronic plaque psoriasis and to evaluate the clinical and immunohistochemical effect of a CCR5 receptor inhibitor. Immunohistochemical analysis showed low but significant increased total numbers of CCR5 positive cells in epidermis and dermis of lesional skin in comparison to non-lesional skin. However, relative expression of CCR5 proportional to the cells observed revealed that the difference between lesional and non-lesional skin was only statistically significant in the epidermis for CD3 positive cells and in the dermis for CD68 positive cells. Quantification of mRNA by reverse transcriptase-polymerase chain reaction only showed an increased expression of CCL5 (RANTES) in lesional skin. A randomized placebo-controlled clinical trial in 32 psoriasis patients revealed no significant clinical effect and no changes at the immunohistochemical level comparing patients treated with placebo or a CCR5 inhibitor SCH351125. We conclude that although CCR5 expression is increased in psoriatic lesions, this receptor does not play a crucial role in the pathogenesis of psoriasis.