Characterization of Lymph Node Tumor Burden in Node-Positive Prostate Cancer Patients after Robotic-Assisted Radical Prostatectomy with Extended Pelvic Lymph Node Dissection.

BACKGROUND: Prostate cancer (PCa) nodal staging does not account for lymph node (LN) tumor burden. The LN anatomical compartment involved with the tumor or the quantified extent of extranodal extension (ENE) have not yet been studied in relation to biochemical recurrence-free survival (BRFS). METHODS: Histopathological slides of 66 pN1 PCa patients who underwent extended pelvic lymph node dissection were reviewed. We recorded metrics to quantify LN tumor burden. We also characterized the LN anatomical compartments involved and quantified the extent of ENE. RESULTS: The median follow-up time was 38 months. The median number of total LNs obtained per patient was 30 (IQR 23-37). In the risk-adjusted cox regression model, the following variables were associated with BRFS: mean size of the largest LN deposit per patient (log2: adjusted hazard ratio (aHR) = 1.91, p < 0.001), the mean total span of all LN deposits per patient (2.07, p < 0.001), and the mean percent surface area of the LN involved with the tumor (1.58, p < 0.001). There was no significant BRFS association for the LN anatomical compartment or the quantified extent of ENE. CONCLUSION: LN tumor burden is associated with BRFS. The LN anatomical compartments and the quantified extent of ENE did not show significant association with BRFS.

Impact of Adherence to Operative Standards and Stage-Specific Guideline-Recommended Therapy in Nonmetastatic Pancreatic Adenocarcinoma.

BACKGROUND: Achieving optimal surgical outcomes in pancreatic adenocarcinoma requires a combination of both curative-intent resection to oncologic standards and stage-specific neoadjuvant or adjuvant therapy. This investigation sought to examine factors associated with receipt of standard-adherent surgery (SAS) and guideline-recommended therapy (GRT) and determine the impact of compliance on patient survival. PATIENTS AND METHODS: From the 2006-2016 National Cancer Database, 21,304 patients underwent resection for nonmetastatic pancreatic adenocarcinoma. SAS was defined as pancreatic resection with negative margins and ≥ 15 lymph nodes examined. Stage-specific GRT was defined by current National Comprehensive Cancer Network guidelines. Multivariable models were used to determine predictors of adherence to SAS and GRT and prognostic impact on overall survival. RESULTS: Overall, SAS was achieved in 39% and GRT in 65% of patients, but only 30% received both SAS and GRT. Increasing age, minority race, uninsured status, and greater comorbidities were associated with a decreased odds of receiving both SAS and GRT (all p < 0.05). SAS (HR 0.79; CI 0.76-0.81; p < 0.001) and GRT (HR 0.67; CI 0.65-0.69; p < 0.001) were each independently associated with a survival advantage. Receipt of both SAS and GRT was associated with significant improvement in median OS compared with receiving neither (2.2 years vs 1.1 years; p < 0.001) which was independently associated with a 78% increased risk of death (HR 1.78; CI 1.70-1.86; p < 0.001). CONCLUSIONS: Despite survival benefits associated with adherence to operative standards and receipt of guideline-recommended therapy, compliance remains poor. Future efforts must be directed toward improved education and implementation efforts around both operative standards and therapy guidelines.

Impact of Mediating and Confounding Variables on the Volume-Outcome Association in the Treatment of Pancreatic Cancer.

BACKGROUND: High-volume centers (HVC), academic centers (AC), and longer travel distances (TD) have been associated with improved outcomes for patients undergoing surgery for pancreatic adenocarcinoma (PAC). Effects of mediating variables on these associations remain undefined. The purpose of this study is to examine the direct effects of hospital volume, facility type, and travel distance on overall survival (OS) in patients undergoing surgery for PAC and characterize the indirect effects of patient-, disease-, and treatment-related mediating variables. PATIENTS AND METHODS: Using the National Cancer Database, patients with non-metastatic PAC who underwent resection were stratified by annual hospital volume (< 11, 11-19, and ≥ 20 cases/year), facility type (AC versus non-AC), and TD (≥ 40 versus < 40 miles). Associations with survival were evaluated using multiple regression models. Effects of mediating variables were assessed using mediation analysis. RESULTS: In total, 19,636 patients were included. Treatment at HVC or AC was associated with lower risk of death [hazard ratio (HR) 0.90, confidence interval (CI) 0.88-0.92; HR 0.89, CI 0.86-0.91, respectively]. TD did not impact OS. Patient-, disease-, and treatment-related variables explained 25.5% and 41.8% of the survival benefit attained from treatment at HVC and AC, reducing the survival benefit directly attributable to each variable to 4.9% and 6.4%, respectively. CONCLUSIONS: Treatment of PAC at HVC and AC was associated with improved OS, but the magnitude of this benefit was less when mediating variables were considered. From a healthcare utilization and cost-resource perspective, further research is needed to identify patients who would benefit most from selective referral to HVC or AC.

Preoperative Risk Prediction for Pancreatectomy: A Comparative Analysis of Three Scoring Systems.

INTRODUCTION: Pancreatectomy is associated with high morbidity and mortality. Therefore, patient selection and risk prediction is paramount. In this study, three validated perioperative risk scoring systems were compared among patients undergoing pancreatectomy to identify the most clinically useful model. MATERIALS AND METHODS: The 2014-2017 American College of Surgeons National Surgical Quality Improvement Program database was queried for pancreatectomy patients. Three models were evaluated: National Surgical Quality Improvement Program Universal Risk Calculator (URC), Model for End-Stage Liver Disease (MELD), and Modified Frailty Index-5 Factor (mFI-5). Outcomes were 30-d mortality and complications. Predictive performance of the models was compared using area under the receiver operating characteristic curve (AUC) and Brier scores. RESULTS: Twenty two thousand one hundred twenty three pancreatectomy patients were identified. The 30-d mortality rate was 1.4% (n = 319). Complications occurred in 6020 cases (27.2%). AUC (95% CI) for 30-d mortality were 0.70 (0.67-0.73), 0.63 (0.60-0.67), and 0.60 (0.57-0.63) for URC, MELD, and mFI-5, respectively, with Brier score of 0.014 for all three models. AUC (95% confidence interval) for any complication was 0.59 (0.58-0.59) for URC, 0.53 (0.52-0.54) for MELD, and 0.53 (0.52-0.54) for mFI-5, with Brier scores 0.193 (URC), 0.200 (MELD), and 0.197 (mFI-5). For individual complications, URC was more predictive than MELD or mFI-5. CONCLUSIONS: Of the validated preoperative risk scoring systems, URC was most predictive of both complications and 30-d mortality. None of the models performed better than fair to good. The lack of predictive accuracy of currently existing models highlights the need for development of improved perioperative risk models.

Clinical Factors and Outcomes When Real-World Heart Teams Overruled STS Risk Scores in TAVR Cases.

Objectives: This study was conducted to determine why heart teams recommended transcatheter aortic valve replacement (TAVR) versus surgical AVR (SAVR) for patients at low predicted risk of mortality (PROM) and describe outcomes of these cases. Background: Historically, referral to TAVR was based predominately on the Society of Thoracic Surgeons (STS) risk model's PROM >3%. In selected cases, heart teams had latitude to overrule these scores. The clinical reasons and outcomes for these cases are unclear. Methods: Retrospective data were gathered for all TAVR and SAVR cases conducted by 9 hospitals between 2013 and 2017. Results: Cases included TAVR patients with STS PROM >3% (n = 2,711) and ≤3% (n = 415) and SAVR with STS PROM ≤3% (n = 1,438). Leading reasons for recommending TAVR in the PROM ≤3% group were frailty (57%), hostile chest (22%), severe lung disease (16%), and morbid obesity (13%), and 44% of cases had multiple reasons. Most postoperative and 30-day outcomes were similar between TAVR groups, but the STS PROM ≤3% group had a one-day shorter length of stay (2.5 ± 3.4 vs. 3.5 ± 4.7 days; p ≤ 0.001) and higher one-year survival (91.6% vs. 86.0%, p=0.002). In patients with STS PROM ≤3%, 30-day mortality was higher for TAVR versus SAVR (2.0% vs. 0.6%; p < 0.001). Conclusions: Heart teams recommended TAVR in patients with STS PROM ≤3% primarily due to frailty, hostile chest, severe lung disease, and/or morbid obesity. Similar postoperative outcomes between these patients and those with STS PROM >3% suggest that decisions to overrule STS PROM ≤3% were merited and may have reduced SAVR 30-day mortality rate.

The CUSUM Slope Equals Observed Minus Expected Mortality and Can Be Visualized by a "Slope-Meter".

We present an additional advantage of the Risk-Adjusted CUSUM (RA-CUSUM), namely, that its slope can be quantified and is in fact equivalent to Observed (O) minus Expected (E) mortality. That is, the height of the RA-CUSUM is the O minus E deaths, which measures performance since the start of the series, and the slope of the RA-CUSUM is the O minus E mortality which measures performance during a chosen interval. We present a useful graphical tool (Slope-Meter) to allow approximation of this mortality difference by the viewer.

Comparison of 26-mm Evolut and 23-mm Sapien 3 Valves in TAVR for Small Aortic Annulus.

BACKGROUND: Patients with small aortic annuli (SAA) are prone to higher post-transcatheter aortic valve replacement (TAVR) transvalvular gradients and development of prosthesis-patient mismatch (PPM). In many patients with SAA, the choice of TAVR valve commonly involves choosing between the 26-mm Medtronic Evolut 2 (ME26) or the 23-mm Edwards Sapien 3 valve (ES23). We compared echocardiographic and clinical outcomes in patients with SAA undergoing TAVR with either valve. METHODS: We queried the Providence St. Joseph Health Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry database for patients undergoing TAVR with either the ES23 or ME26 between July 2015 and December 2018 at 11 hospitals. Post-TAVR echocardiographic and clinical results in-hospital, at 1 month, and at 1 year were examined. High gradient (HG) was defined as mean gradient (MG) ≥20 mm Hg. RESULTS: We identified 1162 patients with SAA undergoing TAVR with either the ME26 (n = 233) or ES23 valve (n = 929). Baseline characteristics between groups were similar. At 1 month, the ME26 was associated with a lower MG than the ES23 (7.7 ± 4.7 mm Hg vs 13.1 ± 4.9 mm Hg; P<.001) and moderate or severe PPM (11% and 3% vs 27% and 13%; P<.001). Occurrence of HG at 1 year was lower with the ME26 valve vs the ES23 valve (0% vs 15%; P<.001). In-hospital and follow-up clinical outcomes to 1 year were similar for both groups. CONCLUSION: TAVR in SAA with the ME26 is associated with lower incidence of HG or PPM compared with the ES23. While clinical outcomes at 1 year were similar, the long-term implications of these findings remain unknown.

Calibration Factors for STS Risk Model Predictions: Why, How and When They Are Used.

The Society of Thoracic Surgeons (STS) Adult Cardiac Surgery Database is the world's premier adult cardiac surgery outcomes registry. This tutorial explains the following: how STS updates the risk models that are used to calculate the predicted risks of adverse events in the registry; why STS on a quarterly basis adjusts or "calibrates" the observed-to-expected ratios to equal 1 (O/E = 1), thereby effectively making the annual number of adverse events predicted by the model match the annual number of adverse events observed in the entire registry; the differences between the calibrated and uncalibrated O/E ratios; and how and when to use each.

Remdesivir and Mortality in Patients With Coronavirus Disease 2019.

BACKGROUND: The impact of remdesivir (RDV) on mortality rates in coronavirus disease 2019 (COVID-19) is controversial, and the mortality effect in subgroups of baseline disease severity has been incompletely explored. The purpose of this study was to assess the association of RDV with mortality rates in patients with COVID-19. METHODS: In this retrospective cohort study we compared persons receiving RDV with those receiving best supportive care (BSC). Patients hospitalized between 28 February and 28 May 2020 with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 infection were included with the development of COVID-19 pneumonia on chest radiography and hypoxia requiring supplemental oxygen or oxygen saturation ≤94% with room air. The primary outcome was overall survival, assessed with time-dependent Cox proportional hazards regression and multivariable adjustment, including calendar time, baseline patient characteristics, corticosteroid use, and random effects for hospital. RESULTS: A total of 1138 patients were enrolled, including 286 who received RDV and 852 treated with BSC, 400 of whom received hydroxychloroquine. Corticosteroids were used in 20.4% of the cohort (12.6% in RDV and 23% in BSC). Comparing persons receiving RDV with those receiving BSC, the hazard ratio (95% confidence interval) for death was 0.46 (.31-.69) in the univariate model (P < .001) and 0.60 (.40-.90) in the risk-adjusted model (P = .01). In the subgroup of persons with baseline use of low-flow oxygen, the hazard ratio (95% confidence interval) for death in RDV compared with BSC was 0.63 (.39-1.00; P = .049). CONCLUSION: Treatment with RDV was associated with lower mortality rates than BSC. These findings remain the same in the subgroup with baseline use of low-flow oxygen.

Is the 21-Gene Recurrence Score on Core Needle Biopsy Equivalent to Surgical Specimen in Early-Stage Breast Cancer? A Comparison of Gene Expression Between Paired Core Needle Biopsy and Surgical Specimens.

BACKGROUND: Molecular testing on surgical specimens predicts disease recurrence and benefit of adjuvant chemotherapy in hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) early-stage breast cancer (EBC). Testing on core biopsies has become common practice despite limited evidence of concordance between core/surgical samples. In this study, we compared the gene expression of the 21 genes and the recurrence score (RS) between paired core/surgical specimens. METHODS: Eighty patients with HR+/HER2- EBC were evaluated from two publicly available gene expression datasets (GSE73235, GSE76728) with paired core/surgical specimens without neoadjuvant systemic therapy. The expression of the 21 genes was compared in paired samples. A microarray-based RS was calculated and a value ≥ 26 was defined as high-RS. The concordance rate and kappa statistic were used to evaluate the agreement between the RS of paired samples. RESULTS: Overall, there was no significant difference and a high correlation in the gene expression levels of the 21 genes between paired samples. However, CD68 and RPLP0 in GSE73235, AURKA, BAG1, and TFRC in GSE76728, and MYLBL2 and ACTB in both datasets exhibited weak to moderate correlation (r < 0.5). There was a high correlation of the microarray-based RS between paired samples in GSE76728 (r = 0.91, 95% confidence interval [CI] 0.81-0.96) and GSE73235 (r = 0.82, 95% CI 0.71-0.89). There were no changes in RS category in GSE76728, whereas 82% of patients remained in the same RS category in GSE73235 (κ = 0.64). CONCLUSIONS: Gene expression levels of the 21-gene RS showed a high correlation between paired specimens. Potential sampling and biological variability on a set of genes need to be considered to better estimate the RS from core needle biopsy.

Continuous Monitoring of Risk-Adjusted Outcomes: Excess Deaths vs Lives Saved.

Reporting of risk-adjusted surgical outcomes is commonly used to compare providers and track changes over time. Preferred graphical methods use the relationship of the observed to the expected values of outcome events, including their ratio (O/E), and the cumulative sum (CUSUM) of their differences over time, called Risk-Adjusted CUSUM (RA-CUSUM) or Variable Life Adjusted Display (VLAD). We demonstrate these methods using operative mortality data for 7255 isolated coronary artery bypass graft patients from January 2014 to June 2017. RA-CUSUM and VLAD are excellent techniques to display risk-adjusted outcomes and, unlike O/E, can provide continuous monitoring as performance varies over time.

Multiplex immunofluorescence to measure dynamic changes in tumor-infiltrating lymphocytes and PD-L1 in early-stage breast cancer.

BACKGROUND: The H&E stromal tumor-infiltrating lymphocyte (sTIL) score and programmed death ligand 1 (PD-L1) SP142 immunohistochemistry assay are prognostic and predictive in early-stage breast cancer, but are operator-dependent and may have insufficient precision to characterize dynamic changes in sTILs/PD-L1 in the context of clinical research. We illustrate how multiplex immunofluorescence (mIF) combined with statistical modeling can be used to precisely estimate dynamic changes in sTIL score, PD-L1 expression, and other immune variables from a single paraffin-embedded slide, thus enabling comprehensive characterization of activity of novel immunotherapy agents. METHODS: Serial tissue was obtained from a recent clinical trial evaluating loco-regional cytokine delivery as a strategy to promote immune cell infiltration and activation in breast tumors. Pre-treatment biopsies and post-treatment tumor resections were analyzed by mIF (PerkinElmer Vectra) using an antibody panel that characterized tumor cells (cytokeratin-positive), immune cells (CD3, CD8, CD163, FoxP3), and PD-L1 expression. mIF estimates of sTIL score and PD-L1 expression were compared to the H&E/SP142 clinical assays. Hierarchical linear modeling was utilized to compare pre- and post-treatment immune cell expression, account for correlation of time-dependent measurement, variation across high-powered magnification views within each subject, and variation between subjects. Simulation methods (Monte Carlo, bootstrapping) were used to evaluate the impact of model and tissue sample size on statistical power. RESULTS: mIF estimates of sTIL and PD-L1 expression were strongly correlated with their respective clinical assays (p < .001). Hierarchical linear modeling resulted in more precise estimates of treatment-related increases in sTIL, PD-L1, and other metrics such as CD8+ tumor nest infiltration. Statistical precision was dependent on adequate tissue sampling, with at least 15 high-powered fields recommended per specimen. Compared to conventional t-testing of means, hierarchical linear modeling was associated with substantial reductions in enrollment size required (n = 25➔n = 13) to detect the observed increases in sTIL/PD-L1. CONCLUSION: mIF is useful for quantifying treatment-related dynamic changes in sTILs/PD-L1 and is concordant with clinical assays, but with greater precision. Hierarchical linear modeling can mitigate the effects of intratumoral heterogeneity on immune cell count estimations, allowing for more efficient detection of treatment-related pharmocodynamic effects in the context of clinical trials. TRIAL REGISTRATION: NCT02950259 .

Development of a Risk Score and Nomogram to Predict Individual Benefit Attained from the Addition of Adjuvant Chemotherapy in the Treatment of Stage II Colon Cancer.

BACKGROUND: Current guidelines recommend considering adjuvant chemotherapy (AC) for stage II colon cancer (CC) with poor prognostic clinicopathologic and molecular features. However, the relative impact of individual or constellations of high-risk features remains undefined. We developed an individualized point-of-care tool to predict survival benefit attained from the addition of AC. METHODS: The National Cancer Database was queried for all patients with resected stage II CC from 2004 to 2015. A prognostic risk score and nomogram were constructed using twelve clinicopathologic and molecular prognostic factors associated with outcomes for CC. Overall survival (OS) was compared between surgery alone and AC groups. The nomogram was validated for discrimination and calibration using bootstrap-adjusted Harrell's concordance index (C-index). For population-level estimation, OS was compared based on quartiles. RESULTS: Of 132,666 patients with stage II CC, 16.8% received AC. The calibration curve of the constructed nomogram showed a good agreement between predicted and observed median and 3-, 5-, and 10-year survival (bootstrap-adjusted C-index 0.699, CI: 0.698-0.703). Population-level risk score analysis (median [Q1, Q3]; 4.9 [4.6, 5.5]) demonstrated that patients with scores > 3.34 had significantly decreased risk of death with the addition of AC (all p < 0.001). No survival advantage was associated with AC among patients with low risk scores (risk score < 3.34: HR: 0.94, 95% CI: 0.80-1.11, p = 0.47). DISCUSSION: A composite weighted risk score is critical to individualizing AC in select high-risk patients. Our nomogram provides individualized prognostication and estimation of benefit attained from AC. This may better inform treatment decisions and aid future trial design.

Trends in Diagnosis Related Groups for Inpatient Admissions and Associated Changes in Payment From 2012 to 2016.

Importance: Hospitals are reimbursed based on Diagnosis Related Groups (DRGs), which are defined, in part, by patients having 1 or more complications or comorbidities within a given DRG family. Hospitals have made substantial investment in efforts to document these complications and comorbidities. Objective: To examine temporal trends in DRGs with a major complication or comorbidity, compare these findings with 2 alternative measures of disease severity, and estimate associated changes in payment. Design, Setting, and Participants: This retrospective cohort study used data from the all-payer National Inpatient Sample for admissions assigned to 1 of the top 20 reimbursed DRG families at US acute care hospitals from January 1, 2012, to December 31, 2016. Data were analyzed from July 10, 2018, to May 29, 2019. Exposures: Quarter year of hospitalization. Main Outcomes and Measures: The primary outcome was the proportion of DRGs with a major complication or comorbidity. Secondary outcomes were comorbidity scores, risk-adjusted mortality rates, and estimated payment. Changes in assigned DRGs, comorbidity scores, and risk-adjusted mortality rates were analyzed by linear regression. Payment changes were estimated for each DRG by calculating the Centers for Medicare & Medicaid Services weighted payment using 2012 and 2016 case mix and hospitalization counts. Results: Between 2012 and 2016, there were 62 167 976 hospitalizations for the 20 highest-reimbursed DRG families; the sample was 32.9% male and 66.8% White, with a median age of 57 years (interquartile range, 31-73 years). Within 15 of these DRG families (75%), the proportion of DRGs with a major complication or comorbidity increased significantly over time. Over the same period, comorbidity scores were largely stable, with a decrease in 6 DRG families (30%), no change in 10 (50%), and an increase in 4 (20%). Among 19 DRG families with a calculable mortality rate, the risk-adjusted mortality rate significantly decreased in 8 (42%), did not change in 9 (47%), and increased in 2 (11%). The observed DRG shifts were associated with at least $1.2 billion in increased payment. Conclusions and Relevance: In this cohort study, between 2012 and 2016, the proportion of admissions assigned to a DRG with major complication or comorbidity increased for 15 of the top 20 reimbursed DRG families. This change was not accompanied by commensurate increases in disease severity but was associated with increased payment.

Long-Term Durability of Transcatheter Valves: The Importance of Accurate Data.

As transcatheter valves are offered to progressively lower-risk patients, it is increasingly important to have accurate data about durability. Structural valve deterioration (SVD) implies an adverse change in the morphology of the leaflets and function of the valve compared with the state at implantation. However, a recent European statement allows SVD to be defined solely by a threshold mean gradient ≥20 mm Hg. Absolute mean gradients above this threshold may be observed immediately after implantation and represent patient-prosthesis mismatch and not SVD. This paper describes a definition of SVD more in keeping with routine clinical practice, incorporating a change in leaflet morphology and an increase in the grade of transvalvar regurgitation or an increase in gradient from the post-implantation study.

Early cost-utility analysis of tissue-engineered heart valves compared to bioprostheses in the aortic position in elderly patients.

OBJECTIVES: Aortic valve disease is the most frequent indication for heart valve replacement with the highest prevalence in elderly. Tissue-engineered heart valves (TEHV) are foreseen to have important advantages over currently used bioprosthetic heart valve substitutes, most importantly reducing valve degeneration with subsequent reduction of re-intervention. We performed early Health Technology Assessment of hypothetical TEHV in elderly patients (≥ 70 years) requiring surgical (SAVR) or transcatheter aortic valve implantation (TAVI) to assess the potential of TEHV and to inform future development decisions. METHODS: Using a patient-level simulation model, the potential cost-effectiveness of TEHV compared with bioprostheses was predicted from a societal perspective. Anticipated, but currently hypothetical improvements in performance of TEHV, divided in durability, thrombogenicity, and infection resistance, were explored in scenario analyses to estimate quality-adjusted life-year (QALY) gain, cost reduction, headroom, and budget impact. RESULTS: Durability of TEHV had the highest impact on QALY gain and costs, followed by infection resistance. Improved TEHV performance (- 50% prosthetic valve-related events) resulted in lifetime QALY gains of 0.131 and 0.043, lifetime cost reductions of €639 and €368, translating to headrooms of €3255 and €2498 per hypothetical TEHV compared to SAVR and TAVI, respectively. National savings in the first decade after implementation varied between €2.8 and €11.2 million (SAVR) and €3.2-€12.8 million (TAVI) for TEHV substitution rates of 25-100%. CONCLUSIONS: Despite the relatively short life expectancy of elderly patients undergoing SAVR/TAVI, hypothetical TEHV are predicted to be cost-effective compared to bioprostheses, commercially viable and result in national cost savings when biomedical engineers succeed in realising improved durability and/or infection resistance of TEHV.