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 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.

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.

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.

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.

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.

Neoadjuvant Chemotherapy Improves Survival in Patients with Clinical T4b Colon Cancer.

BACKGROUND: In 2016, the National Comprehensive Cancer Network included neoadjuvant chemotherapy as a treatment option for patients with clinical T4b colon cancer. However, there is little published data on the survival impact of neoadjuvant chemotherapy for locally advanced colon cancer. METHODS: Adult patients with non-metastatic clinically staged T3 or T4 colon cancer who underwent surgical resection were identified from the National Cancer Data Base between 2006 and 2014. Treatment was categorized as neoadjuvant chemotherapy followed by surgery and surgery followed by adjuvant chemotherapy. Overall survival was compared between the two groups using propensity score matching. RESULTS: Of 27,575 patients that met inclusion criteria, 26,654 (97%) were treated with surgery followed by adjuvant chemotherapy and 921 (3%) received neoadjuvant chemotherapy followed by surgery. After propensity score matching, patients with T4b colon cancer treated with neoadjuvant chemotherapy had a 23% lower risk of death at 3 years compared to patients that had adjuvant chemotherapy (HR 0.77, 95% CI 0.60-0.98; p = 0.04). However, neoadjuvant chemotherapy did not demonstrate a similar significant benefit for patients with T3 and T4a disease. CONCLUSIONS: Patients with clinical T4b colon cancer treated with neoadjuvant chemotherapy may have an improved survival compared to those who receive adjuvant chemotherapy. Further prospective investigation is warranted.

Bioprosthetic Aortic Valve Durability: A Meta-Regression of Published Studies.

To compare structural valve deterioration (SVD) among bioprosthetic aortic valve types, a PubMed search found 54 papers containing SVD-free curves extending to at least 10 years. The curves were digitized and fit to Weibull distributions, and the mean times to valve failure (MTTF) were calculated. Twelve valve models were collapsed into four valve types: Medtronic (Medtronic, Minneapolis, MN) and Edwards (Edwards Lifesciences, Irvine, CA) porcine; and Sorin (Sorin Group [now LivaNova], London, United Kingdom) and Edwards pericardial. Meta-regression found MTTF was associated with the patient's age, publication year, SVD definition, and valve type. Sorin pericardial valves had significantly lower risk-adjusted MTTF (higher SVD risk), and there were no significant differences in MTTF among the other three valve types.

A primer on using shrinkage to compare in-hospital mortality between centers.

Outcomes of cardiothoracic surgery are usually compared among hospitals or physicians by reporting the frequency of in-hospital mortality. Although there is agreement that these frequencies should be adjusted for case mix, there remains uncertainty about the value of using a statistical model that represents hospitals as random effects as opposed to the conventional approach of fixed effects. For years, the Northern New England Cardiovascular Disease Study Group has compared in-hospital mortality after coronary artery bypass graft surgery among centers using a fixed effects approach. An alternative method using random effects has become increasingly popular, and is the method used by cardiothoracic surgery registries such as the Massachusetts Data Analysis Center. The purpose of this report is to provide a short background on fixed versus random effects modeling, describe the use of shrinkage estimators including empirical Bayes, and illustrate them using data from the Northern New England Cardiovascular Disease Study Group. We conclude that both are acceptable approaches to hospital profiling if done in combination with appropriate risk adjustment.

Clinical evaluation of new heart valve prostheses: update of objective performance criteria.

This article summarizes the long-term clinical results of the Food and Drug Administration-approved heart valves, provides current updates to the objective performance criteria (OPC) used to evaluate new heart valve prostheses, and documents the steps that the International Organization for Standardization Committee used to arrive at the updated OPC. Data were extracted from 19 Food and Drug Administration summaries of safety and effectiveness data reports (31 series) and 56 literature articles (85 series) published from 1999 to 2012. The OPC were calculated for five valve-related complications by valve type (mechanical and bioprosthetic) and valve position (aortic and mitral).

Bayesian stopping guidelines for heart valve premarket approval studies.

OBJECTIVES: The Data Monitoring Committee (DMC) for the premarket approval (PMA) study of a new heart valve prosthesis convenes periodically to review the accumulating results of the study, and determines, among other things, whether there is enough concern with safety to stop the study. Their deliberations are largely subjective, based on their combined experience and expertise, but an objective aid to evaluating complication rates, usually called a stopping rule, is desirable. METHODS: The US Food and Drug Administration has designated objective performance criteria (OPC) for 7 heart valve complications. At the end of the PMA study, when approximately 800 patient-years have been accumulated, the complication rates must compare favorably with the OPC. Given the results to date at an interim review of the data, we use a Bayesian approach to compute the probability of passing the OPC test by the end of study. RESULTS: We provide a method that the DMC can use to predict the probability of passing the OPC test for each complication, and a graphical aid for each number of events, observed at 100 patient-year intervals. CONCLUSIONS: Although the DMC ultimately uses combined experience and expertise to make the decision to stop a PMA valve study, we have provided an objective assessment of the probability of the valve ultimately passing the OPC test to aid in making that decision.

Validation of new york operative mortality risk score for valve and valve/coronary artery bypass grafting operations.

BACKGROUND: New York (NY) valve and valve/coronary artery bypass grafting (CABG) mortality risk models, developed from operations performed in 2007 to 2009, have just been published. These models were validated using NY data from 2004 to 2006. The authors stated that their models "should also be validated by testing them against non-New York populations." Thus, we validated the NY models with the Providence Health & Services-Swedish Health Services (PH&S-SHS) cardiac surgical data and also compared them with The Society of Thoracic Surgeons (STS) mortality risk models. METHODS: The PH&S-SHS validation data set contained 4,021 isolated valve and 2,406 valve/CABG operations, performed from 2008 to 2012. The risk models (NY logistic and score models and the STS models) were recalibrated to equalize the expected and observed number of deaths. Discrimination was tested by C statistics and calibration by Hosmer-Lemeshow statistics. RESULTS: PH&S-SHS operative mortality rates were 2.6% and 5.5% in the valve and valve/CABG operations, respectively, and were lower than the NY rates. The C statistics for the NY logistic valve and valve/CABG models were 0.777 and 0.727, respectively, and were very similar for the NY score models. Calibration was good for the NY valve model (p=0.85), but not for the NY valve/CABG model (p=0.01). The STS models had better discrimination than NY models and good calibration. CONCLUSIONS: The NY logistic and score models for valve operations fit the PH&S-SHS data well with acceptable discrimination and good calibration. The NY models for valve/CABG operations fit the PH&S-SHS data with acceptable discrimination and poor calibration. STS logistic regression models fit the PH&S-SHS data somewhat better.

Effect of hospital culture on blood transfusion in cardiac procedures.

BACKGROUND: In our effort to reduce the use of blood products in cardiac operations in a health care system, we noted variations in transfusion practices among facilities. Interestingly, surgeons practicing at the same hospital had similar transfusion rates. We sought to quantitate the contribution of hospital influence on individual surgeons' transfusion practices. METHODS: Blood transfusion data for coronary artery bypass graft operations at 12 Providence Health & Services facilities between January 2008 and June 2011 were reviewed. Frequency of perioperative blood transfusion, amount of transfusion, components transfused, and timing of transfusions were compared. Variation among surgeons at the same institution vs between institutions was computed based on multilevel mixed-effect logistic and linear regression models. Intraclass correlation coefficients were calculated. RESULTS: A total of 5,744 nonemergency first-time coronary artery bypass graft procedures were performed by 42 not-low volume (n>30 in 2.5 years) surgeons at 12 Providence Health & Services hospitals during the 3.5-year study period. Frequency, amount, timing, and blood component usage were different among facilities but relatively similar for surgeons within a facility. The variance of red blood cell transfusion rate among hospitals (.82) is more than two times that among surgeons practicing within the same hospital (.35). Thus, surgeons contribute 30% to the variation, and 70% of the total variation can be explained by the hospital effect. CONCLUSIONS: In our multihospital system, the hospital that a surgeon practices at plays a larger role in determining blood utilization than the individual surgeon's preference.

Durability of pericardial versus porcine bioprosthetic heart valves.

OBJECTIVES: To compare the probability, and modes, of explantation for Carpentier-Edwards pericardial versus porcine valves. METHODS: Our porcine series began in 1974 and our pericardial series in 1991, with annual prospective follow-up. We used the Kaplan-Meier method and Cox regression for estimation and analysis of patient mortality, and the cumulative incidence function and competing risks regression for estimation and analysis of valve durability. RESULTS: Through the end of 2010, we had implanted 506 porcine and 2449 pericardial aortic valves and 181 porcine and 163 pericardial mitral valves. The corresponding total and maximum follow-up years were 3471 and 24, 11,517 and 18, 864 and 22, and 645 and 9. The corresponding probabilities (cumulative incidence function) of any valve explant were 7%, 8%, 22%, and 8%, and of explant for structural valve deterioration were 4%, 5%, 16%, and 5% at 15 years for the first 3 series and at 8 years for the fourth (pericardial mitral valve) series. Using competing risks regression for structural valve deterioration explant, with age, gender, valve size, and concomitant coronary bypass surgery as covariates, a slight (subhazard ratio, 0.79), but nonsignificant, protective effect was found for the pericardial valve in the aortic position and a greater (subhazard ratio, 0.31) and almost significant (P = .08) protective effect of the pericardial valve in the mitral position. Leaflet tear was responsible for 61% of the structural valve deterioration explants in the porcine series and 46% in the pericardial series. CONCLUSIONS: Using competing risks regression, the pericardial valve had a subhazard ratio for structural valve deterioration explant of less than 1 in both positions, approaching statistical significance in the mitral position. The mode of structural valve deterioration was predominantly leaflet tear for porcine valves and fibrosis/calcification for pericardial valves.