Elliot Wakeam

Gene Expression Profiles in Peripheral Blood Mononuclear Cells Can Distinguish Patients with Non–Small Cell Lung Cancer from Patients with Nonmalignant Lung Disease

Early diagnosis of lung cancer followed by surgery presently is the most effective treatment for non-small cell lung cancer (NSCLC). An accurate, minimally invasive test that could detect early disease would permit timely intervention and potentially reduce mortality. Recent studies have shown that the peripheral blood can carry information related to the presence of disease, including prognostic information and information on therapeutic response. We have analyzed gene expression in peripheral blood mononuclear cell samples including 137 patients with NSCLC tumors and 91 patient controls with nonmalignant lung conditions, including histologically diagnosed benign nodules. Subjects were primarily smokers and former smokers. We have identified a 29-gene signature that separates these two patient classes with 86% accuracy (91% sensitivity, 80% specificity). Accuracy in an independent validation set, including samples from a new location, was 78% (sensitivity of 76% and specificity of 82%). An analysis of this NSCLC gene signature in 18 NSCLCs taken presurgery, with matched samples from 2 to 5 months postsurgery, showed that in 78% of cases, the signature was reduced postsurgery and disappeared entirely in 33%. Our results show the feasibility of using peripheral blood gene expression signatures to identify early-stage NSCLC in at-risk populations.

A 10-gene classifier for distinguishing head and neck squamous cell carcinoma and lung squamous cell carcinoma.

Purpose: The risk of developing metastatic squamous cell carcinoma for patients with head and neck squamous cell carcinoma (HNSCC) is very high. Because these patients are often heavy tobacco users, they are also at risk for developing a second primary cancer, with squamous cell carcinoma of the lung (LSCC) being the most common. The distinction between a lung metastasis and a primary LSCC is currently based on certain clinical and histologic criteria, although the accuracy of this approach remains in question. Experimental Design: Gene expression patterns derived from 28 patients with HNSCC or LSCC from a single center were analyzed using penalized discriminant analysis. Validation was done on previously published data for 134 total subjects from four independent Affymetrix data sets. Results: We identified a panel of 10 genes (CXCL13, COL6A2, SFTPB, KRT14, TSPYL5, TMP3, KLK10, MMP1, GAS1, and MYH2) that accurately distinguished these two tumor types. This 10-gene classifier was validated on 122 subjects derived from four independent data sets and an average accuracy of 96% was shown. Gene expression values were validated by quantitative reverse transcription-PCR derived on 12 independent samples (seven HNSCC and five LSCC). The 10-gene classifier was also used to determine the site of origin of 12 lung lesions from patients with prior HNSCC. Conclusions: The results suggest that penalized discriminant analysis using these 10 genes will be highly accurate in determining the origin of squamous cell carcinomas in the lungs of patients with previous head and neck malignancies.

Failure to rescue in safety-net hospitals: availability of hospital resources and differences in performance.

IMPORTANCE Failure to rescue (FTR), the mortality rate among surgical patients with complications, is an emerging quality indicator. Hospitals with a high safety-net burden, defined as the proportion of patients covered by Medicaid or uninsured, provide a disproportionate share of medical care to vulnerable populations. Given the financial strains on hospitals with a high safety-net burden, availability of clinical resources may have a role in outcome disparities. OBJECTIVES To assess the association between safety-net burden and FTR and to evaluate the effect of clinical resources on this relationship. DESIGN, SETTING, AND PARTICIPANTS A retrospective cohort of 46,519 patients who underwent high-risk inpatient surgery between January 1, 2007, and December 31, 2010, was assembled using the Nationwide Inpatient Sample. Hospitals were divided into the following 3 safety-net categories: high-burden hospitals (HBHs), moderate-burden hospitals (MBHs), and low-burden hospitals (LBHs). Bivariate and multivariate analyses controlling for patient, procedural, and hospital characteristics, as well as clinical resources, were used to evaluate the relationship between safety-net burden and FTR. MAIN OUTCOMES AND MEASURES FTR. RESULTS Patients in HBHs were younger (mean age, 65.2 vs 68.2 years; P = .001), more likely to be of black race (11.3% vs 4.2%, P < .001), and less likely to undergo an elective procedure (39.3% vs 48.6%, P = .002) compared with patients in LBHs. The HBHs were more likely to be large, major teaching facilities and to have high levels of technology (8.6% vs 4.0%, P = .02), sophisticated internal medicine (7.7% vs 4.3%, P = .10), and high ratios of respiratory therapists to beds (39.7% vs 21.1%, P < .001). However, HBHs had lower proportions of registered nurses (27.9% vs 38.8%, P = .02) and were less likely to have a positron emission tomographic scanner (15.4% vs 22.0%, P = .03) and a fully implemented electronic medical record (12.6% vs 17.8%, P = .03). Multivariate analyses showed that HBHs (adjusted odds ratio, 1.35; 95% CI, 1.19-1.53; P < .001) and MBHs (adjusted odds ratio, 1.15; 95% CI, 1.05-1.27; P = .005) were associated with higher odds of FTR compared with LBHs, even after adjustment for clinical resources. CONCLUSIONS AND RELEVANCE Despite access to resources that can improve patient rescue rates, HBHs had higher odds of FTR, suggesting that availability of hospital clinical resources alone does not explain increased FTR rates.

Gene Therapy for Lung Neoplasms

Both advanced-stage lung cancer and malignant pleural mesothelioma are associated with a poor prognosis. Advances in treatment regimens for both diseases have had only a modest effect on their progressive course. Gene therapy for thoracic malignancies represents a novel therapeutic approach and has been evaluated in several clinical trials. Strategies have included induction of apoptosis, tumor suppressor gene replacement, suicide gene expression, cytokine-based therapy, various vaccination approaches, and adoptive transfer of modified immune cells. This review considers the clinical results, limitations, and future directions of gene therapy trials for thoracic malignancies.

Risk and Patterns of Secondary Complications in Surgical Inpatients

IMPORTANCE Little empirical evidence exists on how a first (index) complication influences the risk of specific subsequent secondary complications. Understanding these risks is important to elucidate clinical pathways of failure to rescue or death after postoperative complication. OBJECTIVE To understand patterns of secondary complications in the American College of Surgeons National Surgical Quality Improvement Program (NSQIP). DESIGN, SETTING, AND PARTICIPANTS Matched analysis using a cohort of 890 604 patients undergoing elective inpatient surgery from January 1, 2005, through December 31, 2011, identified in the NSQIP Participant Use Data File. Five index complications were studied: pneumonia, acute myocardial infarction, deep space surgical site infection, bleeding or transfusion event, and acute renal failure. Each patient with an index complication was matched to a control patient based on propensity for the index event and the number of event-free days. Outcomes were compared using conditional logistic regression. MAIN OUTCOMES AND MEASURES Rates of 30-day secondary complications and 30-day mortality. RESULTS Five cohorts were developed, each with 1:1 matching to controls, which were well balanced. Index pneumonia (n = 7947) was associated with increased odds of 30-day reintubation (odds ratio [OR], 17.1; 95% CI, 13.8-21.3; P < .001), ventilatory failure (OR, 15.9; 95% CI, 12.8-19.8; P < .001), sepsis (OR, 7.3; 95% CI, 6.2-8.6; P < .001), and shock (OR, 13.0; 95% CI, 10.4-16.2; P < .001). Index acute myocardial infarction was associated with increased rates of secondary bleeding or transfusion events (OR, 4.3; 95% CI, 3.3-5.8; P < .001), pneumonia (OR, 5.1; 95% CI, 2.6-10.2; P < .001), cardiac arrest (OR, 12.0; 95% CI, 7.5-19.2; P < .001), and reintubation (OR, 11.7; 95% CI, 8.4-16.3; P < .001). Deep space surgical site infection was associated with dehiscence (OR, 30.4; 95% CI, 19.9-46.5; P < .001), sepsis (OR, 13.1; 95% CI, 10.2-16.7; P < .001), shock (OR, 10.6; 95% CI, 6.4-17.7; P < .001), kidney injury (OR, 8.6; 95% CI, 3.9-18.8; P < .001), and acute renal failure (OR, 10.5; 95% CI, 3.8-29.3; P < .001). Index acute renal failure was associated with increased odds of cardiac arrest (OR, 25.3; 95% CI, 9.3-68.6; P < .001), reintubation (OR, 11.3; 95% CI, 7.4-17.1; P < .001), ventilatory failure (OR, 12.4; 95% CI, 8.2-18.8; P < .001), bleeding or transfusion events (OR, 11.3; 95% CI, 6.3-20.5; P < .001), and shock (OR, 11.2; 95% CI, 7.2-17.3; P < .001). CONCLUSIONS AND RELEVANCE This investigation quantified the effect of index complications on patient risk of specific secondary complications. The defined pathways merit investigation as unique targets for quality improvement and benchmarking.

Gene Therapy for Mesothelioma and Lung Cancer

Both malignant pleural mesothelioma and advanced stage lung cancer are associated with a poor prognosis. Unfortunately, current treatment regimens have had only a modest effect on their progressive course. Gene therapy for thoracic malignancies represents a novel therapeutic approach and has been evaluated in a number of clinical trials over the last two decades. Using viral vectors or anti-sense RNA, strategies have included induction of apoptosis, tumor suppressor gene replacement, suicide gene expression, cytokine-based therapy, various vaccination approaches, and adoptive transfer of modified immune cells. This review will consider the clinical results, limitations, and future directions of gene therapy trials for thoracic malignancies.

Hospital-level Variation in Secondary Complications After Surgery.

Objectives:To assess whether hospital rates of secondary complications could serve as a performance benchmark and examine associations with mortality. Background:Failure to rescue (death after postoperative complication) is a challenging target for quality improvement. Secondary complications (complications after a first or “index” complication) are intermediate outcomes in the rescue process that may provide specific improvement targets and give us insight into how rescue fails. Methods:We used American College of Surgeons’ National Surgical Quality Improvement Program data (2008–2012) to define hospital rates of secondary complications after 5 common index complications: pneumonia, surgical site infection (SSI), urinary tract infection, transfusion/bleed events, and acute myocardial infarction (MI). Hospitals were divided into quintiles on the basis of risk- and reliability-adjusted rates of secondary complications, and these rates were compared along with mortality. Results:A total of 524,860 patients were identified undergoing one of the 62 elective, inpatient operations. After index pneumonia, secondary complication rates varied from 57.99% in the highest quintile to 22.93% in the lowest [adjusted odds ratio (OR), 4.64; confidence interval (CI), 3.95–5.45). Wide variation was seen after index SSI (58.98% vs 14.81%; OR, 8.53; CI, 7.41–9.83), urinary tract infection (38.41% vs 8.60%; OR, 7.81; CI, 6.48–9.40), transfusion/bleeding events (27.14% vs 12.88%; OR, 2.54; CI, 2.31–2.81), and acute MI (64.45% vs 23.86%, OR, 6.87; CI, 5.20–9.07). Hospitals in the highest quintile had significantly greater mortality after index pneumonia (10.41% vs 6.20%; OR, 2.17; CI, 1.6–2.94), index MI (18.25% vs 9.65%; OR, 2.67; CI, 1.80–3.94), and index SSI (2.75% vs 0.82%; OR, 3.93; CI, 2.26–6.81). Conclusions:Hospital-level rates of secondary complications (failure to arrest complications) vary widely, are associated with mortality, and may be useful for quality improvement and benchmarking.

Risk Prediction Accuracy Differs for Emergency Versus Elective Cases in the ACS-NSQIP.

Background: Accurate risk estimation is essential when benchmarking surgical outcomes for reimbursement and engaging in shared decision-making. The greater complexity of emergency surgery patients may bias outcome comparisons between elective and emergency cases. Objective: To test whether an established risk modelling tool, the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) predicts mortality comparably for emergency and elective cases. Methods: From the ACS-NSQIP 2011–2012 patient user files, we selected core emergency surgical cases also common to elective scenarios (gastrointestinal, vascular, and hepato-biliary-pancreatic). After matching strategy for Common Procedure Terminology (CPT) and year, we compared the accuracy of ACS-NSQIP predicted mortality probabilities using the observed-to-expected ratio (O:E), c-statistic, and Brier score. Results: In all, 56,942 emergency and 136,311 elective patients were identified as having a common CPT and year. Using a 1:1 matched sample of 37,154 emergency and elective patients, the O:E ratios generated by ACS-NSQIP models differ significantly between the emergency [O:E = 1.031; 95% confidence interval (CI) = 1.028–1.033] and elective populations (O:E = 0.79; 95% CI = 0.77–0.80, P < 0.0001) and the c-statistics differed significantly (emergency c-statistic = 0.927; 95% CI = 0.921–0.932 and elective c-statistic = 0.887; 95% CI = 0.861–0.912, P = 0.003). The Brier score, tested across a range of mortality rates, did not differ significantly for samples with mortality rates of 6.5% and 9% (eg, emergency Brier score = 0.058; 95% CI = 0.048–0.069 versus elective Brier score = 0.057; 95% CI = 0.044–0.07, P = 0.87, among 2217 patients with 6.5% mortality). When the mortality rate was low (1.7%), Brier scores differed significantly (emergency 0.034; 95% CI = 0.027–0.041 versus elective 0.016; 95% CI = 0.009–0.023, P value for difference 0.0005). Conclusion: ACS-NSQIP risk estimates used for benchmarking and shared decision-making appear to differ between emergency and elective populations.

The association of intensivists with failure-to-rescue rates in outlier hospitals: Results of a national survey of intensive care unit organizational characteristics

PURPOSE Critical care is often an integral part of rescue for patients with surgical complications. We sought to understand critical care characteristics predictive of failure-to-rescue (FTR) performance at the hospital level. METHODS Using 2009 to 2011 FTR data from Hospital Compare, we identified 144 outlier hospitals with significantly better/worse performance than the national average. We surveyed intensive care unit (ICU) directors and nurse managers regarding physical structures, patient composition, staffing, care protocols, and rapid response teams (RRTs). Hospitals were compared using descriptive statistics and logistic regression. RESULTS Of 67 hospitals completing the survey, 56.1% were low performing, and 43.9% were high performing. Responders were more likely to be teaching hospitals (40.9% vs 25.0%; P=.05) but were similar to nonresponders in terms of size, region, ownership, and FTR performance. Poor performers were more likely to serve higher proportions of Medicaid patients (68.4% vs 20.7%; P<.0001) and be level 1 trauma centers (55.9% vs 25.9%; P=.02). After controlling for these 2 characteristics, an intensivist on the RRT (adjusted odds ratio, 4.27; confidence interval, 1.45-23.02; P=.005) and an internist on staff in the ICU (adjusted odds ratio, 2.13; P=.04) were predictors of high performance. CONCLUSIONS Intensivists on the RRT and internists in the ICU may represent discrete organizational strategies for improving patient rescue. Hospitals with high Medicaid burden fare poorly on the FTR metric.

Comparing Preoperative Targets to Failure-to-Rescue for Surgical Mortality Improvement

BACKGROUND Failure-to-rescue (FTR or death after postoperative complication) is thought to explain surgical mortality excesses across hospitals, and FTR is an emerging performance measure and target for quality improvement. We compared the FTR population to preoperatively identifiable subpopulations for their potential to close the mortality gap between lowest- and highest-mortality hospitals. STUDY DESIGN Patients undergoing small bowel resection, pancreatectomy, colorectal resection, open abdominal aortic aneurysm repair, lower extremity arterial bypass, and nephrectomy were identified in the 2007 to 2011 Nationwide Inpatient Sample. Lowest- and highest-mortality hospitals were defined using risk- and reliability-adjusted mortality quintiles. Five target subpopulations were established a priori: the FTR population, predicted high-mortality risk (predicted highest-risk quintile), emergency surgery, elderly (>75 years old), and diabetic patients. RESULTS Across the lowest mortality quintile (n=282 hospitals, 56,893 patients) and highest-mortality quintile (282 hospitals, 45,784 patients), respectively, the size of target subpopulations varied only for the FTR population (20.2% vs 22.4%, p=0.002) but not for other subpopulations. Variation in mortality rates across lowest- and highest-mortality hospitals was greatest for the high-mortality risk (7.5% vs 20.2%, p<0.0001) and FTR subpopulations (7.8% vs 18.9%, p<0.0001). The FTR and high-risk populations had comparable sensitivity (81% and 75%) and positive predictive value (19% and 20%, respectively) for mortality. In Monte Carlo simulations, the mortality gap between the lowest- and highest-mortality hospitals was reduced by nearly 75% when targeting the FTR population or the high-risk population, 78% for the emergency surgery population, but less for elderly (51%) and diabetic (17%) populations. CONCLUSIONS Preoperatively identifiable patients with high estimated mortality risk may be preferable to the FTR population as a target for surgical mortality reduction.