Christine V. Kinnier

Examination of national lymph node evaluation practices for adult extremity soft tissue sarcoma

Lymph node evaluation recommendations for extremity soft tissue sarcoma (ESTS) are absent from national guidelines. Our objectives were (1) to assess rates and predictors of nodal evaluation, and (2) to assess rates and predictors of nodal metastases.

Successful bilateral lung transplantation for lymphangiomatosis.

Lymphangiomatosis is a rare disease of lymphatic proliferation for which no adequate treatment is known. We report the first successful case of bilateral lung transplantation for the treatment of end‐stage pulmonary lymphangiomatosis. A successful outcome was achieved with continued survival beyond 4 years posttransplant and stable lung function. The primary obstacles to significant gains in pulmonary function were thoracic, skeletal and abdominal lymphangiomatosis, which led to pulmonary restriction. Our report demonstrates that pulmonary lymphangiomatosis should be included among those diseases for which lung transplantation is considered potentially beneficial treatment but also emphasizes the importance of screening patients carefully for chest wall and abdominal lymphangiomas that may impede recovery.

Association between hospital imaging use and venous thromboembolism events rates based on clinical data.

Objective:The objective was to assess the presence and extent of venous thromboembolic (VTE) surveillance bias using high-quality clinical data. Background:Hospital VTE rates are publicly reported and used in pay-for-performance programs. Prior work suggested surveillance bias: hospitals that look more for VTE with imaging studies find more VTE, thereby incorrectly seem to have worse performance. However, these results have been questioned as the risk adjustment and VTE measurement relied on administrative data. Methods:Data (2009–2010) from 208 hospitals were available for analysis. Hospitals were divided into quartiles according to VTE imaging use rates (Medicare claims). Observed and risk-adjusted postoperative VTE event rates (regression models using American College of Surgeons National Surgical Quality Improvement Project data) were examined across VTE imaging use rate quartiles. Multivariable linear regression models were developed to assess the impact of hospital characteristics (American Hospital Association) and hospital imaging use rates on VTE event rates. Results:The mean risk-adjusted VTE event rates at 30 days after surgery increased across VTE imaging use rate quartiles: 1.13% in the lowest quartile to 1.92% in the highest quartile (P < 0.001). This statistically significant trend remained when examining only the inpatient period. Hospital VTE imaging use rate was the dominant driver of hospital VTE event rates (P < 0.001), as no other hospital characteristics had significant associations. Conclusions:Even when examined with clinically ascertained outcomes and detailed risk adjustment, VTE rates reflect hospital imaging use and perhaps signify vigilant, high-quality care. The VTE outcome measure may not be an accurate quality indicator and should likely not be used in public reporting or pay-for-performance programs.

Innate immune activation by the viral PAMP poly I:C potentiates pulmonary graft-versus-host disease after allogeneic hematopoietic cell transplant

Respiratory viral infections cause significant morbidity and increase the risk for chronic pulmonary graft-versus-host disease (GVHD) after hematopoietic cell transplantation (HCT). Our overall hypothesis is that local innate immune activation potentiates adaptive alloimmunity. In this study, we hypothesized that a viral pathogen-associated molecular pattern (PAMP) alone can potentiate pulmonary GVHD after allogeneic HCT. We, therefore, examined the effect of pulmonary exposure to polyinosinic:polycytidylic acid (poly I:C), a viral mimetic that activates innate immunity, in an established murine HCT model. Poly I:C-induced a marked pulmonary T cell response in allogeneic HCT mice as compared to syngeneic HCT, with increased CD4+ cells in the lung fluid and tissue. This lymphocytic inflammation persisted at 2 weeks post poly I:C exposure in allogeneic mice and was associated with CD3+ cell infiltration into the bronchiolar epithelium and features of epithelial injury. In vitro, poly I:C enhanced allospecific proliferation in a mixed lymphocyte reaction. In vivo, poly I:C exposure was associated with an early increase in pulmonary monocyte recruitment and activation as well as a decrease in CD4+FOXP3+ regulatory T cells in allogeneic mice as compared to syngeneic. In contrast, intrapulmonary poly I:C did not alter the extent of systemic GVHD in either syngeneic or allogeneic mice. Collectively, our results suggest that local activation of pulmonary innate immunity by a viral molecular pattern represents a novel pathway that contributes to pulmonary GVHD after allogeneic HCT, through a mechanism that includes increased recruitment and maturation of intrapulmonary monocytes.

Comparison of postoperative complication risk prediction approaches based on factors known preoperatively to surgeons versus patients

BACKGROUND Estimating the risk of postoperative complications can be performed by surgeons with detailed clinical information or by patients with limited information. Our objective was to compare three estimation models: (1) the All Information Model, using variables available from the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP); (2) the Surgeon Assessment Model, using variables available to surgeons preoperatively, and (3) the Patient-Entered Model, using information that patients know about their own health. STUDY DESIGN Using the ACS NSQIP 2011 data for general and colon surgery, standard ACS NSQIP regression methods were used to develop models. Each model examined Overall and Serious Morbidity as outcomes. The models were assessed using the c-statistic, Hosmer-Lemshow statistic, and Akaike Information Criterion. RESULTS The overall morbidity rate was 13.0%, and the serious morbidity rate was 10.5% for patients undergoing general surgery (colon surgery: 31.8% and 26.0%, respectively). There was a small decrement in the c-statistic as the number of predictors decreased. The Akaike Information Criterion likelihood ratio increased between the All Information and Surgeon Assessment models, but decreased in the Patient-Entered Model. The Hosmer-Lemshow statistic suggested good model fit for five colon surgery models and one general surgery model. CONCLUSION Although a small decline in model performance was observed, the magnitude suggests that it may not be clinically meaningful as the risk predictions offered are superior to simply providing unadjusted complications rates. The Surgeon Assessment and Patient-Entered models with fewer predictors can be used with relative confidence to predict a patients risk.

Evaluation of hospital factors associated with hospital postoperative venous thromboembolism imaging utilisation practices

Background Recent research suggests that hospital rates of postoperative venous thromboembolism (VTE) are subject to surveillance bias: the more hospitals ‘look for’ VTE, the more VTE they find. However, little is known about what drives variation in hospital VTE imaging rates. We conducted an observational study to examine hospital and market characteristics that were associated with hospital-level rates of postoperative VTE imaging, focusing on hospitals with particularly high rates. Methods For Medicare beneficiaries undergoing 11 major operations (2009–2010) at 2820 hospitals, hospital-level postoperative VTE imaging use rates were calculated. Hospital characteristics associated with hospital VTE imaging use rates were examined including case severity, size, ownership, VTE process measure adherence, accreditations, staffing, malpractice environment, and county market factors. Associations between explanatory variables and VTE imaging rates were assessed using quantile regressions at the 25th, median, 75th and 90th quantiles. Results Mean postoperative VTE imaging rates ranged from 85.26 (SD=67.38) per 1000 discharges in the lowest quartile of hospitals ranked by VTE imaging rates to 168.86 (SD=76.70) in the highest quartile. Drivers of high imaging rates at the 90th quantile were high resident-to-bed ratio (coefficient=51.35, p<0.01), Joint Commission accreditation (coefficient=19.05, p<0.01), presence of other hospitals in the same market with high imaging rates (coefficient=15.29, p<0.01), average case severity (coefficient=11.97, p<0.01), local malpractice costs (coefficient=11.29, p<0.01), and market competition (coefficient=11.03, p<0.01). Conclusions Hospital teaching status, resident-to-bed ratio, malpractice environment and local market factors drive hospital postoperative VTE imaging use, suggesting that non-clinical forces predominantly drive hospital VTE imaging practices.

Innate immune activation potentiates alloimmune lung disease independent of chemokine (C-X-C motif) receptor 3

BACKGROUND Pulmonary graft-versus-host disease (GVHD) after hematopoietic cell transplant (HCT) and allograft rejection after lung transplant are parallel immunologic processes that lead to significant morbidity and mortality. Our murine model of pulmonary GVHD after inhaled lipopolysaccharide (LPS) suggests that innate immune activation potentiates pulmonary transplant-related alloimmunity. We hypothesized that the chemokine (C-X-C motif) receptor 3 (CXCR3) receptor is necessary for the development of LPS-induced pulmonary GVHD. METHODS Recipient mice underwent allogeneic or syngeneic HCT, followed by inhaled LPS. CXCR3 inhibition was performed by using CXCR3-knockout donors or by systemic anti-CXCR3 antibody blockade. Pulmonary histopathology, cellular sub-populations, cytokine proteins, and transcripts were analyzed. RESULTS Compared with the lungs of LPS-unexposed and syngeneic controls, lungs of LPS-exposed allogeneic HCT mice demonstrated prominent lymphocytic peri-vascular and peri-bronchiolar infiltrates. This pathology was associated with increased CD4(+) and CD8(+) T cells as well as an increase in CXCR3 expression on T cells, a 2-fold upregulation of CXCR3 transcript, and a 4-fold increase in its ligand CXCL10/Interferon gamma-induced protein 10 kDa (IP-10). CXCR3 inhibition using gene-knockout strategy or antibody blockade did not change the severity of pulmonary pathology, with a mean pathology score of 6.5 for sufficient vs 6.5 for knockout (p = 1.00) and a mean score of 6.8 for antibody blockade vs 7.4 for control (p = 0.46). CXCR3 inhibition did not prevent CD3 infiltration or prevent production of interleukin-12p40 or significantly change other Th1, Th2, or Th17 cytokines in the lung. CONCLUSIONS In the setting of allogeneic HCT, innate immune activation by LPS potentiates pulmonary GVHD through CXCR3-independent mechanisms. Clinical strategies focused on inhibition of CXCR3 may prove insufficient to ameliorate transplant-related lung disease.

Original pre-clinical scienceInnate immune activation potentiates alloimmune lung disease independent of chemokine (C-X-C motif) receptor 3

BACKGROUND Pulmonary graft-versus-host disease (GVHD) after hematopoietic cell transplant (HCT) and allograft rejection after lung transplant are parallel immunologic processes that lead to significant morbidity and mortality. Our murine model of pulmonary GVHD after inhaled lipopolysaccharide (LPS) suggests that innate immune activation potentiates pulmonary transplant-related alloimmunity. We hypothesized that the chemokine (C-X-C motif) receptor 3 (CXCR3) receptor is necessary for the development of LPS-induced pulmonary GVHD. METHODS Recipient mice underwent allogeneic or syngeneic HCT, followed by inhaled LPS. CXCR3 inhibition was performed by using CXCR3-knockout donors or by systemic anti-CXCR3 antibody blockade. Pulmonary histopathology, cellular sub-populations, cytokine proteins, and transcripts were analyzed. RESULTS Compared with the lungs of LPS-unexposed and syngeneic controls, lungs of LPS-exposed allogeneic HCT mice demonstrated prominent lymphocytic peri-vascular and peri-bronchiolar infiltrates. This pathology was associated with increased CD4(+) and CD8(+) T cells as well as an increase in CXCR3 expression on T cells, a 2-fold upregulation of CXCR3 transcript, and a 4-fold increase in its ligand CXCL10/Interferon gamma-induced protein 10 kDa (IP-10). CXCR3 inhibition using gene-knockout strategy or antibody blockade did not change the severity of pulmonary pathology, with a mean pathology score of 6.5 for sufficient vs 6.5 for knockout (p = 1.00) and a mean score of 6.8 for antibody blockade vs 7.4 for control (p = 0.46). CXCR3 inhibition did not prevent CD3 infiltration or prevent production of interleukin-12p40 or significantly change other Th1, Th2, or Th17 cytokines in the lung. CONCLUSIONS In the setting of allogeneic HCT, innate immune activation by LPS potentiates pulmonary GVHD through CXCR3-independent mechanisms. Clinical strategies focused on inhibition of CXCR3 may prove insufficient to ameliorate transplant-related lung disease.

Postoperative Venous Thromboembolism Outcomes Measure – Analytic Exploration of Potential Misclassification of Hospital Quality Due to Surveillance Bias

Several studies have demonstrated the presence of surveillance bias in the Agency for Healthcare Research and Quality Patient Safety Indicator #12 (PSI12), Postoperative Venous Thromboembolism (VTE), in which hospitals with higher rates of VTE-related diagnostic imaging also have disproportionately higher PSI12 rates.1 Surveillance bias in PSI12 raises a subsequent question that has received less attention: how accurate is PSI12 in (a) identifying truly poor-quality hospitals (“true positives” for poor VTE outcomes) versus those that only appear to be poor-quality hospitals due to high VTE-imaging rates (“false positives”); and (b) identifying truly high-quality hospitals with low VTE rates (“true negatives”) versus those that only appear to be high-quality hospitals because of inappropriately low VTE imaging rates (“false negatives”). Because incentives are tied to PSI12, it is important to understand the PSI12s potential for hospital misclassification with respect to quality. In the absence of a universal screening protocol, VTE-imaging rates are generally below 100%. Imaging is not performed at random, but targeted at patients who are symptomatic or at greater risk for VTE such that patients are prioritized for imaging based on observable signs and symptoms of VTE and factors. This implies that there are diminishing returns to VTE-imaging. Because of this targeting/prioritization, imaging will reveal clinically-significant VTE until imaging rates exceed the true incidence of clinically-significant VTE. At that point, additional imaging will detect non-clinically-significant clots2 for which treatment may not have a favorable cost-effectiveness profile. Because the PSI12 numerator counts all diagnosed VTE events as identified on the basis of International Classification of Diseases, 9th Revision (ICD-9-CM) codes,3 higher VTE-imaging rates can inflate the numerator because ICD-9-CM codes do not differentiate between clinically-significant and subclinical VTE. If subclinical VTE could be reliably distinguished from clinically-significant VTE, subclinical events could be excluded from the numerator to eliminate this source of surveillance bias. There is, however, another problem with PSI12—one which lurks in the denominator: “all surgical discharges age 18 and older defined by specific DRGs or MS-DRGs and an ICD-9-CM code for an operating room procedure.”3 For any rate measure, all observations in the denominator should be at risk for experiencing the numerator event. In PSI2, the numerator counts patients diagnosed with VTE, but VTE diagnosis depends on imaging. Although all surgical patients are at risk for postoperative VTE, not all patients are at equal risk for imaging due to practice variations, differences in organizational/institutional characteristics (e.g. technological capacity and radiology staffing) and/or heterogeneity in hospital culture. The PSI12 denominator represents the actual population at risk of VTE diagnosis only under 100% screening. To illustrate how this denominator problem along with the inability to differentiate and exclude subclinical VTE from clinically-significant events in the numerator can jointly lead to inaccurate conclusions about hospital quality, consider two hypothetical hospitals, Hospital-X and Hospital-Z. The x-axes in Figure 1 show the number of patients in Hospital-X and Hospital-Z that are in the PSI12 denominator. The primary y- axis shows the true, underlying incidence of VTE in each hospital. In practice, this true rate is unobservable, but for the purposes of this hypothetical illustration, we assume it is known. Dark-shaded regions depict the proportion of each hospitals denominator that develops clinically-significant VTE, while light-shaded regions depict the proportion developing subclinical VTE. Hospital-X has better VTE-related quality of care: its underlying clinically-significant VTE incidence is 20%. Hospital-Z has poorer quality-of-care: its clinically-significant VTE incidence is 40%. Both hospitals have a 30% incidence of subclinical VTE. Figure 1 Hypothetical Illustration of Hospital Misclassification Due to Surveillance Bias in PSI12 The secondary y-axis shows the number of patients that receive VTE-imaging. At 10% surveillance (Line A), both hospitals have identical PSI12 rates of 10%, although Hospital-X has higher quality than Hospital-Z. In Hospital-X, 50% of clinically-significant VTE went undetected, compared to 75% in Hospital-Z. Based on PSI12, both hospitals not only appear the same, but they appear to have better VTE outcomes than they actually do. At 20% surveillance (Line 2), both hospitals have PSI12 rates of 20%. This captures all clinically-significant VTE in Hospital-X, but 50% of clinically-significant VTE remain undetected in Hospital-Z. At 40% surveillance (Line 3), both hospitals have PSI12 rates of 40%. However, in Hospital-X, this is comprised of 20 clinically-significant VTE plus an additional 20 subclinical VTE. In Hospital-Z all 40 cases were clinically-significant. At 100% screening (Line 4), the observed PSI12 rates of Hospital X and Z are 50% and 70%, respectively. The relative ordering is accurate (Hospital-X has lower rates of VTE than Hospital-Z), although VTE rates are inflated due to inclusion of both clinically-significant and subclinical VTE. By means of stylized construction, Figure 1 reveals that, holding underlying clinical quality constant, PSI12 may not reflect true clinical quality due to variation in VTE imaging rates. Furthermore, holding surveillance rates constant, PSI12 rates can still fail to reflect true levels of clinical quality due to unobserved heterogeneity in underlying VTE incidence across hospitals. The analysis of surveillance bias in PSI12 is not simply an empirical or theoretical exercise in measurement science. The potential for PSI12 to misclassify hospitals with respect to quality of care can lead to unintended consequences on multiple levels. Consumers may unwittingly choose “the wrong” hospital based on ostensibly low PSI12 rates if those rates are low because of inadequate surveillance. By the same token, consumers may reject higher quality hospitals because of ostensibly higher PSI12 rates that are high because of more intense surveillance. Payers may misdirect financial rewards towards “false negative” hospitals (worse outcomes than reflected in PSI12) away from “false positive” (better outcomes than reflected in PSI12). Finally, inefficiency in hospital resource allocation may ensue if hospital quality improvement (QI) leaders/teams use PSI12 to guide investment in QI activities. Developing an empirical approach to quantify the magnitude of misclassification in PSI12 due to surveillance bias hinges on the existence of a gold standard for measuring true underlying VTE incidence that is independent of VTE surveillance imaging. To our knowledge, no such gold standard exists. Nevertheless, PSI12 can be improved if administrative codes are developed and implemented that enable reliable identification and exclusion of subclinical VTE from the measure numerator. Regardless, stakeholders should consider the limitations of this measure when using PSI12 as a basis for evaluating hospital quality.

The Need to Revisit VTE Quality Measures

Objectives To prospectively determine the incidence of venous thromboembolism (VTE) following major head and neck surgery. At the midpoint of enrollment, an interim analysis was performed to determine if it was ethical to continue this study as an observational study without routine anticoagulation. Design Prospective, observational cohort study. Setting Academic surgical center. Patients The interim analysis comprised 47 subjects.