A Nationwide Rise in the Use of Stents for Benign Esophageal Perforation.

BACKGROUND: Surgical repair or drainage is the standard treatment for benign esophageal perforation. The United States Food and Drug Administration has approved the use of esophageal stents for the management of malignant esophageal stricture or fistula, or both. We hypothesize that increasing enthusiasm and experience with esophageal stents has led to greater use of stents for the management of benign esophageal perforation. METHODS: We performed a retrospective cohort study (2007 to 2014) of patients with benign esophageal perforation using MarketScan (Thomson Reuters, New York, NY), a commercial claims database. Patients had 6 months of follow-up. Regression was used for risk-adjustment. RESULTS: Benign esophageal perforation was treated in 659 patients (mean age, 49 years; 41% women), comprising surgical repair in 449 (69%), surgical drainage in 110 (17%), and stent in 100 (15%). Stent use increased from 7% in 2007 to 30% in 2014 (p < 0.001 for trend). Over the same period, surgical repair decreased from 71% to 53% (p = 0.001 for trend), but surgical drainage did not change (p = 0.24). After adjustment for other factors that could vary over time, stent use increased by 28% per year (incidence rate ratio, 1.28; 95% confidence interval, 1.17 to 1.39). Changes in risk-adjusted deaths, discharges home, readmissions, or costs over the same period were not significant (all p > 0.05 for trend). CONCLUSIONS: The use of stents for the management of benign esophageal perforation has increased by over fourfold in just 8 years, but short-term outcomes have not changed over time for this population of patients. A national registry for off-label use of esophageal stents may clarify the indications for and risks and benefits of stenting benign esophageal perforations.

Gaps in Guideline-Concordant Use of Diagnostic Tests Among Lung Cancer Patients.

BACKGROUND: Practice guidelines recommend routine use of pulmonary function tests (PFTs), computed tomography (CT), and positron emission tomography (PET) for the workup of resectable lung cancer patients. Little is known about the frequency of guideline concordance in routine practice. METHODS: A cohort study (2007 to 2013) of 15,951 lung cancer patients undergoing lobectomy or pneumonectomy was conducted with MarketScan, a claims database of individuals with employer-provided health insurance. Guideline concordance was defined by claims for PFT within 180 days of resection and for CT and PET within 90 days of resection. Generalized linear models were used to evaluate temporal trends, patient characteristics, and costs associated with guideline-concordant care. RESULTS: Overall, 61% of patients received guideline-concordant care, increasing from 57% in 2007 to 66% in 2013 (p < 0.001). Compared with patients who received guideline-discordant care, patients with guideline-concordant care more frequently underwent repeat testing (PFT: 21% versus 12%, p < 0.001; CT: 46% versus 22%, p < 0.001; PET: 2.3% versus 1.1%, p < 0.001). Health plan-adjusted mean total test-related costs were higher among guideline-concordant patients who underwent repeat testing than patients who did not ($4,304 versus $3,454, p < 0.001). CONCLUSIONS: Forty percent of lung cancer patients treated with surgical procedures did not receive recommended noninvasive cancer staging and physiologic assessment before resection. Guideline concordance was associated with repeat testing, and repeat testing was associated with higher costs. These findings support the need for quality improvement interventions that can increase guideline concordance while curbing potential excess use of diagnostic tests.

External validation of a prediction model for pathologic N2 among patients with a negative mediastinum by positron emission tomography.

BACKGROUND: A prediction model for pathologic N2 (pN2) among lung cancer patients with a negative mediastinum by positron emission tomography (PET) was recently internally validated. Our study sought to determine the external validity of that model. METHODS: A cohort study [2005-2013] was performed of lung cancer patients with a negative mediastinum by PET. Previously published model coefficients were used to estimate the probability of pN2 based on tumor location and size, nodal enlargement by computed tomography (CT), maximum standardized uptake value (SUVmax) of the primary tumor, N1 disease by PET, and pretreatment histology. RESULTS: Among 239 patients, 18 had pN2 [7.5%, 95% confidence interval (CI): 4.5-12%]. Model discrimination was excellent (c-statistic 0.80, 95% CI: 0.75-0.85) and the model fit the data well (P=0.191). The accuracy of the model was as follows: sensitivity 100%, 95% CI: 81-100%; specificity 49%, 95% CI: 42-56%; positive predictive value (PPV) 14%, 95% CI: 8-21%, and negative predictive value (NPV) 100%, 95% CI: 97-100%. CI inspection revealed a significantly higher c-statistic in this external validation cohort compared to the internal validation cohort. The model's apparently poor specificity for patient selection is in fact significantly better than usual care (i.e., aggressive but allowable guideline concordant staging) and minimum guideline mandated selection criteria for invasive staging. CONCLUSIONS: A prediction model for pN2 is externally valid. The high NPV of this model may allow pulmonologists and thoracic surgeons to more comfortably minimize the number of invasive procedures performed among patients with a negative mediastinum by PET.

Minimally invasive resection of early lung cancers.

Low-dose computed tomography (LDCT) screening decreases lung cancer mortality in high-risk individuals and has now been approved and adopted for lung cancer screening in the United States. As more LDCT lung cancer screening programs are implemented, more patients with early-stage lung cancer who could benefit from surgical intervention will be identified. Although lobectomy currently remains the standard of care for early-stage non-small-cell lung cancer (NSCLC), thoracic surgeons are increasingly adopting minimally invasive surgery via thoracoscopy as a viable-and perhaps even preferred-approach for select lung cancer resections. Video-assisted thoracic surgery (VATS) lobectomy has been associated with decreased perioperative morbidity, and similar rates of locoregional recurrence and cancer-free survival can be achieved compared with the standard open surgical procedure. However, as lung cancers are detected at earlier stages, the optimal extent of lung resection for long-term cure continues to be investigated. For patients with very small-sized lung tumors and indolent lesions, cancer-free survival may not necessarily be compromised by undergoing less invasive approaches that intentionally resect less lung tissue, such as sublobar resections (eg, segmentectomy and wedge resection). This review looks at the current data and guidelines for thoracoscopic resection of stage I NSCLC and discusses the potential for limited lung resection in patients with the disease.

VATS versus open surgery for lung cancer resection: moving beyond the incision.

Surgery remains the primary therapy in the treatment of early-stage lung cancer. Traditionally, anatomic resection via open thoracotomy has been the conventional approach, but as experience with minimally invasive lung surgery has increased, video-assisted thoracoscopic surgical (VATS) lobectomy is being performed more commonly for treatment of lung cancer. Proponents of VATS have argued that thoracoscopic resection for lung cancer is not only safe but is also superior to the open approach. VATS enthusiasts even have proposed that this approach should be the standard of care and a metric for quality in lung cancer surgery. Such zeal for promoting a "preferred" technique, however, obscures focus from other time-proven, but perhaps less fashionable, factors that have a tremendous impact on quality and lung cancer outcomes, namely cancer staging and quality of cancer surgery. Rather than debate incisions, thoracic surgeons should advocate for specialty care and surgical quality that assures the best short- and long-term outcomes for patients, regardless of the surgical approach.

Appropriateness of imaging for lung cancer staging in a national cohort.

PURPOSE: Optimizing evidence-based care to improve quality is a critical priority in the United States. We sought to examine adherence to imaging guideline recommendations for staging in patients with locally advanced lung cancer in a national cohort. METHODS: We identified 3,808 patients with stage IIB, IIIA, or IIIB lung cancer by using the national Department of Veterans Affairs (VA) Central Cancer Registry (2004-2007) and linked these patients to VA and Medicare databases to examine receipt of guideline-recommended imaging based on National Comprehensive Cancer Network and American College of Radiology Appropriateness Criteria. Our primary outcomes were receipt of guideline-recommended brain imaging and positron emission tomography (PET) imaging. We also examined rates of overuse defined as combined use of bone scintigraphy (BS) and PET, which current guidelines recommend against. All imaging was assessed during the period 180 days before and 180 days after diagnosis. RESULTS: Nearly 75% of patients received recommended brain imaging, and 60% received recommended PET imaging. Overuse of BS and PET occurred in 25% of patients. More advanced clinical stage and later year of diagnosis were the only clinical or demographic factors associated with higher rates of guideline-recommended imaging after adjusting for covariates. We observed considerable regional variation in recommended PET imaging and overuse of combined BS and PET. CONCLUSION: Receipt of guideline-recommended imaging is not universal. PET appears to be underused overall, whereas BS demonstrates continued overuse. Wide regional variation suggests that these findings could be the result of local practice patterns, which may be amenable to provider education efforts such as Choosing Wisely.

Ninety-day costs of video-assisted thoracic surgery versus open lobectomy for lung cancer.

BACKGROUND: Complications after pulmonary resection lead to higher costs of care. Video-assisted thoracoscopic surgery (VATS) for lobectomy is associated with fewer complications, but lower inpatient costs for VATS have not been uniformly demonstrated. Because some complications occur after discharge, we compared 90-day costs of VATS lobectomy versus open lobectomy and explored whether differential health care use after discharge might account for any observed differences in costs. METHODS: A cohort study (2007-2011) of patients with lung cancer who had undergone resection was conducted using MarketScan-a nationally representative sample of persons with employer-provided health insurance. Total costs reflect payments made for inpatient, outpatient, and pharmacy claims up to 90 days after discharge. RESULTS: Among 9,962 patients, 31% underwent VATS lobectomy. Compared with thoracotomy, VATS was associated with lower rates of prolonged length of stay (PLOS) (3.0% versus 7.2%; p<0.001), 90-day emergency department (ED) use (22% versus 24%; p=0.005), and 90-day readmission (10% versus 12%; p=0.026). Risk-adjusted 90-day costs were $3,476 lower for VATS lobectomy (p=0.001). Differential rates of PLOS appeared to explain this cost difference. After adjustment for PLOS, costs were $1,276 lower for VATS, but this difference was not significant (p=0.125). In the fully adjusted model, PLOS was associated with the highest cost differential (+$50,820; p<0.001). CONCLUSIONS: VATS lobectomy is associated with lower 90-day costs--a relationship that appears to be mediated by lower rates of PLOS. Although VATS may lead to lower rates of PLOS among patients undergoing lobectomy, observational studies cannot verify this assertion. Strategies that reduce PLOS will likely result in cost-savings that can increase the value of thoracic surgical care.

Lung resection outcomes and costs in Washington State: a case for regional quality improvement.

BACKGROUND: A regional quality improvement effort does not exist for thoracic surgery in the United States. To initiate the development of one, we sought to describe temporal trends and hospital-level variability in associated outcomes and costs of pulmonary resection in Washington (WA) State. METHODS: A cohort study (2000-2011) was conducted of operated-on lung cancer patients. The WA State discharge database was used to describe outcomes and costs for operations performed at all nonfederal hospitals within the state. RESULTS: Over 12 years, 8,457 lung cancer patients underwent pulmonary resection across 49 hospitals. Inpatient deaths decreased over time (adjusted p-trend=0.023) but prolonged length of stay did not (adjusted p-trend=0.880). Inflation-adjusted hospital costs increased over time (adjusted p-trend<0.001). Among 24 hospitals performing at least 1 resection per year, 5 hospitals were statistical outliers in rates of death (4 lower and 1 higher than the state average), and 13 were outliers with respect to prolonged length of stay (7 higher and 6 lower than the state average) and costs (5 higher and 8 lower than the state average). When evaluated for rates of death and costs, there were hospitals with fewer deaths/lower costs, fewer deaths/higher costs, more deaths/lower costs, and more deaths/higher costs. CONCLUSIONS: Variability in outcomes and costs over time and across hospitals suggest opportunities to improve the quality and value of thoracic surgery in WA State. Examples from cardiac surgery suggest that a regional quality improvement collaborative is an effective way to meaningfully and rapidly act upon these opportunities.

Surgical and endoscopic palliation of advanced lung cancer.

Pulmonary symptoms from advanced-stage lung cancer often require palliative treatments for compassionate patient care. Although many of these symptoms can result from complications of advanced lung cancer treatment regimens (ie, radiation/chemotherapy-induced lung toxicity) or the patient's underlying comorbid conditions and poor constitution, a significant number of patients have symptoms that originate from the primary tumor itself or from locoregional metastases within the thoracic cavity. These complications from advanced-stage lung cancer can be a serious threat to life and require appropriate intervention.

Exportin 1 inhibition attenuates nuclear factor-kappaB-dependent gene expression.

Activation of nuclear factor (NF)-kappaB is mediated by signal-induced phosphorylation of IkappaBalpha, subsequent IkappaBalpha degradation, and then translocation of unbound NF-kappaB to the nucleus. Termination of gene expression occurs when IkappaBalpha binds NF-kappaB subunits (Rel A) in the nucleus. Leptomycin B specifically inhibits export of IkappaBalpha and the inactive IkappaBalpha/Rel A complex via the nuclear export protein exportin 1. We hypothesized that inhibition of IkappaBalpha nuclear export would increase nuclear IkappaBalpha and attenuate NF-kappaB inflammatory gene expression in pulmonary microvascular endothelial cells. We found that inhibition of exportin 1 causes nuclear accumulation of both endogenous NF-kappaB (Rel A) and IkappaBalpha. IL-1beta causes nuclear accumulation of NF-kappaB (Rel A) but does not increase nuclear IkappaBalpha. Inhibition of exportin 1 before IL-1beta prevented an increase in the nuclear ratio of NF-kappaB (Rel A) to IkappaBalpha and decreases NF-kappaB DNA binding. Furthermore, inhibition of exportin 1 attenuates IL-1beta-induced phosphorylation of IkappaBalpha without affecting IkappaB kinase phosphorylation. Lastly, inhibition of exportin 1 attenuates monocyte chemoattractant protein, IL-8, and intercellular adhesion molecule expression in response to IL-1beta stimulation. We suggest that the decrease in cell activation due to exportin 1 inhibition is a result of termination of NF-kappaB DNA binding due to increased concentration of IkappaBalpha in the nucleus.

Stored packed red blood cell transfusion up-regulates inflammatory gene expression in circulating leukocytes.

SUMMARY BACKGROUND DATA: The transfusion of more than 6 units of packed red blood cells (PRBCs) within the first 12 hours of injury is the strongest independent predictor of multiple organ failure (MOF). This suggests that stored blood contains bioactive factors that may modify the immunoinflammatory response. METHODS: To simulate postinjury major transfusions ex vivo, we obtained whole blood from 4 healthy adults and divided it into four 7-mL groups (I-IV). Group I was not diluted. Group II had 7 mL of 0.9% sterile saline (SS) added. Group III received 3.5 mL each of leuko-reduced stored PRBC and SS (simulating a major transfusion). Group IV received 3.5 mL each of SS and a hemoglobin-based oxygen carrier (PolyHeme) to evaluate the effects of hemoglobin alone. The hemoglobin content in groups III and IV was measured to be equal. Total leukocyte RNA was purified, and its gene array profiles were obtained. RESULTS: Of the 56,475 oligonucleotide probe sets interrogated, 415 were statistically different (P < 0.001). Fourteen of the 415 probe sets were inflammatory-related. The PRBC group had a significantly different expression profile compared with the others and included up-regulation of the interleukin-8, toll-like receptor 4, cryropyrin, prostaglandin-endoperoxide synthase-2, and heparinase genes. CONCLUSIONS: PRBCs activate inflammatory genes in circulating leukocytes, which may be central to the pathogenesis of the adverse inflammatory responses that lead to postinjury MOF.

Normal mesenteric lymph blunts the pulmonary inflammatory response to endotoxin.

BACKGROUND: Mesenteric lymph may provide the mechanistic link between gut ischemia and acute lung injury after hemorrhagic shock (HS). Studies have focused on the toxic mediators that develop in the post-shock mesenteric lymph (PSML). However, a complementary possibility is that there is loss of protective mediators found in pre-shock normal mesenteric lymph (NML) after HS. We hypothesize that NML protects against inflammatory insults to the pulmonary endothelium and that this effect is lost in PSML. MATERIALS AND METHODS: Primary human pulmonary endothelial cells (HMVECs) were incubated with NML or PSML collected from rats subjected to HS and resuscitation and then stimulated with 20 ng/mL LPS. ICAM-1 surface expression was measured by flow cytometry. In subsequent experiments, lipoproteins were extracted from NML before incubation and LPS-induced ICAM-1 expression determined. RESULTS: Mean fluorescent intensity (MFI) of LPS-induced ICAM-1 in NML and PSML treated HMVECs were 10.1 +/- 2.3 versus 27.7 +/- 0.83, respectively (P < 0.05). This represented at 71% decrease in ICAM-1 expression by NML compared to ICAM-1 expression in LPS-induced controls (MFI: 34.6 +/- 6.9). Lipoprotein extraction from NML abolished this protective effect (MFI: 31.2 +/- 5.3 versus Control + LPS: 33.5 +/- 3.6, P > 0.05). Baseline ICAM-1 levels were not significantly different among control, NML, and PSML groups. CONCLUSION: Lipoproteins in NML contain anti-inflammatory properties that decrease ICAM-1 expression induced by LPS in pulmonary endothelium. Decreased protective lipoproteins after HS and resuscitation may contribute to the toxicity associated with PSML from the ischemic gut.

Bioactivity of postshock mesenteric lymph depends on the depth and duration of hemorrhagic shock.

Mesenteric hypoperfusion due to circulatory shock is a key event in the pathogenesis of subsequent distant organ injury. Postshock mesenteric lymph (PSML) has been shown to contain proinflammatory mediators elaborated from the ischemic gut. We hypothesize that the relative bioactivity of PSML depends on the depth and duration of circulatory shock. To first determine the timing of PSML bioactivity, we subjected rats to hemorrhagic shock (30 mm Hg x 45 min) and then resuscitation with 50 vol% of shed blood and normal saline (4x shed blood) over 2 h. Mesenteric lymph was collected hourly up to 6 h after shock. Superoxide release was measured from human neutrophils (polymorphonuclear neutrophils [PMNs]) incubated with lymph fractions collected from each of the hourly time points. Rats were then subjected to four different shock variations: (1) 30 mm Hg x 45 min, (2) 30 mm Hg x 15 min, (3) 45 mm Hg x 45 min, and (4) 45 mm Hg x 15 min, and were resuscitated. PSML flow depends on depth of shock, but not duration of shock or resuscitation volume. Maximal PSML bioactivity, as measured by PMN priming for the respiratory burst, occurred during the third postshock hour, which correlated with peak lymph flow rate. PSML bioactivity was greatest with 30 mm Hg x 45 min, followed by 30 mm Hg x 15 min, 45 mm Hg x 45 min, and 45 mm Hg x 15 min. Hemorrhagic shock provokes the release of bioactive agents in PSML that is dependent on both depth and duration of shock.

Hemoglobin-based oxygen carriers in trauma care: scientific rationale for the US multicenter prehosptial trial.

BACKGROUND: The greatest need for blood substitutes worldwide is in patients with unanticipated acute blood loss, and trauma is the most likely scenario. The blood substitutes reaching advanced clinical trials today are red blood cell (RBC) substitutes derived from hemoglobin. The hemoglobin-based oxygen carriers (HBOCs) tested currently in advanced clinical trials are polymerized hemoglobin solutions. METHODS: In the USA, the standard approach to restoring oxygen delivery for hemorrhagic shock has been crystalloid administration to expand intravascular volume, followed by stored RBCs for critical anemia. Allogeneic RBCs, however, may have adverse immunoinflammatory effects that increase the risk of postinjury multiple organ failure (MOF). Phase II in hospital clinical trials, as well as in vitro and in vivo work, suggest that resuscitation with an HBOC--in lieu of stored RBCs--attenuates the systemic inflammatory response invoked in the pathogenesis of MOF. Specifically, an HBOC has been shown to obviate stored RBC-provoked polymorphonuclear neutrophil (PMN) priming, endothelial activation, and systemic release of interleukins (IL) 6, 8, and 10. In a 2-event rodent study of shock-induced PMN-mediated acute respiratory distress syndrome (ARDS), the simulated prehospital administration of an HBOC markedly attenuated lung injury. RESULTS: Based on this background and work by others, we have initiated a US multicenter prehospital trial in which severely injured patients with major blood loss [systolic blood pressure (SBP)500 injured patients have been enrolled in this multicenter trial, and the final interim analyses support the original target of 720.

Polymerized hemoglobin induces heme oxygenase-1 protein expression and inhibits intercellular adhesion molecule-1 protein expression in human lung microvascular endothelial cells.

BACKGROUND: Our clinical trials using a polymerized hemoglobin solution (PolyHb) as a red cell substitute in severely injured patients suggested that this hemoglobin-based oxygen carrier has a systemic antiinflammatory effect. Heme oxygenase-1 (HO-1) has recently been shown to be cytoprotective, and is known to be induced by heme moieties. We investigated the effects of this hemoglobin-based oxygen carrier on HO-1 induction and proinflammatory activation of pulmonary endothelium. STUDY DESIGN: Human lung microvascular endothelial cells were grown to confluence and preincubated with either cell media (control) or with an equal volume mixture of polymerized hemoglobin/cell media (experimental). The cell cultures were subsequently stimulated with lipopolysaccharide. HO-1 expression was detected by protein immunoblot and further quantified by ELISA; intercellular adhesion molecule-1 protein expression was measured by flow cytometry. RESULTS: Polymerized hemoglobin induced synthesis of HO-1 protein in human lung microvascular endothelial cells and, concurrently, inhibited lipopolysaccharide-induced intercellular adhesion molecule-1 protein cell surface expression. CONCLUSIONS: Polymerized hemoglobin attenuates lipopolysaccharide-stimulated expression of intercellular adhesion molecule-1 protein, which is associated with upregulation of the cytoprotective protein HO-1 in human pulmonary endothelial cells. This antiinflammatory effect offers a novel mechanism by which hemoglobin-based oxygen carrier solutions may be exploited therapeutically as resuscitative fluids.