Spatial heterogeneity of radiolabeled choline positron emission tomography in tumors of patients with non-small cell lung cancer: first-in-patient evaluation of [18F]fluoromethyl-(1,2-2H4)-choline.

Purpose: The spatio-molecular distribution of choline and its metabolites in tumors is highly heterogeneous. Due to regulation of choline metabolism by hypoxic transcriptional signaling and other survival factors, we envisage that detection of such heterogeneity in patient tumors could provide the basis for advanced localized therapy. However, non-invasive methods to assess this phenomenon in patients are limited. We investigated such heterogeneity in Non-Small Cell Lung Cancer (NSCLC) with [18F]fluoromethyl-(1,2-2H4) choline ([18F]D4-FCH) and positron emission tomography/computed tomography (PET/CT). Experimental design: [18F]D4-FCH (300.5±72.9MBq [147.60-363.6MBq]) was administered intravenously to 17 newly diagnosed NSCLC patients. PET/CT scans were acquired concurrently with radioactive blood sampling to permit mathematical modelling of blood-tissue transcellular rate constants. Comparisons were made with biopsy-derived choline kinase-α (CHKα) expression and diagnostic [18F]fluorodeoxyglucose ([18F]FDG) scans. Results: Oxidation of [18F]D4-FCH to [18F]D4-fluorobetaine was suppressed (48.58±0.31% parent at 60 min) likely due to the deuterium isotope effect embodied within the design of the radiotracer. Early (5 min) and late (60 min) images showed specific uptake of tracer in all 51 lesions (tumors, lymph nodes and metastases) from 17 patients analyzed. [18F]D4-FCH-derived uptake (SUV60max) in index primary lesions (n=17) ranged between 2.87-10.13; lower than that of [18F]FDG PET [6.89-22.64]. Mathematical modelling demonstrated net irreversible uptake of [18F]D4-FCH at steady-state, and parametric mapping of the entire tumor showed large intratumorally heterogeneity in radiotracer retention, which is likely to have influenced correlations with biopsy-derived CHKα expression. Conclusions: [18F]D4-FCH is detectable in NSCLC with large intratumorally heterogeneity, which could be exploited in the future for targeting localized therapy.

Successful aortic aneurysm repair in a woman with severe von Willebrand (type 3) disease.

von Willebrand disease type 3 (VWD3) is a rare but the most severe form of von Willebrand disease; it is due to almost complete lack of von Willebrand factor activity (VWF:RCo). It is inherited as autosomal recessive trait; whilst heterozygote carriers have mild, or no symptoms, patients with VWD3 show severe bleeding symptoms. In the laboratory, this is characterised by undetectable VWF:Ag, VWF:RCo, and reduced levels of factor VIII < 0.02 IU/dL. The bleeding is managed with von Willebrand/FVIII factor concentrate replacement therapy. In this rare but challenging case we report on the successful excision and repair of an ascending aortic aneurysm following adequate VWF/FVIII factor concentrate replacement using Haemate-P.

The right ventricular annular velocity reduction caused by coronary artery bypass graft surgery occurs at the moment of pericardial incision.

BACKGROUND: Right ventricular (RV) long-axis function is known to be depressed after cardiac surgery, but the mechanism is not known. We hypothesized that intraoperative transesophageal echocardiography could pinpoint the time at which this happens to help narrow the range of plausible mechanisms. METHOD: Transthoracic echocardiography was conducted in 33 patients before and after elective coronary artery bypass graft. In an intensively monitored cohort of 9 patients, we also monitored RV function intraoperatively using serial pulsed wave tissue Doppler (PW TD) transesophageal echocardiography. RESULTS: There was no significant difference in myocardial velocities from the onset of the operation up to the beginning of pericardial incision, change in RV PW TD S' velocities 3% +/- 2% (P = not significant). Within the first 3 minutes of opening the pericardium, RV PW TD S' velocities had reduced by 43% +/- 17% (P < .001). At 5 minutes postpericardial incision, 2 minutes later, the velocities had more than halved, by 54% +/- 11% (P < .0001). Velocities thereafter remained depressed throughout the operation, with final intraoperative S' reduction being 61% +/- 11% (P < .0001). One month after surgery, in the full 33-patient cohort, transthoracic echocardiogram data showed a 55% +/- 12% (P < .0001) reduction in RV S' velocities compared with preoperative values. CONCLUSIONS: Minute-by-minute monitoring during cardiac surgery reveals that, virtually, all the losses in RV systolic velocity occurs within the first 3 minutes after pericardial incision. Right ventricular long-axis reduction during coronary bypass surgery results not from cardiopulmonary bypass but rather from pericardial incision.

Stentless Versus Stented Bioprosthetic Aortic Valves: A Consensus Statement of the International Society of Minimally Invasive Cardiothoracic Surgery (ISMICS) 2008.

OBJECTIVE: : The purpose of this consensus conference was to determine whether stentless bioprosthetic valves improve clinical and resource outcomes compared with stented valves in patients undergoing aortic valve replacement, and to outline evidence-based recommendations for the use of stentless and stented bioprosthetic valves in adult aortic valve replacement. METHODS: : Before the consensus conference, the best available evidence was reviewed in that systematic reviews, randomized trials, and nonrandomized trials were considered in descending order of validity and importance. At the consensus conference, evidence-based statements were created, and consensus processes were used to determine the ensuing recommendations. The American Heart Association/American College of Cardiology system was used to label the level of evidence and class of recommendation. RESULTS AND RECOMMENDATIONS: : Seventeen randomized studies published in 23 articles involving 1317 patients, and 14 nonrandomized trial published in 18 articles involving 2485 patients were included in the meta-analysis and consensus conference. All randomized trials inserted the stentless bioprosthetic valves in the subcoronary configuration. The consensus panel agreed upon the following statements and recommendations in patients undergoing aortic valve replacement:Because there were no randomized control trial comparing subcoronary stentless prosthetic valve and root replacement, the following recommendations are derived from expert opinion:

Stentless versus stented bioprosthetic aortic valves: a systematic review and meta-analysis of controlled trials.

OBJECTIVE: : This meta-analysis sought to determine whether stentless bioprosthetic valves improve clinical and resource outcomes compared with stented valves in patients undergoing aortic valve replacement. METHODS: : A comprehensive search was undertaken to identify all randomized and nonrandomized controlled trials comparing stentless to stented bioprosthetic valves in patients undergoing aortic valve replacement available up to March 2008. The primary outcomes were clinical and resource outcomes in randomized controlled trial (RCT). Secondary outcomes clinical and resource outcomes in nonrandomized controlled trial (non-RCT). Odds ratios (OR), weighted mean differences (WMD), or standardized mean differences and their 95% confidence intervals (CI) were analyzed as appropriate. RESULTS: : Seventeen RCTs published in 23 articles involving 1317 patients, and 14 non-RCTs published in 18 articles involving 2485 patients were included in the meta-analysis. For the primary analysis of randomized trials, mortality for stentless versus stented valve groups did not differ at 30 days (OR 1.36, 95% CI 0.68-2.72), 1 year (OR 1.01, 95% CI 0.55-1.85), or 2 to 10 years follow-up (OR 0.82, 95% CI 0.50-1.33). Aggregate event rates for all-cause mortality at 30 days were 3.7% versus 2.9%, at 1 year were 5.5% versus 5.9% and at 2 to 10 years were 17% versus 19% for stentless versus stented valve groups, respectively. Stroke or neurologic complications did not differ between stentless (3.6%) and stented (4.0%) valve groups. Risk of prosthesis-patient mismatch was numerically lower in the stentless group (11.0% vs. 31.3%, OR 0.30, 95% CI 0.05-1.66), but this parameter was reported in few trials and did not reach statistical significance. Effective orifice area index was significantly greater for stentless aortic valve compared with stented valves at 30 days (WMD 0.12 cm/m), at 2 to 6 months (WMD 0.15 cm/m), and at 1 year (WMD 0.26 cm/m). Mean gradient at 1 month was significantly lower in the stentless valve group (WMD -6 mm Hg), at 2 to 6 month follow-up (WMD -4 mm Hg,), at 1 year follow-up (WMD -3 mm Hg) and up to 3 year follow-up (WMD -3 mm Hg) compared with the stented valve group. Although the left ventricular mass index was generally lower in the stentless group versus the stented valve group, the aggregate estimates of mean difference did not reach significance during any time period of follow-up (1 month, 2-6 months, 1 year, and 8 years). CONCLUSIONS: : Evidence from randomized trials shows that subcoronary stentless aortic valves improve hemodynamic parameters of effective orifice area index, mean gradient, and peak gradient over the short and long term. These improvements have not led to proven impact on patient morbidity, mortality, and resource-related outcomes; however, few trials reported on clinical outcomes beyond 1 year and definitive conclusions are not possible until sufficient evidence addresses longer-term effects.

Minimal access aortic valve replacement: is it worth it?

Controversy surrounds the use of minimal access aortic valve replacement (AVR). This meta-analytical study quantified the effects of minimal access AVR on morbidity and mortality compared with conventional AVR and evaluated study heterogeneity and robustness of the findings using sensitivity analysis. Overall, meta-analysis suggested marginal benefits in perioperative mortality (4,667 patients; odds ratio, 0.72; 95% confidence interval, 0.51-1.00; p = 0.05), intensive care unit stay, total hospital stay, and ventilation time in the minimal access AVR group, although cross-clamp, cardiopulmonary bypass, and total operation times were longer. Study heterogeneity and apparent benefits in perioperative mortality were related to study quality, although results for intensive care unit and hospital stay were maintained according to the sensitivity analysis. This suggests that minimal access AVR can be offered on the basis of patient choice and cosmesis rather than evident clinical benefit.

Does previous percutaneous coronary stenting compromise the long-term efficacy of subsequent coronary artery bypass surgery? A microsimulation study.

BACKGROUND: This study aims to compare long-term survival and health-related quality of life in patients undergoing coronary artery bypass surgery with and without previous coronary stenting. METHODS: Markov microsimulation was used to model long-term survival and quality of life after surgical revascularization using data from referenced sources. Probabilistic sensitivity analysis was used to investigate the effect of uncertainty associated with the model parameters on the microsimulation results. RESULTS: Percutaneous coronary stenting was found to significantly decrease the effectiveness of coronary surgery. The model suggests that after a single stenting procedure ten-year survival was reduced by 3.3% (SD 0.7%), from 79.9% (SD 1.3%) to 76.6% (SD 1.4%). Similarly, after multiple stenting procedures ten-year survival was reduced by 3.5% (SD 0.7%) to 76.4% (SD 1.4%). Over a ten-year period a single stenting procedure reduced the quality adjusted life year (QALY) payoff by 0.25 QALY (SD 0.11 QALY) and multiple stenting procedures reduced the QALY payoff by 0.27 QALY (SD 0.08 QALY). CONCLUSIONS: This study suggests that patients who undergo surgical bypass after stenting have worse long-term outcomes than patients who undergo surgical revascularization without previous percutaneous intervention. The pathophysiological mechanisms for this are not fully understood and must be further investigated. The findings of this study suggest that the timing of surgical bypass in relation to percutaneous intervention is important. This may have significant implications for clinical practice, suggesting that greater emphasis should be placed on selecting the optimum initial revascularization strategy.

Does minimal-access aortic valve replacement reduce the incidence of postoperative atrial fibrillation?

As the most common sequela of cardiac valvular surgery, atrial fibrillation (AF) has an important impact on postoperative morbidity. Minimal-access aortic valve replacement (AVR), with purported benefits on operative outcomes, has emerged as an alternative to conventional AVR. We used meta-analysis to determine whether minimal access influences the incidence of postoperative AF after AVR. Further, we sought first to evaluate via sensitivity analysis the impact of any differences and to identify the sources of possible heterogeneity between studies; second, we sought to evaluate any indirect effect of minimal-access AVR on other surrogate outcomes related to postoperative AF. We identified 10 studies from 26 comparative randomized and nonrandomized reports that documented the primary outcome of interest: new-onset AF. Overall meta-analysis showed no significant difference between minimal-access and conventional AVR in the incidence of postoperative AF (odds ratio, 0.85; 2,262 patients; P=0.24; 95% confidence interval, 0.66-1.11). Nor were there any apparent differences in surrogate outcome measures of intensive care unit stay, total length of stay, or stroke among studies that displayed a notable difference in AF incidence between groups. Sensitivity analysis that included only high-quality studies similarly showed no significant difference in the incidence of AF and further showed several intraoperative variables as potential sources of heterogeneity between studies. Therefore, minimal access may not have a significant effect on postoperative AF. Future randomized studies must take into account the potential sources of heterogeneity identified here to better demonstrate any differences between the 2 approaches in the onset of AF.

The antiphospholipid syndrome and heart valve surgery.

The antiphospholipid syndrome (APLS) is a complex autoimmune disease often connected to systemic lupus erythematodes. Main features are thromboses, fetal loss and specific antibodies. The involved autoantibodies are directed against plasma proteins such as beta2glycoprotein1 (beta2GPI) or prothrombin which depend on negatively charged phospholipids. Direct antibodies against phospholipids are of no importance for APLS. Clotting tests such as activated partial thromboplastin time or diluted Russell's viper venom test (dRVVT) can show a prolonged time for coagulation despite a prothrombotic state in vivo but the investigator needs awareness about disturbing phospholipid sources and other influential factors. Enzyme linked immuno sorbent assay tests for antibodies against cardiolipin, beta2GPI and prothrombin are valuable solid phase tests with different specificity. Antiphospholipid, anticardiolipin or lupus anticoagulant are misnomers in connection with APLS. They are preserved as a reminiscence of the pioneering work on the way to the still not exactly revealed basics of APLS. Valve operations in APLS patients seem to be rare; a meta-analysis of 57 cases proves that the perioperative management is, at the moment, an empirical approach with high morbidity and mortality in these young patients.

Minimally invasive anterior thoracotomy for routine lung cancer resection.

OBJECTIVES: : A 7-year experience with a minimally invasive approach to routine lung cancer resection is compared with standard lateral open thoracotomy. METHODS: : All patients undergoing lung resection with curative intent for primary lung cancer between July 1998 and November 2005 by a single surgical team were registered. Surgical access was obtained through a mini 5- to 6-cm anterior thoracotomy with video assistance; direct visualization was also used extensively. RESULTS: : Patients (n = 167) underwent major pulmonary resection for primary lung cancer. The minimally invasive group (MI), 137 patients, included 12 fully endoscopic or robotic approaches. The open lateral (OL) approach included 30 patients (18%). Both groups included pneumonectomies (8 MI, 3 OL), sleeve resections (3 MI, 2 OL), chest wall resections (2 MI, 5 OL), and pancoasts (3 MI, 0 OL) and had full lymph node resections. The Kaplan-Meier estimated overall mean survival was 64.5 months (95% CL, 58 to 71 months). Mean estimate survivals were stage 1a, 66%; stage 1b, 65%; stage 2a, 61%; stage 2b, 55%; stage 3a, 52%; stage 3b, 45%. Mean survival in the MI group was 64.3 months versus 59.3 with standard open access (OL) (Χ = 0.003 Mantel-Cox; significance, 0.959). In-hospital mortality rate was 2.2%; conversion from a mini to open procedure was 1.5%. Avoidance of rib spreading (soft tissue retractor) and small incisions appeared to have reduced pain and improved early recovery. CONCLUSIONS: : Kaplan-Meier survival for routine unselected lung cancer resection through a minimal access approach was not significantly different from the open approach and reflects published survival curves.

Video-assisted thoracic surgery in lung cancer resection: a meta-analysis and systematic review of controlled trials.

OBJECTIVES: : This meta-analysis sought to determine whether video-assisted thoracic surgery (VATS) improves clinical and resource outcomes compared with thoracotomy (OPEN) in adults undergoing lobectomy for nonsmall cell lung cancer. METHODS: : A comprehensive search was undertaken to identify all randomized (RCT) and nonrandomized (non-RCT) controlled trials comparing VATS with OPEN thoracotomy available up to April 2007. The primary outcome was survival. Secondary outcomes included any other reported clinical outcome and resource utilization. Odds ratios (OR), weighted mean differences (WMD), or standardized mean differences (SMD), and their 95% confidence intervals (95% CI) were analyzed as appropriate. RESULTS: : Baseline prognosis was more favorable for VATS (more females, smaller tumor size, less advanced stage, histology associated with peripheral location and with more indolent disease) than for OPEN in non-RCTs, but not RCT. Postoperative complications were significantly reduced in the VATS group compared with OPEN surgery when both RCT and non-RCT were considered in aggregate (OR 0.48, 95% CI 0.32-0.70). Although overall blood loss was significantly reduced with VATS compared with OPEN (-80 mL, 95% CI -110 to -50 mL), the incidence of excessive blood loss (generally defined as >500 mL) and incidence of re-exploration for bleeding was not significantly reduced. Pain measured via visual analog scales (10-point VAS) was significantly reduced by <1 point on day 1, by >2 points at 1 week, and by <1 point at week 2 to 4. Similarly, analgesia requirements were significantly reduced in the VATS group. Postoperative vital capacity was significantly improved (WMD 20, 95% CI 15-25), and at 1 year was significantly greater for VATS versus OPEN surgery (WMD 7, 95% CI 2-12). The incidence of patients reporting limited activity at 3 months was reduced (OR 0.04, 95% CI 0.00-0.82), and time to full activity was significantly reduced in the VATS versus OPEN surgery (WMD -1.5, 95% CI -2.1 to -0.9). Overall patient-reported physical function scores did not differ between groups at 3 years follow-up. Hospital length of stay was significantly reduced by 2.6 days despite increased 16 minutes of operating time for VATS versus OPEN. The incidence of cancer recurrence (local or distal) was not significantly different, but chemotherapy delays were significantly reduced for VATS versus OPEN (OR 0.15, 95% CI 0.06-0.38). The need for chemotherapy reduction was also decreased (OR 0.37, 95% CI 0.16-0.87), and the number of patients who did not receive at least 75% of their planned chemotherapy without delays were reduced (OR 0.41, 95% CI 0.18-0.93). The risk of death was not significantly reduced when RCTs were considered alone; however, when non-RCTs (n = 18) were included, the risk of death at 1 to 5 years was significantly reduced (OR 0.72, 95% CI 0.55-0.94; P = 0.02) for VATS versus OPEN. Stage-specific survival to 5 years was not significantly different between groups. CONCLUSIONS: : This meta-analysis suggests that there may be some short term, and possibly even long-term, advantages to performing lung resections with VATS techniques rather than through conventional thoracotomy. Overall, VATS for lobectomy may reduce acute and chronic pain, perioperative morbidity, and improve delivery of adjuvant therapies, without a decrease in stage specific long-term survival. However, the results are largely dependent on non-RCTs, and future adequately powered randomized trials with long-term follow-up are encouraged.

Video-Assisted Thoracic Surgery for Lung Cancer Resection: A Consensus Statement of the International Society of Minimally Invasive Cardiothoracic Surgery (ISMICS) 2007.

OBJECTIVE: : The purpose of this consensus conference was to determine whether video-assisted thoracic surgery (VATS) improves clinical and resource outcomes compared with conventional thoracotomy (OPEN) in adults undergoing lobectomy for lung cancer, and to outline evidence-based recommendations for the use of VATS in performing lobectomy for lung cancer. METHODS: : Before the consensus conference, the best available evidence was reviewed in that systematic reviews, randomized trials, and nonrandomized trials were considered in descending order of validity and importance. At the consensus conference, evidence-based statements were created, and consensus processes were used to determine the ensuing recommendations. The American Heart Association/American College of Cardiology system was used to label the level of evidence and class of recommendation. RESULTS AND RECOMMENDATIONS: : The consensus panel agreed upon the following statements and recommendations in patients with clinical stage I nonsmall cell lung cancer undergoing lung lobectomy:

Fast-track failure after cardiac surgery: development of a prediction model.

OBJECTIVE: Risk factors for unsuccessful fast-tracking of cardiac surgery patients have not been collectively defined in the literature. The aim of this study was to determine risk factors for fast-track failure and incorporate them into a predictive fast-track failure score. DESIGN: Prospective observational study. SETTING: Cardiothoracic Department of St Mary's Hospital, London. PATIENTS: Data were collected from April 2003 to April 2005 including 1,084 patients undergoing heart surgery who were admitted into the fast-track unit. INTERVENTIONS: Multifactorial logistic regression was used to develop a propensity score for estimating the likelihood of fast-track failure. MEASUREMENTS AND MAIN RESULTS: One hundred and sixty-nine patients failed fast-track management (15.6%). Independent predictors for fast-track failure were impaired left ventricular function with or without recent acute coronary syndrome (odds ratios 2.89 and 1.65 respectively), re-do operation (one, two, or more vs. none, odds ratio 1.75, 7.98), extracardiac arteriopathy (odds ratio 2.63), preoperative intra-aortic balloon pump (odds ratio 3.09), raised serum creatinine in micromol/L (120-150, >150 vs. <120, odds ratio 1.57, 11.24), and nonelective (odds ratio 3.43) and complex surgery (odds ratio 2.70). Model validation showed very good discrimination (area under the curve = 0.815) and calibration (c statistic = 8.527, p = .129). CONCLUSIONS: The fast-track failure score incorporates several preoperative factors and has been successfully internally validated; after undergoing external validation and possible recalibration it may be used as a tool to facilitate planning and flow of cardiac surgery patients, based on the predicted probability of failure. Application of this score may limit fast-track failure rates and help to reduce morbidity and cost.

Toll-like receptor 2, 3, and 4 expression and function in human airway smooth muscle.

BACKGROUND: Host defense against microbial pathogens is elicited through the innate immune system by means of Toll-like receptors (TLRs). Airway smooth muscle cells (ASMCs) display proinflammatory and immunomodulatory functions. ASMCs might participate in airway inflammatory responses associated with innate immune activation. OBJECTIVES: We determined the effects of cytokines, TLR ligands, and corticosteroids on TLR expression and function in human ASMCs. METHODS: Real-time PCR and flow cytometry were used to assess TLR mRNA and protein expression, respectively. ASMCs were stimulated with TLR ligands, and chemokine release was measured by means of ELISA. RESULTS: ASMCs expressed TLR1 to TLR10 mRNA, and TLR2 and TLR3 protein expression was demonstrated. TNF-alpha and double-stranded RNA (dsRNA; TLR3 ligand) were potent inducers of TLR2 and TLR3 mRNA expression, and both stimuli had additive or synergistic effects with IFN-gamma on TLR2 and TLR4, but not TLR3, mRNA expression. Peptidoglycan (TLR2 ligand) and LPS (TLR4 ligand) weakly enhanced TLR2 mRNA expression. Peptidoglycan, dsRNA, and LPS induced IL-8 and eotaxin release, with dsRNA being most potent. dsRNA also modulated cytokine-induced chemokine release in a differential manner. Dexamethasone inhibited cytokine- and ligand-induced TLR2, TLR3, and TLR4 expression and chemokine release. However, dexamethasone potentiated TLR2 expression induced by combined IFN-gamma and TNF-alpha stimulation. CONCLUSION: Expression of TLR2, TLR3, and TLR4 is regulated by cytokines and TLR ligands, and their activation mediates chemokine release in ASMCs. CLINICAL IMPLICATIONS: Proinflammatory responses mediated by activation of pathogen-recognition receptors in ASMCs might contribute to infectious exacerbations of airway inflammatory conditions, such as asthma and chronic obstructive pulmonary disease.

GRO-alpha regulation in airway smooth muscle by IL-1beta and TNF-alpha: role of NF-kappaB and MAP kinases.

Airway smooth muscle cells (ASMC) are a source of inflammatory chemokines that may propagate airway inflammatory responses. We investigated the production of the CXC chemokine growth-related oncogene protein-alpha (GRO-alpha) from ASMC induced by cytokines and the role of MAPK and NF-kappaB pathways. ASMC were cultured from human airways, grown to confluence, and exposed to cytokines IL-1beta and TNF-alpha after growth arrest. GRO-alpha release, measured by ELISA, was increased by >50-fold after IL-1beta (0.1 ng/ml) or 5-fold after TNF-alpha (1 ng/ml) in a dose- and time-dependent manner. GRO-alpha release was not affected by the T helper type 2 cytokines IL-4, IL-10, and IL-13. IL-1beta and TNF-alpha also induced GRO-alpha mRNA expression. Supernatants from IL-1beta-stimulated ASMC were chemotactic for neutrophils; this effect was inhibited by anti-GRO-alpha blocking antibody. AS-602868, an inhibitor of IKK-2, and PD-98059, an inhibitor of ERK, inhibited GRO-alpha release and mRNA expression, whereas SP-600125, an inhibitor of JNK, reduced GRO-alpha release without effect on mRNA expression. SB-203580, an inhibitor of p38 MAPK, had no effect. AS-602868 but not PD-98059 or SP-600125 inhibited p65 DNA-binding induced by IL-1beta and TNF-alpha. By chromatin immunoprecipitation assay, IL-1beta and TNF-alpha enhanced p65 binding to the GRO-alpha promoter, which was inhibited by AS-602868. IL-1beta- and TNF-alpha-stimulated expression of GRO-alpha from ASMC is regulated by independent pathways involving NF-kappaB activation and ERK and JNK pathways. GRO-alpha released from ASMC participates in neutrophil chemotaxis.